GENETIC POLYMORPHISMS ASSOCIATED WITH SHORT STATURE, METHODS OF DETECTION AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application serial no.

61/481,982 filed May 3, 2011, the contents of which are hereby incorporated by reference in its entirety into this application.

FIELD OF THE INVENTION

The present invention is in the field of short stature. In particular, the present invention relates to specific single nucleotide polymorphisms (SNPs) in the human genome, and their association with short stature, particularly idiopathic short stature. The SNPs disclosed herein can be used as targets for the design of diagnostic reagents and the development of therapeutic agents, as well as for disorder association and linkage analysis. In particular, the SNPs of the present invention are useful for such uses as identifying an individual (e.g., a child or adolescent) who has an increased or decreased risk for short stature, for early detection of short stature development, for providing clinically important information for mitigating short stature, for predicting the progression or degree of short stature in an individual, for screening and selecting therapeutic agents, and for determining whether an individual should be administered treatment (e.g., growth hormone (GH) and/or insulin-like growth factor-1 (IGF-1)) to alleviate the development of short stature. Methods, assays, kits, and reagents for detecting the presence of these polymorphisms and their encoded products are provided.

BACKGROUND OF THE INVENTION

Short Stature

Short stature, defined as height at or below -2.0 standard deviations (SD) of population mean height, is a common reason for a child to be referred to a pediatrician. Short stature evaluation includes history, i.e. previous history, growth data, parents' heights, pubertal history, and physical examination. General physical examination may disclose features of recognized syndromes (e.g., Turner syndrome) or chronic disorders. A bone age study is usually performed at the initial assessment, which provides information related to growth potential as final adult height is dependent on both growth velocity and degree of skeletal maturity. Certain laboratory studies are used to screen for chronic occult diseases, such as inflammatory bowel disease, coeliac disease, or chronic renal failure, and chromosome karyotype is indicated in girls to exclude Turner syndrome. If the screening programme is not diagnostic, further assessment typically include pituitary function tests and, in particular, an evaluation of the growth hormone axis by the pediatric endocrinologist.

Growth hormone deficiency (GHD) has a reported incidence of 1 in 4,000- 10,000 live births (Preece et al., Clin Endocrinol Metab. 1982 ; l l : l-24; Bernasconi et al., Minerva Pediatr. 1999; 51 :375-94). GHD is suspected if growth velocity is low, skeletal maturation is delayed, and no other endocrine or non-endocrine disease can be identified. To confirm the diagnosis, the growth hormone (GH) axis has been conventionally explored, during the past 40 years, by serum GH measurement(s) following pharmacological stimulation of the pituitary, to assess its GH reserve or secretory capacity (Frasier et al., Pediatrics.\91 ; 53:929-937). In cases of demonstrated GHD and if other treatable causes are excluded, GH therapy is initiated. Note that GHD is associated with secondary insulin-like growth factor- 1 (IGF-1) deficiency, as GH regulates the secretion of IGF-1 (Clemmons, 2006).

When no clear cause has been identified, including no GH deficiency, in children with short stature and/or growth failure and with a prognosis of compromised adult height relative to target height, a widely used term is idiopathic short stature

(ISS) (Leschek et al., J Clin Endocrinol Metab. 2004; 89:3140-3148). The etiology of this condition is unknown or unexplored in the vast majority of cases, but it is now generally well accepted that certain forms of short stature may be related to genetic anomalies (from 3 to 30%) as demonstrated in various cases involving key genes that regulate, directly or indirectly, normal growth development. For example, a number of mutations of the growth hormone receptor, signal transducer and activator of transcription factor 5b (STAT-5b), or IGF-1 gene are known to cause severe IGF-1 deficiency and growth failure (Midyett, et al., J. Clin. Endocrinol. Metab. 2010; 95: 611-619).

Treatments for short stature include growth hormone (GH) (e.g., recombinant

GH) and insulin-like growth factor-1 (IGF-1) (e.g., recombinant IGF-1). Examples of recombinant GH include, but are not limited to, Nutropin®, Humatrope®,

Genotropin®, Norditropin®, Saizen®, and Omnitrope®. An example of recombinant IGF-1 includes, but is not limited to, mecasermin (Increlex®). The treatment of short stature typically depends on the underlying etiology. Use of GH in short children without GHD is a major topic for the child health community. In 2003, the Food and Drug Administration (FDA) approved human recombinant GH for the treatment of children with ISS (short stature of unknown etiology) whose heights are below -2.25 standard deviations of population mean height and who are considered unlikely to reach a normal adult height (Cuttler et al., J Clin Endocrinol Metab. 2005; 90:5502-5504). The data demonstrated an increase not only in short-term growth velocity but also in adult height over that predicted at baseline (Wit et al., J Pediatr. 2005; 146:45-53; Finkelstein et al., Arch Pediatr Adolesc Med. 2002; 156:230-240; Hintz et al., N Engl J Med. 1999; 340:502-507; Kemp et al., J Clin Endocrinol Metab. 2005; 90:5247-53).

Thus, the diagnosis and management of growth disorders has been dominated, for over 40 years, by a GH-centric perspective and a GH-oriented classification system. However, it is well known that the growth effect is the result of GH stimulation of IGF-1 production in the liver and peripheral tissues, particularly bone and muscle. The IGF-1 system has emerged as a true mediator of skeletal growth (both in utero and postnatally) (Rosenfeld, 2006). The GH-IGF-1 system can be viewed like other endocrine systems, with a central, trophic hormone (GH) and a peripherally active hormone (IGF-1). Thus, the availability of both GH and IGF-1 measurements in short, slowly growing children has allowed the matching of GH status to IGF status (Clayton et al., Horm. Res. 2006; 65(suppl l):28-34). Impaired IGF-1 levels resulting from diminished GH secretion could be termed "secondary IGF-1 deficiency". Similarly, a decrease in IGF-1 production, without a concomitant impairment in GH secretion, could be termed "primary IGF-1 deficiency" (Ranke, Horm Res. 2006;65(suppl 1):9-14).

With the exception of defects in IGF production due to malnutrition, liver diseases, renal failure or some hormone deficits (i.e., insulin), the classic condition of primary, impaired IGF-1 production, or total growth hormone insensitivity syndrome (GHIS) is Laron syndrome, which is caused by molecular defects in the GH receptor gene (Laron et al., J Clin Endocrinol Metab. 2004; 89: 1031-1044). The clinical picture bears resemblance to severe GH deficiency with characteristic facial features (i.e., midfacial hypoplasia, prominent forehead), associated with poor musculature, delayed motor development, laryngeal hypoplasia, relative obesity and asymptomatic hypoglycaemia (Rosenbloom, N Engl J Med. 1990; 323: 1367-1374; Savage et al., Nat Clin Pract Endocrinol Metab. 2006; 2:395-407). Classically, patients exhibit high levels of circulating growth hormone and very low IGF-1 concentrations. Untreated patients have postnatal growth failure, resulting in extremely short adult stature and GH treatment is ineffective. Thus, a viable treatment can be IGF-1 (Backeljauw et al., J Clin Endocrinol Metab. 1996; 81:3312-3317; Guevara-Aguirre et al., /. Clin

Endocrinol Metab. 1995; 80: 1393-1398). Other causes of primary IGF-1 deficiency include post-receptor mutations of the signalling molecule STAT-5b which results in impaired GH signal transduction (Kofoed et al., N Engl J Med. 2003; 349: 1110-1112), and patients suffering from primary IGF- 1 deficiency may present with low serum prolactin and IGF-1 gene defects (Woods et al., N Engl J Med. 1996; 335: 1363-1367). Mutations in the acid-labile subunit (ALS), with which IGFBP-3 forms the major circulating carrier complex for IGF-1, are associated with low serum total IGF-1 levels but normal levels of free IGF-1. Patients with ALS mutations have shown short stature in childhood and adolescence but have then caught up in height (Domene et al., N Engl J Med. 2004; 350:70-577).

There is a need to identify new genetic polymorphisms associated with risk for short stature. Such short stature-associated polymorphisms would be useful for, for example, identifying children (especially children who are abnormally short for their age) who are at risk for being of short stature even as adults, thereby enabling an earlier initiation of treatment (e.g., recombinant GH and/or IGF-1) and hence a better clinical outcome for the patient. For example, by initiating short stature treatment earlier based on the presence of short stature-associated genetic polymorphisms in a child (or other individual), it increases the likelihood that the patient will attain a final height closer to normal (even if still below normal) than would have been possible without treatment or with a later or more delayed initiation of treatment.

Single Nucleotide Polymorphisms (SNPs)

The genomes of all organisms undergo spontaneous mutations in the course of their continuing evolution, generating variant forms of progenitor genetic sequences. Gusella, Ann Rev Biochem 55:831-854 (1986). A variant form may confer an evolutionary advantage or disadvantage relative to a progenitor form or may be neutral. In some instances, a variant form confers an evolutionary advantage to individual members of a species and is eventually incorporated into the DNA of many or most members of the species and effectively becomes the progenitor form. Additionally, the effects of a variant form may be both beneficial and detrimental, depending on the environment. For example, a heterozygous sickle cell mutation confers resistance to malaria, but a homozygous sickle cell mutation is usually lethal. In many cases, both progenitor and variant forms survive and co-exist in a species population. The coexistence of multiple forms of a genetic sequence segregating at appreciable frequencies is defined as a genetic polymorphism, which includes single nucleotide polymorphisms (SNPs).

Approximately 90% of all genetic polymorphisms in the human genome are SNPs. SNPs are single base positions in DNA at which different alleles, or alternative nucleotides, exist in a population. The SNP position (interchangeably referred to herein as SNP, SNP site, SNP locus, SNP marker, or marker) is usually preceded by and followed by highly conserved sequences (e.g. , sequences that vary in less than 1/100 or 1/1000 members of the populations). An individual may be homozygous or heterozygous for an allele at each SNP position. A SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP is an amino acid coding sequence.

A SNP may arise from a substitution of one nucleotide for another at the polymorphic site. Substitutions can be transitions or transversions. A transition is the replacement of one purine nucleotide by another purine nucleotide, or one pyrimidine by another pyrimidine. A transversion is the replacement of a purine by a pyrimidine, or vice versa. A SNP may also be a single base insertion or deletion variant referred to as an "indel." Weber et ah, "Human diallelic insertion/deletion polymorphisms," Am J Hum Genet 71(4):854-62 (Oct. 2002).

A synonymous codon change, or silent mutation/SNP (terms such as "SNP", "polymorphism", "mutation", "mutant", "variation", and "variant" are used herein interchangeably), is one that does not result in a change of amino acid due to the degeneracy of the genetic code. A substitution that changes a codon coding for one amino acid to a codon coding for a different amino acid (i.e. , a non- synonymous codon change) is referred to as a missense mutation. A nonsense mutation results in a type of non- synonymous codon change in which a stop codon is formed, thereby leading to premature termination of a polypeptide chain and a truncated protein. A read-through mutation is another type of non- synonymous codon change that causes the destruction of a stop codon, thereby resulting in an extended polypeptide product. While SNPs can be bi-, tri-, or tetra- allelic, the vast majority of SNPs are bi-allelic, and are thus often referred to as "bi-allelic markers," or "di-allelic markers."

As used herein, references to SNPs and SNP genotypes include individual SNPs and/or haplotypes, which are groups of SNPs that are generally inherited together. Haplotypes can have stronger correlations with disorders or other phenotypic effects compared with individual SNPs, and therefore may provide increased diagnostic accuracy in some cases. Stephens et ah, Science 293:489-493 (Jul. 2001).

Causative SNPs are those SNPs that produce alterations in gene expression or in the expression, structure, and/or function of a gene product, and therefore are most predictive of a possible clinical phenotype. One such class includes SNPs falling within regions of genes encoding a polypeptide product, i.e. cSNPs. These SNPs may result in an alteration of the amino acid sequence of the polypeptide product (i. e. , non- synonymous codon changes) and give rise to the expression of a defective or other variant protein. Furthermore, in the case of nonsense mutations, a SNP may lead to premature termination of a polypeptide product. Such variant products can result in a pathological condition, e.g. , a genetic disorder. Examples of genes in which a SNP within a coding sequence causes a genetic disorder include sickle cell anemia and cystic fibrosis.

Causative SNPs do not necessarily have to occur in coding regions; causative

SNPs can occur in, for example, any genetic region that can ultimately affect the expression, structure, and/or activity of the protein encoded by a nucleic acid. Such genetic regions include, for example, those involved in transcription, such as SNPs in transcription factor binding domains, SNPs in promoter regions, in areas involved in transcript processing, such as SNPs at intron-exon boundaries that may cause defective splicing, or SNPs in mRNA processing signal sequences such as polyadenylation signal regions. Some SNPs that are not causative SNPs nevertheless are in close association with, and therefore segregate with, a disorder-causing sequence. In this situation, the presence of a SNP correlates with the presence of, or predisposition to, or an increased risk in developing the disorder. These SNPs, although not causative, are nonetheless also useful for diagnostics, disorder predisposition screening, and other uses.

An association study of a SNP and a specific disorder involves determining the presence or frequency of the SNP allele in biological samples from individuals with the disorder of interest, such as short stature, and comparing the information to that of controls (i.e., individuals who do not have the disorder; controls may be also referred to as "healthy" or "normal" individuals) who are preferably of similar age and race. The appropriate selection of patients and controls is important to the success of SNP association studies. Therefore, a pool of individuals with well- characterized phenotypes is extremely desirable.

A SNP may be screened in diseased tissue samples or any biological sample obtained from a diseased individual, and compared to control samples, and selected for its increased (or decreased) occurrence in a specific disorder, such as short stature. Once a statistically significant association is established between one or more SNP(s) and a disorder (or other phenotype) of interest, then the region around the SNP can optionally be thoroughly screened to identify the causative genetic locus/sequence(s) (e.g. , causative SNP/mutation, gene, regulatory region, etc.) that influences the disorder or phenotype. Association studies may be conducted within the general population and are not limited to studies performed on related individuals in affected families (linkage studies).

Clinical trials have shown that patient response to treatment with

pharmaceuticals is often heterogeneous. There is a continuing need to improve pharmaceutical agent design and therapy. In that regard, SNPs can be used to identify patients most suited to therapy with particular pharmaceutical agents (this is often termed "pharmacogenomics"). Similarly, SNPs can be used to exclude patients from certain treatment due to the patient's increased likelihood of developing toxic side effects or their likelihood of not responding to the treatment. Pharmacogenomics can also be used in pharmaceutical research to assist the drug development and selection process. Linder et ah , Clinical Chemistry 43:254 (1997); Marshall, Nature

Biotechnology 15: 1249 (1997); International Patent Application WO 97/40462, Spectra Biomedical; and Schafer et ah, Nature Biotechnology 16:3 (1998).

SUMMARY OF THE INVENTION

Exemplary embodiments of the present invention relate to the identification of

SNPs, as well as unique combinations of such SNPs and haplotypes of SNPs, that are associated with short stature, particularly idiopathic short stature (short stature is defined as height at or below -2.0 standard deviations of population mean). The polymorphisms disclosed herein are directly useful as targets for the design of diagnostic and prognostic reagents and the development of therapeutic and preventive agents for use in the diagnosis, prognosis, treatment, and/or prevention of short stature.

Based on the identification of SNPs associated with short stature (particularly idiopathic short stature), exemplary embodiments of the present invention also provide methods of detecting these variants as well as the design and preparation of detection reagents needed to accomplish this task. The invention specifically provides, for example, SNPs associated with short stature, isolated nucleic acid molecules (including DNA and RNA molecules) containing these SNPs, variant proteins encoded by nucleic acid molecules containing such SNPs, antibodies to the encoded variant proteins, computer-based and data storage systems containing the novel SNP information, methods of detecting these SNPs in a test sample, methods of identifying individuals (e.g., children or adolescents) who have an altered (i. e., increased or decreased) risk of having short stature, methods for prognosing the degree of short stature, methods of treating an individual who has an increased risk for short stature, based on the presence or absence of one or more particular nucleotides (alleles) at one or more SNPs disclosed herein or the detection of one or more encoded variant products (e.g. , variant mRNA transcripts or variant proteins), methods of identifying individuals (e.g., children or adolescents) who should be administered a treatment for short stature (e.g., GH and/or IGF- 1), methods of screening for compounds useful in the treatment or prevention of short stature, compounds identified by these methods, methods of treating or preventing short stature, etc. In certain embodiments, the individual (e.g., child or adolescent) who is tested for one or more SNPs disclosed herein has a family history of short stature.

Exemplary embodiments of the present invention provide methods for administering a short stature treatment (e.g., GH and/or IGF-1) to an individual (e.g., a child or adolescent) having short stature or who is at risk for developing short stature in the future, based on the individual' s genotype at one or more short stature- associated SNPs disclosed herein. Thus, certain embodiments of the invention provide methods for alleviating an individual' s development of short stature by administering a treatment such as GH and/or IGF- 1 when said individual has one or more short stature-associated SNPs disclosed herein. Various embodiments of the invention also provide methods for enrolling an individual in a clinical trial of a therapeutic agent for treating short stature (e.g., a type of recombinant GH or EGF-1 , or other therapeutic agent for treating short stature), or assigning an individual to an arm (group) within a clinical trial, based on the individual's genotype at one or more short stature- associated SNPs disclosed herein.

Tables 1 and 2 provides gene information, references to the identification of transcript sequences (SEQ ID NOS: 1-39), encoded amino acid sequences (SEQ ID NOS:40-78), genomic sequences (SEQ ID NOS: 135-179), transcript-based context sequences (SEQ ID NOS:79-134) and genomic-based context sequences (SEQ ID NOS: 180-392) that contain the SNPs of the present application, and extensive SNP information that includes observed alleles, allele frequencies, populations/ethnic groups in which alleles have been observed, information about the type of SNP and corresponding functional effect, and, for cSNPs, information about the encoded polypeptide product. The actual transcript sequences (SEQ ID NOS: 1-39), amino acid sequences (SEQ ID NOS:40-78), genomic sequences (SEQ ID NOS: 135-179), transcript-based SNP context sequences (SEQ ID NOS:79-134), and genomic-based SNP context sequences (SEQ ID NOS: 180-392) are provided in the Sequence Listing.

In certain exemplary embodiments, the invention provides methods for identifying an individual who has an altered risk for developing short stature, in which the method comprises detecting a single nucleotide polymorphism (SNP) in any one of the nucleotide sequences of SEQ ID NOS: 1-39, SEQ ID NOS:79-134, SEQ ID NOS: 135-179, and SEQ ID NOS: 180-392 in said individual's nucleic acids, wherein the SNP is specified in Table 1 and/or Table 2, and the presence of the SNP is indicative of an altered risk for short stature in said individual. In certain

embodiments, the short stature is idiopathic short stature. In certain exemplary embodiments of the invention, SNPs that occur naturally in the human genome are provided within isolated nucleic acid molecules. These SNPs are associated with short stature (particular idiopathic short stature) such that they can have a variety of uses in the diagnosis, prognosis, treatment, and/or prevention of short stature and related pathologies. In an alternative embodiment, a nucleic acid of the invention is an amplified polynucleotide, which is produced by amplification of a SNP-containing nucleic acid template. In another embodiment, the invention provides for a variant protein that is encoded by a nucleic acid molecule containing a SNP disclosed herein.

In further embodiments of the invention, reagents for detecting a SNP in the context of its naturally-occurring flanking nucleotide sequences (which can be, e.g. , either DNA or mRNA) are provided. In particular, such a reagent may be in the form of, for example, a hybridization probe or an amplification primer that is useful in the specific detection of a SNP of interest. In an alternative embodiment, a protein detection reagent is used to detect a variant protein that is encoded by a nucleic acid molecule containing a SNP disclosed herein. A preferred embodiment of a protein detection reagent is an antibody or an antigen-reactive antibody fragment. Various embodiments of the invention also provide kits comprising SNP detection reagents, and methods for detecting the SNPs disclosed herein by employing the SNP detection reagents. An exemplary embodiment of the invention provides a kit comprising a SNP detection reagent for use in determining whether a human (e.g., a child or adolescent) should be administered a treatment (e.g., GH and/or IGF- 1) to mitigate development of short stature based upon the presence or absence of a particular allele of one or more SNPs disclosed herein.

In various embodiments, the present invention provides for a method of identifying an individual having an increased or decreased risk of developing short stature (e.g., idiopathic short stature) by detecting the presence or absence of one or more SNP alleles disclosed herein. In other embodiments, a method for diagnosis or prognosis of short stature by detecting the presence or absence of one or more SNP alleles disclosed herein is provided. The present invention also provides methods for determining whether an individual (e.g., a child or adolescent) should be administered treatment, such as GH and/or IGF- 1, to mitigate the development of short stature, by detecting the presence or absence of one or more SNP alleles disclosed herein.

In further exemplary embodiments, methods are provided for testing an individual (a parent or potential parent) who is contemplating having a child, or who is presently pregnant, or who already has a child, for one or more of the SNPs disclosed herein in order to determine the risk that their child will have short stature. In certain embodiments, the individual (the parent or potential parent) has a family history of short stature.

The nucleic acid molecules of the invention can be inserted in an expression vector, such as to produce a variant protein in a host cell. Thus, the present invention also provides for a vector comprising a SNP-containing nucleic acid molecule, genetically-engineered host cells containing the vector, and methods for expressing a recombinant variant protein using such host cells. In another specific embodiment, the host cells, SNP-containing nucleic acid molecules, and/or variant proteins can be used as targets in a method for screening and identifying therapeutic agents (e.g., recombinant proteins or pharmaceutical compounds) useful in the treatment or prevention of short stature.

An aspect of this invention is a method for treating or preventing short stature such as idiopathic short stature, in a human subject wherein said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1 and 2, which method comprises administering to said human subject a therapeutically or prophylactically effective amount of one or more agents (e.g., GH and/or IGF-1) counteracting the effects of the disorder, such as by inhibiting (or stimulating) the activity of a gene, transcript, and/or encoded protein identified in Tables 1 and 2.

Another aspect of this invention is a method for identifying an agent useful in therapeutically or prophylactically treating short stature (such as idiopathic short stature), in a human subject wherein said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1 and 2, which method comprises contacting the gene, transcript, or encoded protein with a candidate agent under conditions suitable to allow formation of a binding complex between the gene, transcript, or encoded protein and the candidate agent and detecting the formation of the binding complex, wherein the presence of the complex identifies said agent.

Another aspect of this invention is a method for treating or preventing short stature (such as idiopathic short stature), in a human subject, in which the method comprises:

(i) determining that said human subject harbors a SNP, gene, transcript, and/or encoded protein identified in Tables 1 and 2, and

(ii) administering to said subject a therapeutically or prophylactically effective amount of one or more agents counteracting the effects of the disorder such as GH and/or IGF-1.

Another aspect of the invention is a method for identifying a human who is in need of receiving treatment for short stature (e.g., GH and/or IGF-1), in which the method comprises detecting an allele of one or more SNPs disclosed herein in said human's nucleic acids, wherein the presence of the allele indicates that said human is at increased risk for short stature and thus is in need of receiving treatment for short stature (e.g., GH and/or IGF-1).

Another aspect of the invention is a method for identifying a human who is in need of receiving treatment for short stature (e.g., GH and/or IGF-1), in which the method comprises detecting an allele of one or more SNPs that are in LD with one or more SNPs disclosed herein in said human's nucleic acids, wherein the presence of the allele of the LD SNP indicates that said human is at increased risk for short stature and thus is in need of receiving treatment for short stature (e.g., GH and/or IGF-1).

Many other uses and advantages of the present invention will be apparent to those skilled in the art upon review of the detailed description of the exemplary embodiments herein. Solely for clarity of discussion, the invention is described in the sections below by way of non-limiting examples.

DESCRIPTION OF THE TEXT (ASCII) FILES SUBMITTED

ELECTRONICALLY VIA EFS-WEB

The following text (ASCII) files are submitted electronically via EFS-Web as part of the instant application:

1) File CD00003 lPRO_SEQLIST.txt provides the Sequence Listing. The Sequence Listing provides the transcript sequences (SEQ ID NOS:l-39) and protein sequences (SEQ ID NOS:40-78) as referred to in Table 1, and genomic sequences (SEQ ID NOS: 135-179) as referred to in Table 2, for each gene (or genomic region for intergenic SNPs) that contains one or more short stature-associated SNPs of the present invention. Also provided in the Sequence Listing are context sequences flanking each SNP, including both transcript-based context sequences as referred to in Table 1 (SEQ ID NOS:79-134) and genomic -based context sequences as referred to in Table 2 (SEQ ID NOS: 180-392). The context sequences generally provide lOObp upstream (5') and lOObp downstream (3') of each SNP, with the SNP in the middle of the context sequence, for a total of 200bp of context sequence surrounding each SNP. File

CD000031PRO_SEQLIST.txt is 6,136 KB in size, and was created on March 31, 2011.

2) File TABLEl_CD000031PRO.txt provides Table 1, which is 62 KB in size and was created on March 31, 2011.

3) File TABLE2_CD00003 lPRO.txt provides Table 2, which is 166 KB in size and was created on March 31, 2011.

These text files are hereby incorporated by reference pursuant to 37 CFR 1.77(b)(4).

DESCRIPTION OF TABLE 1 AND TABLE 2

Table 1 and Table 2 (both submitted electronically via EFS-Web as part of the instant application) disclose the SNP and associated gene/transcript/protein information and sequences for the SNPs and Indels disclosed in Tables 4-10 (which are provided and described in Example 1 below), as well as for the LD SNPs disclosed in Table 3 (which is described in Example 2 below). Table 1 is based on transcript and protein sequences, whereas Table 2 is based on genomic sequences.

For each gene, Table 1 provides a header containing gene, transcript and protein information, followed by a transcript and protein sequence identifier (SEQ ID NO), and then SNP information regarding each SNP found in that gene/transcript including the transcript context sequence. For each gene in Table 2, a header is provided that contains gene and genomic information, followed by a genomic sequence identifier (SEQ ID NO) and then SNP information regarding each SNP found in that gene, including the genomic context sequence.

Note that SNP markers may be included in both Table 1 and Table 2; Table 1 presents the SNPs relative to their transcript sequences and encoded protein sequences, whereas Table 2 presents the SNPs relative to their genomic sequences. In some instances Table 2 may also include, after the last gene sequence, genomic sequences of one or more intergenic regions, as well as SNP context sequences and other SNP information for any SNPs that lie within these intergenic regions. Additionally, in either Table 1 or 2 a "Related Interrogated SNP" may be listed following a SNP which is determined to be in LD with that interrogated SNP according to the given Power value. SNPs can be readily cross-referenced between all Tables based on their Celera hCV (or, in some instances, hDV) identification numbers and/or public rs identification numbers, and to the Sequence Listing based on their corresponding SEQ ID NOs.

The gene/transcript/protein information includes:

- a gene number (1 through n, where n = the total number of genes in the Table),

- a gene symbol, along with an Entrez gene identification number (Entrez Gene database, National Center for Biotechnology Information (NCBI), National Library of Medicine (NLM), National Institutes of Health (NIH))

- a gene name,

- an accession number for the transcript (e.g. , RefSeq NM number, or a Celera hCT identification number if no RefSeq NM number is available) (Table 1 only),

- an accession number for the protein (e.g. , RefSeq NP number, or a Celera hCP identification number if no RefSeq NP number is available) (Table 1 only),

- the chromosome number of the chromosome on which the gene is located, - an OMIM ("Online Mendelian Inheritance in Man" database, Johns Hopkins University/NCBI) public reference number for the gene, and OMIM information such as alternative gene/protein name(s) and/or symbol(s) in the OMIM entry.

Note that, due to the presence of alternative splice forms, multiple

transcript/protein entries may be provided for a single gene entry in Table 1 ; i. e. , for a single Gene Number, multiple entries may be provided in series that differ in their transcript/protein information and sequences.

Following the gene/transcript/protein information is a transcript context sequence (Table 1), or a genomic context sequence (Table 2), for each SNP within that gene.

After the last gene sequence, Table 2 may include additional genomic sequences of intergenic regions (in such instances, these sequences are identified as "Intergenic region:" followed by a numerical identification number), as well as SNP context sequences and other SNP information for any SNPs that lie within each intergenic region (such SNPs are identified as "INTERGENIC" for SNP type).

Note that the transcript, protein, and transcript-based SNP context sequences are all provided in the Sequence Listing. The transcript-based SNP context sequences are provided in both Table 1 and also in the Sequence Listing. The genomic and genomic-based SNP context sequences are provided in the Sequence Listing. The genomic-based SNP context sequences are provided in both Table 2 and in the Sequence Listing. SEQ ID NOs are indicated in Table 1 for the transcript-based context sequences (SEQ ID NOS:79-134); SEQ ID NOs are indicated in Table 2 for the genomic-based context sequences (SEQ ID NOS: 180-392).

The SNP information includes:

- Context sequence (taken from the transcript sequence in Table 1 , the genomic sequence in Table 2) with the SNP represented by its IUB code, including lOObp upstream (5') of the SNP position plus lOObp downstream (3') of the SNP position (the transcript-based SNP context sequences in Table 1 are provided in the Sequence Listing as SEQ ID NOS:79-134; the genomic-based SNP context sequences in Table 2 are provided in the Sequence Listing as SEQ ID NOS: 180-392).

- Celera hCV internal identification number for the SNP (in some instances, an "hDV" number is given instead of an "hCV" number).

- The corresponding public identification number for the SNP, the rs number. - "SNP Chromosome Position" indicates the nucleotide position of the SNP along the entire sequence of the chromosome as provided in NCBI Genome Build 36.

- SNP position (nucleotide position of the SNP within the given transcript sequence (Table 1) or within the given genomic sequence (Table 2)).

- "Related Interrogated SNP" is the interrogated SNP with which the listed

SNP is in LD at the given value of Power.

- SNP source (may include any combination of one or more of the following five codes, depending on which internal sequencing projects and/or public databases the SNP has been observed in: "Applera" = SNP observed during the re-sequencing of genes and regulatory regions of 39 individuals, "Celera" = SNP observed during shotgun sequencing and assembly of the Celera human genome sequence, "Celera Diagnostics" = SNP observed during re-sequencing of nucleic acid samples from individuals who have a disorder, "dbSNP" = SNP observed in the dbSNP public database, "HGBASE" = SNP observed in the HGBASE public database, "HGMD" = SNP observed in the Human Gene Mutation Database (HGMD) public database, "HapMap" = SNP observed in the International HapMap Project public database, "CSNP" = SNP observed in an internal Applied Biosystems (Foster City, CA) database of coding SNPS (cSNPs).

Note that multiple "Applera" source entries for a single SNP indicate that the same SNP was covered by multiple overlapping amplification products and the re- sequencing results (e.g. , observed allele counts) from each of these amplification products is being provided.

- Population/allele/allele count information in the format of

[populationl(first_allele,countlsecond_allele,count)popul ation2(first_allele,countlseco nd_allele,count) total (first_allele,total countlsecond_allele,total count)]. The information in this field includes populations/ethnic groups in which particular SNP alleles have been observed ("cau" = Caucasian, "his" = Hispanic, "chn" = Chinese, and "afr" = African- American, "jpn" = Japanese, "ind" = Indian, "mex" = Mexican, "ain" = "American Indian, "era" = Celera donor, "no_pop" = no population information available), identified SNP alleles, and observed allele counts (within each population group and total allele counts), where available ["-" in the allele field represents a deletion allele of an insertion/deletion ("indel") polymorphism (in which case the corresponding insertion allele, which may be comprised of one or more nucleotides, is indicated in the allele field on the opposite side of the "I"); "-"in the count field indicates that allele count information is not available]. For certain SNPs from the public dbSNP database, population/ethnic information is indicated as follows (this population information is publicly available in dbSNP): "HISP1" = human individual DNA (anonymized samples) from 23 individuals of self-described

HISPANIC heritage; "PAC1" = human individual DNA (anonymized samples) from 24 individuals of self-described PACIFIC RIM heritage; "CAUC1" = human individual DNA (anonymized samples) from 31 individuals of self-described

CAUCASIAN heritage; "AFR1" = human individual DNA (anonymized samples) from 24 individuals of self-described AFRICAN/AFRICAN AMERICAN heritage; "PI" = human individual DNA (anonymized samples) from 102 individuals of self- described heritage; "PA130299515"; "SC_12_A" = SANGER 12 DNAs of Asian origin from Corielle cell repositories, 6 of which are male and 6 female; "SC_12_C" = SANGER 12 DNAs of Caucasian origin from Corielle cell repositories from the CEPH/UTAH library, six male and six female; "SC_12_AA" = SANGER 12 DNAs of African- American origin from Corielle cell repositories 6 of which are male and 6 female; "SC_95_C" = SANGER 95 DNAs of Caucasian origin from Corielle cell repositories from the CEPH/UTAH library; and "SC_12_CA" = Caucasians - 12 DNAs from Corielle cell repositories that are from the CEPH/UTAH library, six male and six female.

Note that for SNPs of "Applera" SNP source, genes/regulatory regions of 39 individuals (20 Caucasians and 19 African Americans) were re-sequenced and, since each SNP position is represented by two chromosomes in each individual (with the exception of SNPs on X and Y chromosomes in males, for which each SNP position is represented by a single chromosome), up to 78 chromosomes were genotyped for each SNP position. Thus, the sum of the African- American ("afr") allele counts is up to 38, the sum of the Caucasian allele counts ("cau") is up to 40, and the total sum of all allele counts is up to 78.

Note that semicolons separate population/allele/count information

corresponding to each indicated SNP source; i.e., if four SNP sources are indicated, such as "Celera," "dbSNP," "HGBASE," and "HGMD," then population/allele/count information is provided in four groups which are separated by semicolons and listed in the same order as the listing of SNP sources, with each population/allele/count information group corresponding to the respective SNP source based on order; thus, in this example, the first population/allele/count information group would correspond to the first listed SNP source (Celera) and the third population/allele/count information group separated by semicolons would correspond to the third listed SNP source (HGBASE); if population/allele/count information is not available for any particular SNP source, then a pair of semicolons is still inserted as a place-holder in order to maintain correspondence between the list of SNP sources and the

corresponding listing of population/allele/count information.

- SNP type (e.g. , location within gene/transcript and/or predicted functional effect) ["MIS-SENSE MUTATION" = SNP causes a change in the encoded amino acid (i.e. , a non-synonymous coding SNP); "SILENT MUTATION" = SNP does not cause a change in the encoded amino acid (i.e. , a synonymous coding SNP); "STOP CODON MUTATION" = SNP is located in a stop codon; "NONSENSE

MUTATION" = SNP creates or destroys a stop codon; "UTR 5" = SNP is located in a 5' UTR of a transcript; "UTR 3" = SNP is located in a 3' UTR of a transcript;

"PUTATIVE UTR 5" = SNP is located in a putative 5' UTR; "PUTATIVE UTR 3" = SNP is located in a putative 3' UTR; "DONOR SPLICE SITE" = SNP is located in a donor splice site (5' intron boundary); "ACCEPTOR SPLICE SITE" = SNP is located in an acceptor splice site (3' intron boundary); "CODING REGION" = SNP is located in a protein-coding region of the transcript; "EXON" = SNP is located in an exon; "INTRON" = SNP is located in an intron; "hmCS" = SNP is located in a human- mouse conserved segment; "TFBS" = SNP is located in a transcription factor binding site; "UNKNOWN" = SNP type is not defined; "INTERGENIC" = SNP is intergenic, i.e., outside of any gene boundary].

- Protein coding information (Table 1 only), where relevant, in the format of [protein SEQ ID NO, amino acid position, (amino acid-1, codonl) (amino acid-2, codon2)]. The information in this field includes SEQ ID NO of the encoded protein sequence, position of the amino acid residue within the protein identified by the SEQ ID NO that is encoded by the codon containing the SNP, amino acids (represented by one-letter amino acid codes) that are encoded by the alternative SNP alleles (in the case of stop codons, "X" is used for the one-letter amino acid code), and alternative codons containing the alternative SNP nucleotides which encode the amino acid residues (thus, for example, for missense mutation-type SNPs, at least two different amino acids and at least two different codons are generally indicated; for silent mutation-type SNPs, one amino acid and at least two different codons are generally indicated, etc.). In instances where the SNP is located outside of a protein-coding region (e.g. , in a UTR region), "None" is indicated following the protein SEQ ID NO.

DESCRIPTION OF TABLE 3

Table 3 provides a list of linkage disequilibrium (LD) SNPs that are related to and derived from certain interrogated SNPs. The interrogated SNPs, which are those SNPs provided in Tables 4- 10 in Example 1 below, are statistically significantly associated with short stature, as described and shown herein, particularly in Example 1 below. The LD SNPs provided in Table 3 all have an r ² value at or above 0.9 (which was set as the Threshold r ² value), and are provided as examples of SNPs which can also serve as markers for short stature based on their being in high LD with an interrogated short stature-associated SNP.

In Table 3, the columns labeled "Interrogated SNP" presents each interrogated SNP as identified by its unique hCV and rs identification number. The columns labeled "LD SNP" presents the hCV and rs numbers of the LD SNPs that are derived from their corresponding interrogated SNPs. The column labeled "Threshold r ² " presents the minimum value of r ² that an LD SNP must meet in reference to an interrogated SNP in order to be included in Table 3 (the Threshold r ² value is set at 0.9 for all SNPs in Table 3). The column labeled " r ² " presents the actual r ² value of the LD SNP in reference to the interrogated SNP to which it is related (since the

Threshold r ² value is set at 0.9, all SNPs in Table 3 will have an r ² value at or above 0.9). The criteria for selecting the LD SNPs provided in Table 3 are further described in Example 2 below.

Sequences, SNP information, and associated gene/transcript/protein information for each of the LD SNPs listed in Table 3 is provided in Tables 1-2.

DETAILED DESCRIPTION OF THE INVENTION

Exemplary embodiments of the present invention provide SNPs associated with short stature, such as idiopathic short stature, as well as uses of these SNPs related to the treatment (including preventive treatment) of short stature. The present invention further provides nucleic acid molecules containing these SNPs, methods and reagents for the detection of the SNPs disclosed herein, uses of these SNPs for the development of detection reagents, and assays or kits that utilize such reagents. The SNPs disclosed herein are useful for diagnosing, prognosing, screening for, and evaluating predisposition to short stature and related pathologies in humans. The SNPs disclosed herein are also useful in the treatment (including preventive treatment) of individuals having or at risk for short stature, such as for determining whether or not to initiate treatment of an individual (e.g., a child or adolescent) who is growing abnormally slowly (e.g., a child or adolescent whose height is below population mean height for their age). Earlier initiation of treatment can lead to better outcomes compared with delayed treatment (or the absence of treatment). For example, earlier initiation of treatment (based on an individual being identified as having one or more alleles associated with increased risk for short stature at one or more SNP positions disclosed herein) can enable an individual to eventually achieve a height that, although perhaps still shorter than normal population mean height, is nonetheless closer to normal population mean height (compared with the height which that individual would have eventually achieved with delayed treatment or in the absence of treatment). Furthermore, such SNPs and their encoded products are useful targets for the development of therapeutic, preventive, and diagnostic agents.

Thus, exemplary embodiments of the present invention provide individual SNPs associated with short stature (particularly idiopathic short stature), as well as combinations of SNPs and haplotypes, polymorphic/variant transcript sequences (SEQ ID NOS:l-39) and genomic sequences (SEQ ID NOS:135-179) containing

SNPs, encoded amino acid sequences (SEQ ID NOS:40-78), and both transcript-based SNP context sequences (SEQ ID NOS:79-134) and genomic-based SNP context sequences (SEQ ID NOS: 180-392) (transcript sequences, protein sequences, and transcript-based SNP context sequences are provided in Table 1 and the Sequence Listing; genomic sequences and genomic-based SNP context sequences are provided in Table 2 and the Sequence Listing), methods of detecting these polymorphisms in a test sample, methods of determining an individual's risk for short stature, methods of screening for compounds useful for treating or preventing short stature, compounds identified by these screening methods, and methods of treating or preventing short stature by administering a treatment (e.g., GH and/or IGF-1) to an individual who is at increased risk for short stature based on their genotype at one or more short stature- associated SNPs disclosed herein.

Exemplary embodiments of the present invention provide methods for identifying an individual (e.g., a child or adolescent) who is at risk for short stature and therefore is in need of receiving treatment for short stature (e.g., GH and/or IGF- 1), methods for determining that an individual is at risk for short stature and then administering a treatment for short stature (e.g., GH and/or IGF-1) to that individual to mitigate development of short stature, methods for determining whether to initiate treatment of an individual child or adolescent who is growing abnormally slowly or who exhibits below normal height for his/her age and gender, etc., based on the individual's genotype at one or more SNPs disclosed herein. In certain embodiments, the individual (e.g., child or adolescent) who is tested for one or more SNPs disclosed herein has a family history of short stature. Embodiments of the invention also provide methods for enrolling an individual in a clinical trial of a therapeutic agent for short stature (and/or assigning an individual to an arm/group within a clinical trial) based on the individual's genotype at one or more SNPs disclosed herein.

In further exemplary embodiments, methods are provided for testing an individual (a parent or potential parent) who is contemplating having a child, or who is presently pregnant, or who already has a child, for one or more of the SNPs disclosed herein in order to determine the risk that their child will have short stature. In certain embodiments, the individual (the parent or potential parent) has a family history of short stature.

Exemplary embodiments of the present invention may include novel SNPs associated with short stature, as well as SNPs that were previously known in the art, but were not previously known to be associated with short stature. Accordingly, the present invention may provide novel compositions and methods based on novel SNPs disclosed herein, and may also provide novel methods of using known, but previously unassociated, SNPs in methods relating to, for example, evaluating an individual's likelihood of having or developing short stature, prognosing the degree of short stature in an individual, and methods of determining whether an individual (e.g., a child or adolescent) should be administered a treatment (e.g., GH and/or IGF-1) for alleviating short stature. In Tables 1 and 2, known SNPs are identified based on the public database in which they have been observed, which is indicated as one or more of the following SNP types: "dbSNP" = SNP observed in dbSNP, "HGBASE" = SNP observed in HGBASE, and "HGMD" = SNP observed in the Human Gene Mutation Database (HGMD).

Particular alleles of the SNPs disclosed herein can be associated with either an increased risk of having or developing short stature, or a decreased risk of having or developing short stature. Thus, whereas certain SNPs (or their encoded products) can be assayed to determine whether an individual possesses a SNP allele that is indicative of an increased risk of having or developing short stature, other SNPs (or their encoded products) can be assayed to determine whether an individual possesses a SNP allele that is indicative of a decreased risk of having or developing short stature. The term "altered" may be used herein to encompass either of these two possibilities (e.g. , an increased or a decreased risk). SNP alleles that are associated with a decreased risk of developing short stature may be referred to as "protective" alleles, and SNP alleles that are associated with an increased risk of developing short stature may be referred to as "susceptibility" alleles, "risk" alleles, or "risk factors".

SNPs can be cross-referenced between all the tables herein in Example 1 as well as Tables 1-3 based on their hCV and/or rs identification numbers. In the tables herein in Example 1, "OR" refers to the odds ratio. Odds ratios (OR) that are greater than one indicate that a given allele (or combination of alleles such as a haplotype or diplotype) is a risk allele (which may also be referred to as a susceptibility allele), whereas odds ratios that are less than one indicate that a given allele is a non-risk allele (which may also be referred to as a protective allele). For a given risk allele, the other alternative allele at the SNP position (which can be derived from the information provided in Tables 1-2, for example) may be considered a non-risk allele. For a given non-risk allele, the other alternative allele at the SNP position may be considered a risk allele. Thus, with respect to risk for a disorder (e.g., risk for short stature), if the risk estimate (odds ratio) for a particular allele at a SNP position is greater than one, this indicates that an individual with this particular allele has a higher risk for the disorder (e.g., short stature) than an individual who has the other allele at the SNP position. In contrast, if the risk estimate (odds ratio) for a particular allele is less than one, this indicates that an individual with this particular allele has a reduced risk for the disorder compared with an individual who has the other allele at the SNP position.

Those skilled in the art will readily recognize that nucleic acid molecules may be double-stranded molecules and that reference to a particular site on one strand refers, as well, to the corresponding site on a complementary strand. In defining a SNP position, SNP allele, or nucleotide sequence, reference to an adenine, a thymine (uridine), a cytosine, or a guanine at a particular site on one strand of a nucleic acid molecule also defines the thymine (uridine), adenine, guanine, or cytosine (respectively) at the corresponding site on a complementary strand of the nucleic acid molecule. Thus, reference may be made to either strand in order to refer to a particular SNP position, SNP allele, or nucleotide sequence. Probes and primers, may be designed to hybridize to either strand and SNP genotyping methods disclosed herein may generally target either strand. Throughout the specification, in identifying a SNP position, reference is generally made to the protein-encoding strand, only for the purpose of convenience.

References to variant peptides, polypeptides, or proteins of the present invention include peptides, polypeptides, proteins, or fragments thereof, that contain at least one amino acid residue that differs from the corresponding amino acid sequence of the art-known peptide/polypeptide/protein (the art-known protein may be interchangeably referred to as the "wild-type," "reference," or "normal" protein). Such variant peptides/polypeptides/proteins can result from a codon change caused by a nonsynonymous nucleotide substitution at a protein-coding SNP position (i.e. , a missense mutation) disclosed by the present invention. Variant peptides/

polypeptides/proteins of the present invention can also result from a nonsense mutation (i. e. , a SNP that creates a premature stop codon, a SNP that generates a read- through mutation by abolishing a stop codon), or due to any SNP disclosed by the present invention that otherwise alters the structure, function, activity, or expression of a protein, such as a SNP in a regulatory region (e.g. a promoter or enhancer) or a SNP that leads to alternative or defective splicing, such as a SNP in an intron or a SNP at an exon/intron boundary. As used herein, the terms "polypeptide," "peptide," and "protein" are used interchangeably.

As used herein, an "allele" may refer to a nucleotide at a SNP position (wherein at least two alternative nucleotides exist in the population at the SNP position, in accordance with the inherent definition of a SNP) or may refer to an amino acid residue that is encoded by the codon which contains the SNP position (where the alternative nucleotides that are present in the population at the SNP position form alternative codons that encode different amino acid residues). An "allele" may also be referred to herein as a "variant". Also, an amino acid residue that is encoded by a codon containing a particular SNP may simply be referred to as being encoded by the SNP.

A phrase such as "as represented by", "as shown by", "as symbolized by", or "as designated by" may be used herein to refer to a SNP within a sequence (e.g., a polynucleotide context sequence surrounding a SNP), such as in the context of "a polymorphism as represented by position 101 of SEQ ID NO:X or its complement". Typically, the sequence surrounding a SNP may be recited when referring to a SNP, however the sequence is not intended as a structural limitation beyond the specific SNP position itself. Rather, the sequence is recited merely as a way of referring to the SNP (in this example, "SEQ ID NO:X or its complement" is recited in order to refer to the SNP located at position 101 of SEQ ID NO:X, but SEQ ID NO:X or its complement is not intended as a structural limitation beyond the specific SNP position itself). In other words, it is recognized that the context sequence of SEQ ID NO:X in this example may contain one or more polymorphic nucleotide positions outside of position 101 and therefore an exact match over the full-length of SEQ ID NO:X is irrelevant since SEQ ID NO:X is only meant to provide context for referring to the SNP at position 101 of SEQ ID NO:X. Likewise, the length of the context sequence is also irrelevant (100 nucleotides on each side of a SNP position has been arbitrarily used in the present application as the length for context sequences merely for convenience and because 201 nucleotides of total length is expected to provide sufficient uniqueness to unambiguously identify a given nucleotide sequence). Thus, since a SNP is a variation at a single nucleotide position, it is customary to refer to context sequence (e.g., SEQ ID NO:X in this example) surrounding a particular SNP position in order to uniquely identify and refer to the SNP. Alternatively, a SNP can be referred to by a unique identification number such as a public "rs" identification number or an internal "hCV" identification number, such as provided herein for each SNP (e.g., in Tables 1-2). For example, in the instant application, "rs9282731", "hCV25995019", and "position 101 of SEQ ID NO:280" all refer to the same SNP.

As used herein, the terms "drug" and "therapeutic agent" are used

interchangeably, and may include, but are not limited to, small molecule compounds, biologies (e.g., antibodies, proteins, protein fragments, fusion proteins, glycoproteins, etc.), nucleic acid agents (e.g., antisense, RNAi/siRNA, and microRNA molecules, etc.), vaccines, etc., which may be used for therapeutic and/or preventive treatment of a disorder (e.g., short stature). Therapeutic proteins and other molecules can be, for example, recombinant/synthesized or purified.

As used herein, short stature is defined as height at or below -2.0 standard deviations of population mean. However, in certain embodiments, short stature may be specified as height at or below -2.25 or -2.5 standard deviations of population mean.

As used herein, a "child" is a human between birth and puberty, and an "adolescent" is a human between puberty and adulthood (generally characterized as being in the teenage stage).

Certain exemplary embodiments of the invention provide the following compositions and uses: (1) a reagent (such as an allele-specific probe or primer, or any other oligonucleotide or other reagent suitable for detecting a polymorphism disclosed herein, which can include detection of any allele of the polymorphism) for use as a diagnostic or predictive agent for short stature; (2) a kit, device, array, or assay component that includes or is coupled with the reagent of (1) above for use in diagnosing or determining an individual' s risk for short stature; (3) the use of the reagent of (1) above for the manufacture of a kit, device, array, or assay component for diagnosing or determining an individual' s risk for short stature; and (4) the use of a polymorphism disclosed herein (e.g., a nucleic acid molecule containing the polymorphism or an oligonucleotide which hybridizes to the polymorphism, etc.) for the manufacture of a reagent for use as a diagnostic or predictive agent for short stature.

The various methods described herein, such as correlating the presence or absence of a polymorphism with an altered (e.g., increased or decreased) risk (or no altered risk) for short stature, can be carried out by automated methods such as by using a computer (or other apparatus/devices such as biomedical devices, laboratory instrumentation, or other apparatus/devices having a computer processor) programmed to carry out any of the methods described herein. For example, computer software (which may be interchangeably referred to herein as a computer program) can perform the step of correlating the presence or absence of a polymorphism in an individual with an altered (e.g., increased or decreased) risk (or no altered risk) for short stature for the individual. Accordingly, certain embodiments of the invention provide a computer (or other apparatus/device) programmed to carry out any of the methods described herein.

Reagants, and kits containing the reagents, for detecting a polymorphism disclosed herein can be manufactured in compliance with regulatory requirements for clinical diagnostic use, such as those set forth by the United States Food and Drug Administration (FDA). Reagents and kits can be manufactured in compliance with "good manufacturing practice" (GMP) guidelines, such as "current good

manufacturing practices" (cGMP) guidelines in the United States. Furthermore, reagents and kits can be registed with the FDA (such as by satisfying 510(k) Pre- Market Notification (PMN) requirements or obtaining Pre-Market Approval (PMA)). Reagents (particularly reagents for clinical diagnostic use) for detecting a

polymorphism disclosed herein can be classified by the FDA (or other agency) as an analyte specific reagent (ASR) (or similar classification), and kits (particularly kits for clinical diagnostic use) containing reagents for detecting a polymorphism disclosed herein can be classified by the FDA (or other agency) as in vitro diagnostic (IVD) kits or laboratory developed tests (LDTs) (or similar classifications), including in vitro diagnostic multivariate index assays (IVDMIAs). Furthermore, reagents and kits can be classified by the FDA (or other agency) as Class I, Class II, or Class III medical devices. Reagents and kits can also be registered with (e.g., approved by) and/or manufactured in compliance with regulatory requirements set forth by the Clinical Laboratory Improvement Amendments Act (CLIA), which is administered by the Centers for Medicare and Medicaid Services (CMS), or other agencies in the United States or throughout the rest of the world.

Reports, Programmed Computers, Business Methods, and Systems

The results of a test (e.g., an individual's risk for short stature based on assaying one or more SNPs disclosed herein, and/or an individual's allele(s)/genotype at one or more SNPs disclosed herein, etc.), and/or any other information pertaining to a test, may be referred to herein as a "report". A tangible report can optionally be generated as part of a testing process (which may be interchangeably referred to herein as "reporting", or as "providing" a report, "producing" a report, or

"generating" a report).

Examples of tangible reports may include, but are not limited to, reports in paper (such as computer-generated printouts of test results) or equivalent formats and reports stored on computer readable medium (such as a CD, USB flash drive or other removable storage device, computer hard drive, or computer network server, etc.). Reports, particularly those stored on computer readable medium, can be part of a database, which may optionally be accessible via the internet (such as a database of patient records or genetic information stored on a computer network server, which may be a "secure database" that has security features that limit access to the report, such as to allow only the patient and the patient' s medical practioners to view the report while preventing other unauthorized individuals from viewing the report, for example). In addition to, or as an alternative to, generating a tangible report, reports can also be displayed on a computer screen (or the display of another electronic device or instrument).

A report can include, for example, an individual's risk for short stature, or may just include the allele(s)/genotype that an individual carries at one or more SNPs disclosed herein, which may optionally be linked to information regarding the significance of having the allele(s)/genotype at the SNP (for example, a report on computer readable medium such as a network server may include hyperlink(s) to one or more journal publications or websites that describe the medical/biological implications, such as increased or decreased disorder risk, for individuals having a certain allele/genotype at the SNP). Thus, for example, the report can include disorder risk or other medical/biological significance as well as optionally also including the allele/genotype information, or the report may just include allele/genotype information without including disorder risk or other medical/biological significance (such that an individual viewing the report can use the allele/genotype information to determine the associated disorder risk or other medical/biological significance from a source outside of the report itself, such as from a medical practioner, publication, website, etc., which may optionally be linked to the report such as by a hyperlink).

A report can further be "transmitted" or "communicated" (these terms may be used herein interchangeably), such as to the individual who was tested, a medical practitioner (e.g., a doctor, nurse, clinical laboratory practitioner, genetic counselor, etc.), a healthcare organization, a clinical laboratory, and/or any other party or requester intended to view or possess the report. The act of "transmitting" or

"communicating" a report can be by any means known in the art, based on the format of the report. Furthermore, "transmitting" or "communicating" a report can include delivering/sending a report ("pushing") and/or retrieving ("pulling") a report. For example, reports can be transmitted/communicated by various means, including being physically transferred between parties (such as for reports in paper format) such as by being physically delivered from one party to another, or by being transmitted electronically (e.g., via e-mail or over the internet, by facsimile, and/or by any wired or wireless communication methods known in the art) such as by being retrieved from a database stored on a computer network server, etc. In certain exemplary embodiments, the invention provides computers (or other apparatus/devices such as biomedical devices or laboratory instrumentation) programmed to carry out the methods described herein. For example, in certain embodiments, the invention provides a computer programmed to receive (i. e., as input) the identity (e.g., the allele(s) or genotype at a SNP) of one or more SNPs disclosed herein and provide (i. e., as output) the disorder risk (e.g., an individual's risk for short stature) or other result (e.g., disorder diagnosis or prognosis, etc.) based on the identity of the SNP(s). Such output (e.g., communication of disorder risk, disorder diagnosis or prognosis, etc.) may be, for example, in the form of a report on computer readable medium, printed in paper form, and/or displayed on a computer screen or other display.

In various exemplary embodiments, the invention further provides methods of doing business (with respect to methods of doing business, the terms "individual" and "customer" are used herein interchangeably). For example, exemplary methods of doing business can comprise assaying one or more SNPs disclosed herein and providing a report that includes, for example, a customer' s risk for short stature (based on which allele(s)/genotype is present at the assayed SNP(s)) and/or that includes the allele(s)/genotype at the assayed SNP(s) which may optionally be linked to information (e.g., journal publications, websites, etc.) pertaining to disorder risk or other biological/medical significance such as by means of a hyperlink (the report may be provided, for example, on a computer network server or other computer readable medium that is internet-accessible, and the report may be included in a secure database that allows the customer to access their report while preventing other unauthorized individuals from viewing the report), and optionally transmitting the report. Customers (or another party who is associated with the customer, such as the customer's doctor, for example) can request/order (e.g., purchase) the test online via the internet (or by phone, mail order, at an outlet/store, etc.), for example, and a kit can be sent/delivered (or otherwise provided) to the customer (or another party on behalf of the customer, such as the customer' s doctor, for example) for collection of a biological sample from the customer (e.g., a buccal swab for collecting buccal cells), and the customer (or a party who collects the customer' s biological sample) can submit their biological samples for assaying (e.g., to a laboratory or party associated with the laboratory such as a party that accepts the customer samples on behalf of the laboratory, a party for whom the laboratory is under the control of (e.g., the laboratory carries out the assays by request of the party or under a contract with the party, for example), and/or a party that receives at least a portion of the customer' s payment for the test). The report (e.g., results of the assay including, for example, the customer's disorder risk and/or allele(s)/genotype at the assayed SNP(s)) may be provided to the customer by, for example, the laboratory that assays the SNP(s) or a party associated with the laboratory (e.g., a party that receives at least a portion of the customer' s payment for the assay, or a party that requests the laboratory to carry out the assays or that contracts with the laboratory for the assays to be carried out) or a doctor or other medical practitioner who is associated with (e.g., employed by or having a consulting or contracting arrangement with) the laboratory or with a party associated with the laboratory, or the report may be provided to a third party (e.g., a doctor, genetic counselor, hospital, etc.) which optionally provides the report to the customer. In further embodiments, the customer may be a doctor or other medical practitioner, or a hospital, laboratory, medical insurance organization, or other medical organization that requests/orders (e.g., purchases) tests for the purposes of having other individuals (e.g., their patients or customers) assayed for one or more SNPs disclosed herein and optionally obtaining a report of the assay results.

In certain exemplary methods of doing business, a kit for collecting a biological sample (e.g., a buccal swab for collecting buccal cells, or other sample collection device) is provided to a medical practitioner (e.g., a physician) which the medical practitioner uses to obtain a sample (e.g., buccal cells, saliva, blood, etc.) from a patient, the sample is then sent to a laboratory (e.g., a CLIA-certified laboratory) or other facility that tests the sample for one or more SNPs disclosed herein (e.g., to determine the genotype of one or more SNPs disclosed herein, such as to determine the patient' s risk for short stature), and the results of the test (e.g., the patient' s genotype at one or more SNPs disclosed herein and/or the patient's disorder risk based on their SNP genotype) are provided back to the medical practitioner (and/or directly to the patient and/or to another party such as a hospital, medical insurance company, genetic counselor, etc.) who may then provide or otherwise convey the results to the patient. The results are typically provided in the form of a report, such as described above.

In certain further exemplary methods of doing business, kits for collecting a biological sample from a customer (e.g., a buccal swab for collecting buccal cells, or other sample collection device) are provided (e.g., for sale), such as at an outlet (e.g., a drug store, pharmacy, general merchandise store, or any other desirable outlet), online via the internet, by mail order, etc., whereby customers can obtain (e.g., purchase) the kits, collect their own biological samples, and submit (e.g., send/deliver via mail) their samples to a laboratory (e.g., a CLIA-certified laboratory) or other facility which tests the samples for one or more SNPs disclosed herein (e.g., to determine the genotype of one or more SNPs disclosed herein, such as to determine the customer's risk for short stature) and provides the results of the test (e.g., of the customer's genotype at one or more SNPs disclosed herein and/or the customer's disorder risk based on their SNP genotype) back to the customer and/or to a third party (e.g., a physician or other medical practitioner, hospital, medical insurance company, genetic counselor, etc.). The results are typically provided in the form of a report, such as described above. If the results of the test are provided to a third party, then this third party may optionally provide another report to the customer based on the results of the test (e.g., the result of the test from the laboratory may provide the customer's genotype at one or more SNPs disclosed herein without disorder risk information, and the third party may provide a report of the customer' s disorder risk based on this genotype result).

Certain further embodiments of the invention provide a system for determining an individual's short stature risk. Certain exemplary systems comprise an integrated "loop" in which an individual (or their medical practitioner) requests a determination of such individual's short stature risk, this determination is carried out by testing a sample from the individual, and then the results of this determination are provided back to the requestor. For example, in certain systems, a sample (e.g., buccal cells, saliva, blood, etc.) is obtained from an individual for testing (the sample may be obtained by the individual or, for example, by a medical practitioner), the sample is submitted to a laboratory (or other facility) for testing (e.g., determining the genotype of one or more SNPs disclosed herein), and then the results of the testing are sent to the patient (which optionally can be done by first sending the results to an

intermediary, such as a medical practioner, who then provides or otherwise conveys the results to the individual and/or acts on the results), thereby forming an integrated loop system for determining an individual's short stature risk. The portions of the system in which the results are transmitted (e.g., between any of a testing facility, a medical practitioner, and/or the individual) can be carried out by way of electronic transmission (e.g., by computer such as via e-mail or the internet, by providing the results on a website or computer network server which may optionally be a secure database, by phone or fax, or by any other wired or wireless transmission methods known in the art). Optionally, the system can further include a risk reduction component (i.e., a disease management system) as part of the integrated loop (for an example of a disease management system, see U.S. patent no. 6,770,029, "Disease management system and method including correlation assessment"). For example, the results of the test can be used to reduce the risk of a disorder in the individual who was tested, such as by implementing a preventive therapy regimen (e.g.,

administration of a treatment such as GH and/or IGF-1 for mitigating short stature), modifying the individual's diet, increasing exercise, reducing stress, and/or implementing any other physiological or behavioral modifications in the individual with the goal of mitigating the disorder. For mitigating short stature risk, this may include any means used in the art for improving aspects of an individual's health relevant to mitigating short stature. Thus, in exemplary embodiments, the system is controlled by the individual and/or their medical practioner in that the individual and/or their medical practioner requests the test, receives the test results back, and (optionally) acts on the test results to reduce the individual's disorder risk, such as by implementing a disease management system. ISOLATED NUCLEIC ACID MOLECULES AND SNP DETECTION

REAGENTS & KITS

Tables 1 and 2 provide a variety of information about each SNP of the present invention that is associated with short stature (particularly idiopathic short stature), including the transcript sequences (SEQ ID NOS: 1-39), genomic sequences (SEQ ID NOS: 135-179), and protein sequences (SEQ ID NOS:40-78) of the encoded gene products (with the SNPs indicated by IUB codes in the nucleic acid sequences). In addition, Tables 1 and 2 include SNP context sequences, which generally include 100 nucleotide upstream (5') plus 100 nucleotides downstream (3') of each SNP position (SEQ ID NOS:79-134 correspond to transcript-based SNP context sequences disclosed in Table 1, and SEQ ID NOS: 180-392 correspond to genomic-based context sequences disclosed in Table 2), the alternative nucleotides (alleles) at each SNP position, and additional information about the variant where relevant, such as SNP type (coding, missense, splice site, UTR, etc.), human populations in which the SNP was observed, observed allele frequencies, information about the encoded protein, etc. Isolated Nucleic Acid Molecules

Exemplary embodiments of the invention provide isolated nucleic acid molecules that contain one or more SNPs disclosed herein, particularly SNPs disclosed in Table 1 and/or Table 2. Isolated nucleic acid molecules containing one or more SNPs disclosed herein (such as in at least one of Tables 1 and 2) may be interchangeably referred to throughout the present text as "SNP-containing nucleic acid molecules." Isolated nucleic acid molecules may optionally encode a full-length variant protein or fragment thereof. The isolated nucleic acid molecules of the present invention also include probes and primers (which are described in greater detail below in the section entitled "SNP Detection Reagents"), which may be used for assaying the disclosed SNPs, and isolated full-length genes, transcripts, cDNA molecules, and fragments thereof, which may be used for such purposes as expressing an encoded protein.

As used herein, an "isolated nucleic acid molecule" generally is one that contains a SNP of the present invention or one that hybridizes to such molecule such as a nucleic acid with a complementary sequence, and is separated from most other nucleic acids present in the natural source of the nucleic acid molecule. Moreover, an "isolated" nucleic acid molecule, such as a cDNA molecule containing a SNP of the present invention, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. A nucleic acid molecule can be fused to other coding or regulatory sequences and still be considered "isolated." Nucleic acid molecules present in non-human transgenic animals, which do not naturally occur in the animal, are also considered "isolated." For example, recombinant DNA molecules contained in a vector are considered "isolated." Further examples of "isolated" DNA molecules include recombinant DNA molecules maintained in heterologous host cells, and purified (partially or substantially) DNA molecules in solution. Isolated RNA molecules include in vivo or in vitro RNA transcripts of the isolated SNP-containing DNA molecules of the present invention. Isolated nucleic acid molecules according to the present invention further include such molecules produced synthetically.

Generally, an isolated SNP-containing nucleic acid molecule comprises one or more SNP positions disclosed by the present invention with flanking nucleotide sequences on either side of the SNP positions. A flanking sequence can include nucleotide residues that are naturally associated with the SNP site and/or heterologous nucleotide sequences. Preferably, the flanking sequence is up to about 500, 300, 100, 60, 50, 30, 25, 20, 15, 10, 8, or 4 nucleotides (or any other length in-between) on either side of a SNP position, or as long as the full-length gene or entire protein-coding sequence (or any portion thereof such as an exon), especially if the SNP-containing nucleic acid molecule is to be used to produce a protein or protein fragment.

For full-length genes and entire protein-coding sequences, a SNP flanking sequence can be, for example, up to about 5KB, 4KB, 3KB, 2KB, 1KB on either side of the SNP. Furthermore, in such instances the isolated nucleic acid molecule comprises exonic sequences (including protein-coding and/or non-coding exonic sequences), but may also include intronic sequences. Thus, any protein coding sequence may be either contiguous or separated by introns. The important point is that the nucleic acid is isolated from remote and unimportant flanking sequences and is of appropriate length such that it can be subjected to the specific manipulations or uses described herein such as recombinant protein expression, preparation of probes and primers for assaying the SNP position, and other uses specific to the SNP-containing nucleic acid sequences.

An isolated SNP-containing nucleic acid molecule can comprise, for example, a full-length gene or transcript, such as a gene isolated from genomic DNA (e.g. , by cloning or PCR amplification), a cDNA molecule, or an mRNA transcript molecule. Polymorphic transcript sequences are referred to in Table 1 and provided in the

Sequence Listing (SEQ ID NOS: l-39), and polymorphic genomic sequences are referred to in Table 2 and provided in the Sequence Listing (SEQ ID NOS: 135-179).

Furthermore, fragments of such full-length genes and transcripts that contain one or more SNPs disclosed herein are also encompassed by the present invention, and such fragments may be used, for example, to express any part of a protein, such as a particular functional domain or an antigenic epitope.

Thus, the present invention also encompasses fragments of the nucleic acid sequences as disclosed in Tables 1 and 2 (transcript sequences are referred to in Table 1 as SEQ ID NOS: 1-39, genomic sequences are referred to in Table 2 as SEQ ID

NOS: 135-179, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:79-134, and genomic -based SNP context sequences are referred to in Table 2 as SEQ ID NOS: 180-392) and their complements. The actual sequences referred to in the tables are provided in the Sequence Listing. A fragment typically comprises a contiguous nucleotide sequence at least about 8 or more nucleotides, more preferably at least about 12 or more nucleotides, and even more preferably at least about 16 or more nucleotides. Furthermore, a fragment could comprise at least about 18, 20, 22, 25, 30, 40, 50, 60, 80, 100, 150, 200, 250 or 500 nucleotides in length (or any other number in between). The length of the fragment will be based on its intended use. For example, the fragment can encode epitope-bearing regions of a variant peptide or regions of a variant peptide that differ from the normal/wild-type protein, or can be useful as a polynucleotide probe or primer. Such fragments can be isolated using the nucleotide sequences provided in Table 1 and/or Table 2 for the synthesis of a polynucleotide probe. A labeled probe can then be used, for example, to screen a cDNA library, genomic DNA library, or mRNA to isolate nucleic acid corresponding to the coding region. Further, primers can be used in amplification reactions, such as for purposes of assaying one or more SNPs sites or for cloning specific regions of a gene.

An isolated nucleic acid molecule of the present invention further

encompasses a SNP-containing polynucleotide that is the product of any one of a variety of nucleic acid amplification methods, which are used to increase the copy numbers of a polynucleotide of interest in a nucleic acid sample. Such amplification methods are well known in the art, and they include but are not limited to, polymerase chain reaction (PCR) (U.S. Patent Nos. 4,683,195 and 4,683,202; PCR Technology: Principles and Applications for DNA Amplification, ed. H.A. Erlich, Freeman Press, NY, NY (1992)), ligase chain reaction (LCR) (Wu and Wallace, Genomics 4:560

(1989); Landegren et al. , Science 241 : 1077 (1988)), strand displacement amplification (SDA) (U.S. Patent Nos. 5,270,184 and 5,422,252), transcription-mediated amplification (TMA) (U.S. Patent No. 5,399,491), linked linear amplification (LLA) (U.S. Patent No. 6,027,923) and the like, and isothermal amplification methods such as nucleic acid sequence based amplification (NASBA) and self-sustained sequence replication (Guatelli et al., Proc Natl Acad Sci USA 87: 1874 (1990)). Based on such methodologies, a person skilled in the art can readily design primers in any suitable regions 5 ' and 3 ' to a SNP disclosed herein. Such primers may be used to amplify DNA of any length so long that it contains the SNP of interest in its sequence.

As used herein, an "amplified polynucleotide" of the invention is a SNP- containing nucleic acid molecule whose amount has been increased at least two fold by any nucleic acid amplification method performed in vitro as compared to its starting amount in a test sample. In other preferred embodiments, an amplified polynucleotide is the result of at least ten fold, fifty fold, one hundred fold, one thousand fold, or even ten thousand fold increase as compared to its starting amount in a test sample. In a typical PCR amplification, a polynucleotide of interest is often amplified at least fifty thousand fold in amount over the unamplified genomic DNA, but the precise amount of amplification needed for an assay depends on the sensitivity of the subsequent detection method used.

Generally, an amplified polynucleotide is at least about 16 nucleotides in length. More typically, an amplified polynucleotide is at least about 20 nucleotides in length. In a preferred embodiment of the invention, an amplified polynucleotide is at least about 30 nucleotides in length. In a more preferred embodiment of the invention, an amplified polynucleotide is at least about 32, 40, 45, 50, or 60 nucleotides in length. In yet another preferred embodiment of the invention, an amplified polynucleotide is at least about 100, 200, 300, 400, or 500 nucleotides in length. While the total length of an amplified polynucleotide of the invention can be as long as an exon, an intron or the entire gene where the SNP of interest resides, an amplified product is typically up to about 1,000 nucleotides in length (although certain amplification methods may generate amplified products greater than 1000 nucleotides in length). More preferably, an amplified polynucleotide is not greater than about 600-700 nucleotides in length. It is understood that irrespective of the length of an amplified polynucleotide, a SNP of interest may be located anywhere along its sequence.

In a specific embodiment of the invention, the amplified product is at least about 201 nucleotides in length, comprises one of the transcript-based context sequences or the genomic-based context sequences shown in Tables 1 and 2. Such a product may have additional sequences on its 5 ' end or 3' end or both. In another embodiment, the amplified product is about 101 nucleotides in length, and it contains a SNP disclosed herein. Preferably, the SNP is located at the middle of the amplified product (e.g. , at position 101 in an amplified product that is 201 nucleotides in length, or at position 51 in an amplified product that is 101 nucleotides in length), or within 1, 2, 3 , 4, 5, 6, 7, 8, 9, 10, 12, 15, or 20 nucleotides from the middle of the amplified product. However, as indicated above, the SNP of interest may be located anywhere along the length of the amplified product.

The present invention provides isolated nucleic acid molecules that comprise, consist of, or consist essentially of one or more polynucleotide sequences that contain one or more SNPs disclosed herein, complements thereof, and SNP-containing fragments thereof.

Accordingly, the present invention provides nucleic acid molecules that consist of any of the nucleotide sequences shown in Table 1 and/or Table 2 (transcript sequences are referred to in Table 1 as SEQ ID NOS: 1-39, genomic sequences are referred to in Table 2 as SEQ ID NOS: 135- 179, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:79-134, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS:180-392), or any nucleic acid molecule that encodes any of the variant proteins referred to in Table 1 (SEQ ID NOS:40-78). The actual sequences referred to in the tables are provided in the Sequence Listing. A nucleic acid molecule consists of a nucleotide sequence when the nucleotide sequence is the complete nucleotide sequence of the nucleic acid molecule.

The present invention further provides nucleic acid molecules that consist essentially of any of the nucleotide sequences referred to in Table 1 and/or Table 2 (transcript sequences are referred to in Table 1 as SEQ ID NOS:l-39, genomic sequences are referred to in Table 2 as SEQ ID NOS: 135-179, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:79-134, and genomic-based SNP context sequences are referred to in Table 2 as SEQ ID NOS: 180-392), or any nucleic acid molecule that encodes any of the variant proteins referred to in Table 1 (SEQ ID NOS:40-78). The actual sequences referred to in the tables are provided in the Sequence Listing. A nucleic acid molecule consists essentially of a nucleotide sequence when such a nucleotide sequence is present with only a few additional nucleotide residues in the final nucleic acid molecule.

The present invention further provides nucleic acid molecules that comprise any of the nucleotide sequences shown in Table 1 and/or Table 2 or a SNP-containing fragment thereof (transcript sequences are referred to in Table 1 as SEQ ID NOS: 1-39, genomic sequences are referred to in Table 2 as SEQ ID NOS: 135-179, transcript-based SNP context sequences are referred to in Table 1 as SEQ ID NOS:79-134, and genomic- based SNP context sequences are referred to in Table 2 as SEQ ID NOS:180-392), or any nucleic acid molecule that encodes any of the variant proteins provided in Table 1 (SEQ ID NOS:40-78). The actual sequences referred to in the tables are provided in the Sequence Listing. A nucleic acid molecule comprises a nucleotide sequence when the nucleotide sequence is at least part of the final nucleotide sequence of the nucleic acid molecule. In such a fashion, the nucleic acid molecule can be only the nucleotide sequence or have additional nucleotide residues, such as residues that are naturally associated with it or heterologous nucleotide sequences. Such a nucleic acid molecule can have one to a few additional nucleotides or can comprise many more additional nucleotides. A brief description of how various types of these nucleic acid molecules can be readily made and isolated is provided below, and such techniques are well known to those of ordinary skill in the art. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000).

The isolated nucleic acid molecules can encode mature proteins plus additional amino or carboxyl-terminal amino acids or both, or amino acids interior to the mature peptide (when the mature form has more than one peptide chain, for instance). Such sequences may play a role in processing of a protein from precursor to a mature form, facilitate protein trafficking, prolong or shorten protein half -life, or facilitate manipulation of a protein for assay or production. As generally is the case in situ, the additional amino acids may be processed away from the mature protein by cellular enzymes.

Thus, the isolated nucleic acid molecules include, but are not limited to, nucleic acid molecules having a sequence encoding a peptide alone, a sequence encoding a mature peptide and additional coding sequences such as a leader or secretory sequence (e.g. , a pre-pro or pro-protein sequence), a sequence encoding a mature peptide with or without additional coding sequences, plus additional non-coding sequences, for example introns and non-coding 5' and 3' sequences such as transcribed but untranslated sequences that play a role in, for example, transcription, mRNA processing (including splicing and polyadenylation signals), ribosome binding, and/or stability of mRNA. In addition, the nucleic acid molecules may be fused to heterologous marker sequences encoding, for example, a peptide that facilitates purification.

Isolated nucleic acid molecules can be in the form of RNA, such as mRNA, or in the form DNA, including cDNA and genomic DNA, which may be obtained, for example, by molecular cloning or produced by chemical synthetic techniques or by a combination thereof. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000). Furthermore, isolated nucleic acid molecules, particularly SNP detection reagents such as probes and primers, can also be partially or completely in the form of one or more types of nucleic acid analogs, such as peptide nucleic acid (PNA). U.S. Patent Nos. 5,539,082; 5,527,675;

5,623,049; and 5,714,331. The nucleic acid, especially DNA, can be double-stranded or single-stranded. Single-stranded nucleic acid can be the coding strand (sense strand) or the complementary non-coding strand (anti-sense strand). DNA, RNA, or PNA segments can be assembled, for example, from fragments of the human genome (in the case of DNA or RNA) or single nucleotides, short oligonucleotide linkers, or from a series of oligonucleotides, to provide a synthetic nucleic acid molecule.

Nucleic acid molecules can be readily synthesized using the sequences provided herein as a reference; oligonucleotide and PNA oligomer synthesis techniques are well known in the art. See, e.g. , Corey, "Peptide nucleic acids: expanding the scope of nucleic acid recognition," Trends Biotechnol 15(6):224-9 (Jun. 1997), and Hyrup et al , "Peptide nucleic acids (PNA): synthesis, properties and potential applications," Bioorg Med Chem 4(l):5-23) (Jan. 1996). Furthermore, large-scale automated oligonucleotide/PNA synthesis (including synthesis on an array or bead surface or other solid support) can readily be accomplished using commercially available nucleic acid synthesizers, such as the Applied Biosystems (Foster City, CA) 3900 High- Throughput DNA Synthesizer or Expedite 8909 Nucleic Acid Synthesis System, and the sequence information provided herein.

The present invention encompasses nucleic acid analogs that contain modified, synthetic, or non-naturally occurring nucleotides or structural elements or other alternative/modified nucleic acid chemistries known in the art. Such nucleic acid analogs are useful, for example, as detection reagents (e.g. , primers/probes) for detecting one or more SNPs identified in Table 1 and/or Table 2. Furthermore, kits/systems (such as beads, arrays, etc.) that include these analogs are also encompassed by the present invention. For example, PNA oligomers that are based on the polymorphic sequences of the present invention are specifically contemplated. PNA oligomers are analogs of DNA in which the phosphate backbone is replaced with a peptide-like backbone. Lagriffoul et al. , Bioorganic & Medicinal Chemistry Letters 4: 1081-1082 (1994); Petersen et al , Bioorganic & Medicinal Chemistry Letters 6:793-796 (1996); Kumar et al , Organic Letters 3(9): 1269-1272 (2001); WO 96/04000. PNA hybridizes to complementary RNA or DNA with higher affinity and specificity than conventional oligonucleotides and oligonucleotide analogs. The properties of PNA enable novel molecular biology and biochemistry applications unachievable with traditional oligonucleotides and peptides.

Additional examples of nucleic acid modifications that improve the binding properties and/or stability of a nucleic acid include the use of base analogs such as inosine, intercalators (U.S. Patent No. 4,835,263) and the minor groove binders (U.S. Patent No. 5,801,115). Thus, references herein to nucleic acid molecules, SNP- containing nucleic acid molecules, SNP detection reagents (e.g. , probes and primers), oligonucleotides/polynucleotides include PNA oligomers and other nucleic acid analogs. Other examples of nucleic acid analogs and alternative/modified nucleic acid chemistries known in the art are described in Current Protocols in Nucleic Acid Chemistry, John Wiley & Sons, N.Y. (2002).

The present invention further provides nucleic acid molecules that encode fragments of the variant polypeptides disclosed herein as well as nucleic acid molecules that encode obvious variants of such variant polypeptides. Such nucleic acid molecules may be naturally occurring, such as paralogs (different locus) and orthologs (different organism), or may be constructed by recombinant DNA methods or by chemical synthesis. Non- naturally occurring variants may be made by mutagenesis techniques, including those applied to nucleic acid molecules, cells, or organisms. Accordingly, the variants can contain nucleotide substitutions, deletions, inversions and insertions (in addition to the SNPs disclosed in Tables 1 and 2).

Variation can occur in either or both the coding and non-coding regions. The variations can produce conservative and/or non-conservative amino acid substitutions.

Further variants of the nucleic acid molecules disclosed in Tables 1 and 2, such as naturally occurring allelic variants (as well as orthologs and paralogs) and synthetic variants produced by mutagenesis techniques, can be identified and/or produced using methods well known in the art. Such further variants can comprise a nucleotide sequence that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a nucleic acid sequence disclosed in Table 1 and/or Table 2 (or a fragment thereof) and that includes a novel SNP allele disclosed in Table 1 and/or Table 2. Further, variants can comprise a nucleotide sequence that encodes a polypeptide that shares at least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a polypeptide sequence disclosed in Table 1 (or a fragment thereof) and that includes a novel SNP allele disclosed in Table 1 and/or Table 2. Thus, an aspect of the present invention that is specifically contemplated are isolated nucleic acid molecules that have a certain degree of sequence variation compared with the sequences shown in Tables 1-2, but that contain a novel SNP allele disclosed herein. In other words, as long as an isolated nucleic acid molecule contains a novel SNP allele disclosed herein, other portions of the nucleic acid molecule that flank the novel SNP allele can vary to some degree from the specific transcript, genomic, and context sequences referred to and shown in Tables 1 and 2, and can encode a polypeptide that varies to some degree from the specific polypeptide sequences referred to in Table 1.

To determine the percent identity of two amino acid sequences or two nucleotide sequences of two molecules that share sequence homology, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more of the length of a reference sequence is aligned for comparison purposes. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein, amino acid or nucleic acid "identity" is equivalent to amino acid or nucleic acid "homology"). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. Computational Molecular Biology, A.M. Lesk, ed., Oxford University Press, N.Y (1988);

Biocomputing: Informatics and Genome Projects, D.W. Smith, ed., Academic Press, N.Y. (1993); Computer Analysis of Sequence Data, Part 1, A.M. Griffin and H.G.

Griffin, eds., Humana Press, N.J. (1994); Sequence Analysis in Molecular Biology, G. von Heinje, ed., Academic Press, N.Y. (1987); and Sequence Analysis Primer, M.

Gribskov and J. Devereux, eds., M. Stockton Press, N.Y. (1991). In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch algorithm (/ Mol Biol (48): 444-453 (1970)) which has been incorporated into the GAP program in the GCG software package, using either a Blossom 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. J. Devereux et al, Nucleic Acids Res.

12(1):387 (1984). In another embodiment, the percent identity between two amino acid or nucleotide sequences is determined using the algorithm of E. Myers and W. Miller (CABIOS 4: 11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.

The nucleotide and amino acid sequences of the present invention can further be used as a "query sequence" to perform a search against sequence databases; for example, to identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0). Altschul et al. , J Mol Biol 215:403-10 (1990). BLAST nucleotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to the nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to the proteins of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized. Altschul et al. , Nucleic Acids Res 25(17):3389-3402 (1997). When utilizing BLAST and gapped BLAST programs, the default parameters of the respective programs {e.g., XBLAST and NBLAST) can be used. In addition to BLAST, examples of other search and sequence comparison programs used in the art include, but are not limited to, FASTA (Pearson, Methods Mol Biol 25, 365-389 (1994)) and KERR (Dufresne et al. , Nat Biotechnol 20(12): 1269-71 (Dec. 2002)).

For further information regarding bioinformatics techniques, see Current Protocols in Bioinformatics, John Wiley & Sons, Inc., N.Y.

The present invention further provides non-coding fragments of the nucleic acid molecules disclosed in Table 1 and/or Table 2. Preferred non-coding fragments include, but are not limited to, promoter sequences, enhancer sequences, intronic sequences, 5' untranslated regions (UTRs), 3' untranslated regions, gene modulating sequences and gene termination sequences. Such fragments are useful, for example, in controlling heterologous gene expression and in developing screens to identify gene-modulating agents. SNP Detection Reagents

In a specific aspect of the present invention, the SNPs disclosed in Table 1 and/or Table 2, and their associated transcript sequences (referred to in Table 1 as SEQ ID NOS: 1-39), genomic sequences (referred to in Table 2 as SEQ ID NOS: 135-179), and context sequences (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS:79-134; genomic-based context sequences are provided in Table 2 as SEQ ID NOS: 180-392), can be used for the design of SNP detection reagents. The actual sequences referred to in the tables are provided in the Sequence Listing. As used herein, a "SNP detection reagent" is a reagent that specifically detects a specific target SNP position disclosed herein, and that is preferably specific for a particular nucleotide (allele) of the target SNP position (i.e., the detection reagent preferably can differentiate between different alternative nucleotides at a target SNP position, thereby allowing the identity of the nucleotide present at the target SNP position to be determined).

Typically, such detection reagent hybridizes to a target SNP-containing nucleic acid molecule by complementary base-pairing in a sequence specific manner, and discriminates the target variant sequence from other nucleic acid sequences such as an art-known form in a test sample. An example of a detection reagent is a probe that hybridizes to a target nucleic acid containing one or more of the SNPs referred to in Table 1 and/or Table 2. In a preferred embodiment, such a probe can differentiate between nucleic acids having a particular nucleotide (allele) at a target SNP position from other nucleic acids that have a different nucleotide at the same target SNP position. In addition, a detection reagent may hybridize to a specific region 5' and/or 3' to a SNP position, particularly a region corresponding to the context sequences referred to in Table 1 and/or Table 2 (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS:79-134; genomic-based context sequences are referred to in Table 2 as SEQ ID NOS: 180-392). Another example of a detection reagent is a primer that acts as an initiation point of nucleotide extension along a complementary strand of a target polynucleotide. The SNP sequence information provided herein is also useful for designing primers, e.g. allele-specific primers, to amplify (e.g., using PCR) any SNP of the present invention.

In one preferred embodiment of the invention, a SNP detection reagent is an isolated or synthetic DNA or RNA polynucleotide probe or primer or PNA oligomer, or a combination of DNA, RNA and/or PNA, that hybridizes to a segment of a target nucleic acid molecule containing a SNP identified in Table 1 and/or Table 2. A detection reagent in the form of a polynucleotide may optionally contain modified base analogs, intercalators or minor groove binders. Multiple detection reagents such as probes may be, for example, affixed to a solid support (e.g. , arrays or beads) or supplied in solution (e.g. probe/primer sets for enzymatic reactions such as PCR, RT- PCR, TaqMan assays, or primer-extension reactions) to form a SNP detection kit.

A probe or primer typically is a substantially purified oligonucleotide or PNA oligomer. Such oligonucleotide typically comprises a region of complementary nucleotide sequence that hybridizes under stringent conditions to at least about 8, 10, 12, 16, 18, 20, 22, 25, 30, 40, 50, 55, 60, 65, 70, 80, 90, 100, 120 (or any other number in- between) or more consecutive nucleotides in a target nucleic acid molecule. Depending on the particular assay, the consecutive nucleotides can either include the target SNP position, or be a specific region in close enough proximity 5' and/or 3' to the SNP position to carry out the desired assay.

Other preferred primer and probe sequences can readily be determined using the transcript sequences (SEQ ID NOS: l-39), genomic sequences (SEQ ID NOS: 135- 179), and SNP context sequences (transcript-based context sequences are referred to in Table 1 as SEQ ID NOS:79-134; genomic-based context sequences are referred to in Table 2 as SEQ ID NOS: 180-392) disclosed in the Sequence Listing and in Tables 1 and 2. The actual sequences referred to in the tables are provided in the Sequence

Listing. It will be apparent to one of skill in the art that such primers and probes are directly useful as reagents for genotyping the SNPs of the present invention, and can be incorporated into any kit/system format.

In order to produce a probe or primer specific for a target SNP-containing sequence, the gene/transcript and/or context sequence surrounding the SNP of interest is typically examined using a computer algorithm that starts at the 5' or at the 3' end of the nucleotide sequence. Typical algorithms will then identify oligomers of defined length that are unique to the gene/SNP context sequence, have a GC content within a range suitable for hybridization, lack predicted secondary structure that may interfere with hybridization, and/or possess other desired characteristics or that lack other undesired characteristics.

A primer or probe of the present invention is typically at least about 8 nucleotides in length. In one embodiment of the invention, a primer or a probe is at least about 10 nucleotides in length. In a preferred embodiment, a primer or a probe is at least about 12 nucleotides in length. In a more preferred embodiment, a primer or probe is at least about 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 nucleotides in length. While the maximal length of a probe can be as long as the target sequence to be detected, depending on the type of assay in which it is employed, it is typically less than about 50, 60, 65, or 70 nucleotides in length. In the case of a primer, it is typically less than about 30 nucleotides in length. In a specific preferred embodiment of the invention, a primer or a probe is within the length of about 18 and about 28 nucleotides. However, in other embodiments, such as nucleic acid arrays and other embodiments in which probes are affixed to a substrate, the probes can be longer, such as on the order of 30-70, 75, 80, 90, 100, or more nucleotides in length (see the section below entitled "SNP Detection Kits and Systems").

For analyzing SNPs, it may be appropriate to use oligonucleotides specific for alternative SNP alleles. Such oligonucleotides that detect single nucleotide variations in target sequences may be referred to by such terms as "allele-specific oligonucleotides," "allele-specific probes," or "allele-specific primers." The design and use of allele- specific probes for analyzing polymorphisms is described in, e.g. , Mutation

Detection: A Practical Approach, Cotton et ah , eds., Oxford University Press (1998); Saiki et al , Nature 324: 163-166 (1986); Dattagupta, EP235J26; and Saiki, WO 89/11548.

While the design of each allele-specific primer or probe depends on variables such as the precise composition of the nucleotide sequences flanking a SNP position in a target nucleic acid molecule, and the length of the primer or probe, another factor in the use of primers and probes is the stringency of the condition under which the hybridization between the probe or primer and the target sequence is performed. Higher stringency conditions utilize buffers with lower ionic strength and/or a higher reaction temperature, and tend to require a more perfect match between probe/primer and a target sequence in order to form a stable duplex. If the stringency is too high, however, hybridization may not occur at all. In contrast, lower stringency conditions utilize buffers with higher ionic strength and/or a lower reaction temperature, and permit the formation of stable duplexes with more mismatched bases between a probe/primer and a target sequence. By way of example and not limitation, exemplary conditions for high stringency hybridization conditions using an allele- specific probe are as follows: prehybridization with a solution containing 5X standard saline phosphate EDTA (SSPE), 0.5% NaDodS0 ₄ (SDS) at 55°C, and incubating probe with target nucleic acid molecules in the same solution at the same temperature, followed by washing with a solution containing 2X SSPE, and 0.1 SDS at 55°C or room temperature.

Moderate stringency hybridization conditions may be used for allele- specific primer extension reactions with a solution containing, e.g. , about 50mM KCl at about 46°C. Alternatively, the reaction may be carried out at an elevated temperature such as 60°C. In another embodiment, a moderately stringent hybridization condition suitable for oligonucleotide ligation assay (OLA) reactions wherein two probes are ligated if they are completely complementary to the target sequence may utilize a solution of about lOOmM KCl at a temperature of 46°C.

In a hybridization-based assay, allele- specific probes can be designed that hybridize to a segment of target DNA from one individual but do not hybridize to the corresponding segment from another individual due to the presence of different polymorphic forms (e.g. , alternative SNP alleles/nucleotides) in the respective DNA segments from the two individuals. Hybridization conditions should be sufficiently stringent that there is a significant detectable difference in hybridization intensity between alleles, and preferably an essentially binary response, whereby a probe hybridizes to only one of the alleles or significantly more strongly to one allele.

While a probe may be designed to hybridize to a target sequence that contains a SNP site such that the SNP site aligns anywhere along the sequence of the probe, the probe is preferably designed to hybridize to a segment of the target sequence such that the SNP site aligns with a central position of the probe (e.g. , a position within the probe that is at least three nucleotides from either end of the probe). This design of probe generally achieves good discrimination in hybridization between different allelic forms.

In another embodiment, a probe or primer may be designed to hybridize to a segment of target DNA such that the SNP aligns with either the 5 ' most end or the 3' most end of the probe or primer. In a specific preferred embodiment that is particularly suitable for use in a oligonucleotide ligation assay (U.S. Patent No.

4,988,617), the 3 'most nucleotide of the probe aligns with the SNP position in the target sequence.

Oligonucleotide probes and primers may be prepared by methods well known in the art. Chemical synthetic methods include, but are not limited to, the phosphotriester method described by Narang et al, Methods in Enzymology 68:90 (1979); the phosphodiester method described by Brown et al., Methods in

Enzymology 68: 109 (1979); the diethylphosphoamidate method described by

Beaucage et al., Tetrahedron Letters 22: 1859 (1981); and the solid support method described in U.S. Patent No. 4,458,066.

Allele- specific probes are often used in pairs (or, less commonly, in sets of 3 or 4, such as if a SNP position is known to have 3 or 4 alleles, respectively, or to assay both strands of a nucleic acid molecule for a target SNP allele), and such pairs may be identical except for a one nucleotide mismatch that represents the allelic variants at the SNP position. Commonly, one member of a pair perfectly matches a reference form of a target sequence that has a more common SNP allele (i.e., the allele that is more frequent in the target population) and the other member of the pair perfectly matches a form of the target sequence that has a less common SNP allele (i.e., the allele that is rarer in the target population). In the case of an array, multiple pairs of probes can be immobilized on the same support for simultaneous analysis of multiple different polymorphisms.

In one type of PCR-based assay, an allele-specific primer hybridizes to a region on a target nucleic acid molecule that overlaps a SNP position and only primes amplification of an allelic form to which the primer exhibits perfect complementarity. Gibbs, Nucleic Acid Res 17:2427-2448 (1989). Typically, the primer's 3' -most nucleotide is aligned with and complementary to the SNP position of the target nucleic acid molecule. This primer is used in conjunction with a second primer that hybridizes at a distal site. Amplification proceeds from the two primers, producing a detectable product that indicates which allelic form is present in the test sample. A control is usually performed with a second pair of primers, one of which shows a single base mismatch at the polymorphic site and the other of which exhibits perfect complementarity to a distal site. The single-base mismatch prevents amplification or substantially reduces amplification efficiency, so that either no detectable product is formed or it is formed in lower amounts or at a slower pace. The method generally works most effectively when the mismatch is at the 3'-most position of the oligonucleotide (i.e., the 3 '-most position of the oligonucleotide aligns with the target SNP position) because this position is most destabilizing to elongation from the primer (see, e.g. , WO 93/22456). This PCR-based assay can be utilized as part of the TaqMan assay, described below. In a specific embodiment of the invention, a primer of the invention contains a sequence substantially complementary to a segment of a target SNP-containing nucleic acid molecule except that the primer has a mismatched nucleotide in one of the three nucleotide positions at the 3 '-most end of the primer, such that the mismatched nucleotide does not base pair with a particular allele at the SNP site. In a preferred embodiment, the mismatched nucleotide in the primer is the second from the last nucleotide at the 3 '-most position of the primer. In a more preferred embodiment, the mismatched nucleotide in the primer is the last nucleotide at the 3 '-most position of the primer.

In another embodiment of the invention, a SNP detection reagent of the invention is labeled with a fluorogenic reporter dye that emits a detectable signal. While the preferred reporter dye is a fluorescent dye, any reporter dye that can be attached to a detection reagent such as an oligonucleotide probe or primer is suitable for use in the invention. Such dyes include, but are not limited to, Acridine, AMCA, BODIPY, Cascade Blue, Cy2, Cy3, Cy5, Cy7, Dabcyl, Edans, Eosin, Erythrosin, Fluorescein, 6- Fam, Tet, Joe, Hex, Oregon Green, Rhodamine, Rhodol Green, Tamra, Rox, and Texas Red.

In yet another embodiment of the invention, the detection reagent may be further labeled with a quencher dye such as Tamra, especially when the reagent is used as a self- quenching probe such as a TaqMan (U.S. Patent Nos. 5,210,015 and 5,538,848) or

Molecular Beacon probe (U.S. Patent Nos. 5,118,801 and 5,312,728), or other stemless or linear beacon probe (Livak et al, PCR Method Appl 4:357-362 (1995); Tyagi et al, Nature Biotechnology 14:303-308 (1996); Nazarenko et al, Nucl Acids Res 25:2516- 2521 (1997); U.S. Patent Nos. 5,866,336 and 6,117,635.

The detection reagents of the invention may also contain other labels, including but not limited to, biotin for streptavidin binding, hapten for antibody binding, and oligonucleotide for binding to another complementary oligonucleotide such as pairs of zipcodes.

The present invention also contemplates reagents that do not contain (or that are complementary to) a SNP nucleotide identified herein but that are used to assay one or more SNPs disclosed herein. For example, primers that flank, but do not hybridize directly to a target SNP position provided herein are useful in primer extension reactions in which the primers hybridize to a region adjacent to the target SNP position (i.e. , within one or more nucleotides from the target SNP site). During the primer extension reaction, a primer is typically not able to extend past a target SNP site if a particular nucleotide (allele) is present at that target SNP site, and the primer extension product can be detected in order to determine which SNP allele is present at the target SNP site. For example, particular ddNTPs are typically used in the primer extension reaction to terminate primer extension once a ddNTP is incorporated into the extension product (a primer extension product which includes a ddNTP at the 3 ' -most end of the primer extension product, and in which the ddNTP is a nucleotide of a SNP disclosed herein, is a composition that is specifically contemplated by the present invention). Thus, reagents that bind to a nucleic acid molecule in a region adjacent to a SNP site and that are used for assaying the SNP site, even though the bound sequences do not necessarily include the SNP site itself, are also contemplated by the present invention.

SNP Detection Kits and Systems

A person skilled in the art will recognize that, based on the SNP and associated sequence information disclosed herein, detection reagents can be developed and used to assay any SNP of the present invention individually or in combination, and such detection reagents can be readily incorporated into one of the established kit or system formats which are well known in the art. The terms "kits" and "systems," as used herein in the context of SNP detection reagents, are intended to refer to such things as combinations of multiple SNP detection reagents, or one or more SNP detection reagents in combination with one or more other types of elements or components (e.g. , other types of biochemical reagents, containers, packages such as packaging intended for commercial sale, substrates to which SNP detection reagents are attached, electronic hardware components, etc.). Accordingly, the present invention further provides SNP detection kits and systems, including but not limited to, packaged probe and primer sets (e.g. TaqMan probe/primer sets),

arrays/microarrays of nucleic acid molecules, and beads that contain one or more probes, primers, or other detection reagents for detecting one or more SNPs of the present invention. The kits/systems can optionally include various electronic hardware components; for example, arrays ("DNA chips") and microfluidic systems ("lab-on-a-chip" systems) provided by various manufacturers typically comprise hardware components. Other kits/systems (e.g. , probe/primer sets) may not include electronic hardware components, but may be comprised of, for example, one or more SNP detection reagents (along with, optionally, other biochemical reagents) packaged in one or more containers.

In some embodiments, a SNP detection kit typically contains one or more detection reagents and other components (e.g. a buffer, enzymes such as DNA polymerases or ligases, chain extension nucleotides such as deoxynucleotide triphosphates, and in the case of Sanger-type DNA sequencing reactions, chain terminating nucleotides, positive control sequences, negative control sequences, and the like) necessary to carry out an assay or reaction, such as amplification and/or detection of a SNP-containing nucleic acid molecule. A kit may further contain means for determining the amount of a target nucleic acid, and means for comparing the amount with a standard, and can comprise instructions for using the kit to detect the SNP-containing nucleic acid molecule of interest. In one embodiment of the present invention, kits are provided which contain the necessary reagents to carry out one or more assays to detect one or more SNPs disclosed herein. In a preferred embodiment of the present invention, SNP detection kits/systems are in the form of nucleic acid arrays, or compartmentalized kits, including microfluidic/lab-on-a-chip systems.

Exemplary kits of the invention can comprise a container containing a SNP detection reagent which detects a SNP disclosed herein, said container can optionally be enclosed in a package (e.g., a box for commercial sale), and said package can further include other containers containing any or all of the following: enzyme (e.g., polymerase or ligase, any of which can be thermostable), dNTPs and/or ddNTPs (which can optionally be detectably labeled, such as with a fluorescent label or mass tag, and such label can optionally differ between any of the dATPs, dCTPs, dGTPs, dTTPs , ddATPs , ddCTPs , ddGTPs , and/or ddTTPs , so that each of these dNTPs and/or ddNTPs can be distinguished from each other by detection of the label, and any of these dNTPs and/or ddNTPs can optionally be stored in the same container or each in separate containers), buffer, controls (e.g., positive control nucleic acid, or a negative control), reagent(s) for extracting nucleic acid from a test sample, and instructions for using the kit (such as instructions for correlating the presence or absence of a particular allele or genotype with an increased or decreased risk for a disorder such as short stature). The SNP detection reagent can comprise, for example, at least one primer and/or probe, any of which can optionally be allele-specific, and any of which can optionally be detectably labeled (e.g., with a fluorescent label). SNP detection kits/systems may contain, for example, one or more probes, or pairs of probes, that hybridize to a nucleic acid molecule at or near each target SNP position. Multiple pairs of allele-specific probes may be included in the kit/system to simultaneously assay large numbers of SNPs, at least one of which is a SNP of the present invention. In some kits/systems, the allele-specific probes are immobilized to a substrate such as an array or bead. For example, the same substrate can comprise allele-specific probes for detecting at least 1 ; 10; 100; 1000; 10,000; 100,000 (or any other number in-between) or substantially all of the SNPs shown in Table 1 and/or Table 2.

The terms "arrays," "microarrays," and "DNA chips" are used herein interchangeably to refer to an array of distinct polynucleotides affixed to a substrate, such as glass, plastic, paper, nylon or other type of membrane, filter, chip, or any other suitable solid support. The polynucleotides can be synthesized directly on the substrate, or synthesized separate from the substrate and then affixed to the substrate. In one embodiment, the microarray is prepared and used according to the methods described in Chee et al , U.S. Patent No. 5,837,832 and PCT application

W095/11995; D.J. Lockhart et al, Nat Biotech 14: 1675-1680 (1996); and M. Schena et al, Proc Natl Acad Sci 93: 10614-10619 (1996), all of which are incorporated herein in their entirety by reference. In other embodiments, such arrays are produced by the methods described by Brown et al. , U.S. Patent No. 5,807,522.

Nucleic acid arrays are reviewed in the following references: Zammatteo et al. , "New chips for molecular biology and diagnostics," Biotechnol Annu Rev 8:85- 101 (2002); Sosnowski et al., "Active microelectronic array system for DNA hybridization, genotyping and pharmacogenomic applications," Psychiatr Genet 12(4): 181-92 (Dec. 2002); Heller, "DNA microarray technology: devices, systems, and applications," Annu Rev Biomed Eng 4: 129-53 (2002); Epub Mar. 22, 2002; Kolchinsky et al. , "Analysis of SNPs and other genomic variations using gel -based chips," Hum Mutat 19(4):343-60 (Apr. 2002); and McGall et al , "High-density genechip oligonucleotide probe arrays," Adv Biochem Eng Biotechnol 77:21-42 (2002).

Any number of probes, such as allele-specific probes, may be implemented in an array, and each probe or pair of probes can hybridize to a different SNP position. In the case of polynucleotide probes, they can be synthesized at designated areas (or synthesized separately and then affixed to designated areas) on a substrate using a light- directed chemical process. Each DNA chip can contain, for example, thousands to millions of individual synthetic polynucleotide probes arranged in a grid-like pattern and miniaturized (e.g., to the size of a dime). Preferably, probes are attached to a solid support in an ordered, addressable array.

A microarray can be composed of a large number of unique, single-stranded polynucleotides, usually either synthetic antisense polynucleotides or fragments of cDNAs, fixed to a solid support. Typical polynucleotides are preferably about 6-60 nucleotides in length, more preferably about 15-30 nucleotides in length, and most preferably about 18-25 nucleotides in length. For certain types of microarrays or other detection kits/systems, it may be preferable to use oligonucleotides that are only about 7-20 nucleotides in length. In other types of arrays, such as arrays used in conjunction with chemiluminescent detection technology, preferred probe lengths can be, for example, about 15-80 nucleotides in length, preferably about 50-70 nucleotides in length, more preferably about 55-65 nucleotides in length, and most preferably about 60 nucleotides in length. The microarray or detection kit can contain polynucleotides that cover the known 5' or 3' sequence of a gene/transcript or target SNP site, sequential polynucleotides that cover the full-length sequence of a gene/transcript; or unique polynucleotides selected from particular areas along the length of a target gene/transcript sequence, particularly areas corresponding to one or more SNPs disclosed in Table 1 and/or Table 2. Polynucleotides used in the microarray or detection kit can be specific to a SNP or SNPs of interest (e.g. , specific to a particular SNP allele at a target SNP site, or specific to particular SNP alleles at multiple different SNP sites), or specific to a polymorphic gene/transcript or genes/transcripts of interest.

Hybridization assays based on polynucleotide arrays rely on the differences in hybridization stability of the probes to perfectly matched and mismatched target sequence variants. For SNP genotyping, it is generally preferable that stringency conditions used in hybridization assays are high enough such that nucleic acid molecules that differ from one another at as little as a single SNP position can be differentiated (e.g. , typical SNP hybridization assays are designed so that hybridization will occur only if one particular nucleotide is present at a SNP position, but will not occur if an alternative nucleotide is present at that SNP position). Such high stringency conditions may be preferable when using, for example, nucleic acid arrays of allele-specific probes for SNP detection. Such high stringency conditions are described in the preceding section, and are well known to those skilled in the art and can be found in, for example, Current Protocols in Molecular Biology 6.3.1-6.3.6, John Wiley & Sons, N.Y. (1989).

In other embodiments, the arrays are used in conjunction with

chemiluminescent detection technology. The following patents and patent applications, which are all hereby incorporated by reference, provide additional information pertaining to chemiluminescent detection. U.S. patent applications that describe chemiluminescent approaches for microarray detection: 10/620332 and 10/620333. U.S. patents that describe methods and compositions of dioxetane for performing chemiluminescent detection: Nos. 6,124,478; 6,107,024; 5,994,073; 5,981,768; 5,871,938; 5,843,681; 5,800,999 and 5,773,628. And the U.S. published application that discloses methods and compositions for microarray controls:

US2002/0110828.

In one embodiment of the invention, a nucleic acid array can comprise an array of probes of about 15-25 nucleotides in length. In further embodiments, a nucleic acid array can comprise any number of probes, in which at least one probe is capable of detecting one or more SNPs disclosed in Table 1 and/or Table 2, and/or at least one probe comprises a fragment of one of the sequences selected from the group consisting of those disclosed in Table 1, Table 2, the Sequence Listing, and sequences complementary thereto, said fragment comprising at least about 8 consecutive nucleotides, preferably 10, 12, 15, 16, 18, 20, more preferably 22, 25, 30, 40, 47, 50, 55, 60, 65, 70, 80, 90, 100, or more consecutive nucleotides (or any other number in- between) and containing (or being complementary to) a novel SNP allele disclosed in Table 1 and/or Table 2. In some embodiments, the nucleotide complementary to the SNP site is within 5, 4, 3, 2, or 1 nucleotide from the center of the probe, more preferably at the center of said probe.

A polynucleotide probe can be synthesized on the surface of the substrate by using a chemical coupling procedure and an ink jet application apparatus, as described in PCT application W095/251116 (Baldeschweiler et al.) which is incorporated herein in its entirety by reference. In another aspect, a "gridded" array analogous to a dot (or slot) blot may be used to arrange and link cDNA fragments or oligonucleotides to the surface of a substrate using a vacuum system, thermal, UV, mechanical or chemical bonding procedures. An array, such as those described above, may be produced by hand or by using available devices (slot blot or dot blot apparatus), materials (any suitable solid support), and machines (including robotic instruments), and may contain 8, 24, 96, 384, 1536, 6144 or more polynucleotides, or any other number which lends itself to the efficient use of commercially available instrumentation.

Using such arrays or other kits/systems, the present invention provides methods of identifying the SNPs disclosed herein in a test sample. Such methods typically involve incubating a test sample of nucleic acids with an array comprising one or more probes corresponding to at least one SNP position of the present invention, and assaying for binding of a nucleic acid from the test sample with one or more of the probes.

Conditions for incubating a SNP detection reagent (or a kit/system that employs one or more such SNP detection reagents) with a test sample vary. Incubation conditions depend on such factors as the format employed in the assay, the detection methods employed, and the type and nature of the detection reagents used in the assay. One skilled in the art will recognize that any one of the commonly available hybridization, amplification and array assay formats can readily be adapted to detect the SNPs disclosed herein.

A SNP detection kit/system of the present invention may include components that are used to prepare nucleic acids from a test sample for the subsequent amplification and/or detection of a SNP-containing nucleic acid molecule. Such sample preparation components can be used to produce nucleic acid extracts

(including DNA and/or RNA), proteins or membrane extracts from any bodily fluids (such as blood, serum, plasma, urine, saliva, phlegm, gastric juices, semen, tears, sweat, etc.), skin, hair, cells (especially nucleated cells) such as buccal cells (e.g., as obtained by buccal swabs), biopsies, or tissue specimens. The test samples used in the above-described methods will vary based on such factors as the assay format, nature of the detection method, and the specific tissues, cells or extracts used as the test sample to be assayed. Methods of preparing nucleic acids, proteins, and cell extracts are well known in the art and can be readily adapted to obtain a sample that is compatible with the system utilized. Automated sample preparation systems for extracting nucleic acids from a test sample are commercially available, and examples are Qiagen' s BioRobot 9600, Applied Biosystems' PRISM™ 6700 sample preparation system, and Roche Molecular Systems' COB AS AmpliPrep System.

Another form of kit contemplated by the present invention is a

compartmentalized kit. A compartmentalized kit includes any kit in which reagents are contained in separate containers. Such containers include, for example, small glass containers, plastic containers, strips of plastic, glass or paper, or arraying material such as silica. Such containers allow one to efficiently transfer reagents from one compartment to another compartment such that the test samples and reagents are not cross-contaminated, or from one container to another vessel not included in the kit, and the agents or solutions of each container can be added in a quantitative fashion from one compartment to another or to another vessel. Such containers may include, for example, one or more containers which will accept the test sample, one or more containers which contain at least one probe or other SNP detection reagent for detecting one or more SNPs of the present invention, one or more containers which contain wash reagents (such as phosphate buffered saline, Tris-buffers, etc.), and one or more containers which contain the reagents used to reveal the presence of the bound probe or other SNP detection reagents. The kit can optionally further comprise compartments and/or reagents for, for example, nucleic acid amplification or other enzymatic reactions such as primer extension reactions, hybridization, ligation, electrophoresis (preferably capillary electrophoresis), mass spectrometry, and/or laser- induced fluorescent detection. The kit may also include instructions for using the kit. Exemplary compartmentalized kits include microfluidic devices known in the art. See, e.g. , Weigl et ah, "Lab-on-a-chip for drug development," Adv Drug Deliv Rev

55(3):349-77 (Feb. 2003). In such microfluidic devices, the containers may be referred to as, for example, microfluidic "compartments," "chambers," or "channels."

Microfluidic devices, which may also be referred to as "lab-on-a-chip" systems, biomedical micro-electro-mechanical systems (bioMEMs), or

multicomponent integrated systems, are exemplary kits/systems of the present invention for analyzing SNPs. Such systems miniaturize and compartmentalize processes such as probe/target hybridization, nucleic acid amplification, and capillary electrophoresis reactions in a single functional device. Such microfluidic devices typically utilize detection reagents in at least one aspect of the system, and such detection reagents may be used to detect one or more SNPs of the present invention. One example of a microfluidic system is disclosed in U.S. Patent No. 5,589,136, which describes the integration of PCR amplification and capillary electrophoresis in chips. Exemplary microfluidic systems comprise a pattern of microchannels designed onto a glass, silicon, quartz, or plastic wafer included on a microchip. The movements of the samples may be controlled by electric, electroosmotic or hydrostatic forces applied across different areas of the microchip to create functional microscopic valves and pumps with no moving parts. Varying the voltage can be used as a means to control the liquid flow at intersections between the micro- machined channels and to change the liquid flow rate for pumping across different sections of the microchip. See, for example, U.S. Patent Nos. 6,153,073, Dubrow et ah , and 6,156,181, Parce et al.

For genotyping SNPs, an exemplary microfluidic system may integrate, for example, nucleic acid amplification, primer extension, capillary electrophoresis, and a detection method such as laser induced fluorescence detection. In a first step of an exemplary process for using such an exemplary system, nucleic acid samples are amplified, preferably by PCR. Then, the amplification products are subjected to automated primer extension reactions using ddNTPs (specific fluorescence for each ddNTP) and the appropriate oligonucleotide primers to carry out primer extension reactions which hybridize just upstream of the targeted SNP. Once the extension at the 3' end is completed, the primers are separated from the unincorporated fluorescent ddNTPs by capillary electrophoresis. The separation medium used in capillary electrophoresis can be, for example, polyacrylamide, polyethyleneglycol or dextran. The incorporated ddNTPs in the single nucleotide primer extension products are identified by laser-induced fluorescence detection. Such an exemplary microchip can be used to process, for example, at least 96 to 384 samples, or more, in parallel. USES OF NUCLEIC ACID MOLECULES

The nucleic acid molecules of the present invention have a variety of uses, especially for the diagnosis, prognosis, treatment, and prevention of short stature. For example, the nucleic acid molecules of the invention are useful for predicting an individual's risk for developing short stature, for prognosing the progression of short stature (e.g., the degree of short stature) in an individual, in evaluating whether an individual should initiate treatment such as treatment with GH and/or IGF-1 to mitigate or treat short stature, etc. For example, the nucleic acid molecules are useful as hybridization probes, such as for genotyping SNPs in messenger RNA, transcript, cDNA, genomic DNA, amplified DNA or other nucleic acid molecules, and for isolating full-length cDNA and genomic clones encoding the variant peptides disclosed in Table 1 as well as their orthologs.

A probe can hybridize to any nucleotide sequence along the entire length of a nucleic acid molecule referred to in Table 1 and/or Table 2. Preferably, a probe of the present invention hybridizes to a region of a target sequence that encompasses a SNP position indicated in Table 1 and/or Table 2. More preferably, a probe hybridizes to a SNP-containing target sequence in a sequence-specific manner such that it distinguishes the target sequence from other nucleotide sequences which vary from the target sequence only by which nucleotide is present at the SNP site. Such a probe is particularly useful for detecting the presence of a SNP-containing nucleic acid in a test sample, or for determining which nucleotide (allele) is present at a particular SNP site (i.e., genotyping the SNP site).

A nucleic acid hybridization probe may be used for determining the presence, level, form, and/or distribution of nucleic acid expression. The nucleic acid whose level is determined can be DNA or RNA. Accordingly, probes specific for the SNPs described herein can be used to assess the presence, expression and/or gene copy number in a given cell, tissue, or organism. These uses are relevant for diagnosis of disorders involving an increase or decrease in gene expression relative to normal levels. In vitro techniques for detection of mRNA include, for example, Northern blot hybridizations and in situ hybridizations. In vitro techniques for detecting DNA include Southern blot hybridizations and in situ hybridizations. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000).

Probes can be used as part of a diagnostic test kit for identifying cells or tissues in which a variant protein is expressed, such as by measuring the level of a variant protein-encoding nucleic acid (e.g., mRNA) in a sample of cells from a subject or determining if a polynucleotide contains a SNP of interest.

Thus, the nucleic acid molecules of the invention can be used as hybridization probes to detect the SNPs disclosed herein, thereby determining whether an individual with the polymorphism(s) is at risk for short stature, or determining whether an individual should be treated to prevent or mitigate short stature, such as treatment with GH and/or IGF-1. Detection of a SNP associated with a disorder phenotype provides a diagnostic tool for an active disorder and/or genetic predisposition to the disorder.

Furthermore, the nucleic acid molecules of the invention are therefore useful for detecting a gene (gene information is disclosed in Table 2, for example) which contains a SNP disclosed herein and/or products of such genes, such as expressed mRNA transcript molecules (transcript information is disclosed in Table 1, for example), and are thus useful for detecting gene expression. The nucleic acid molecules can optionally be implemented in, for example, an array or kit format for use in detecting gene expression.

The nucleic acid molecules of the invention are also useful as primers to amplify any given region of a nucleic acid molecule, particularly a region containing a SNP identified in Table 1 and/or Table 2.

The nucleic acid molecules of the invention are also useful for constructing recombinant vectors (described in greater detail below). Such vectors include expression vectors that express a portion of, or all of, any of the variant peptide sequences referred to in Table 1. Vectors also include insertion vectors, used to integrate into another nucleic acid molecule sequence, such as into the cellular genome, to alter in situ expression of a gene and/or gene product. For example, an endogenous coding sequence can be replaced via homologous recombination with all or part of the coding region containing one or more specifically introduced SNPs.

The nucleic acid molecules of the invention are also useful for expressing antigenic portions of the variant proteins, particularly antigenic portions that contain a variant amino acid sequence (e.g. , an amino acid substitution) caused by a SNP disclosed in Table 1 and/or Table 2.

The nucleic acid molecules of the invention are also useful for constructing vectors containing a gene regulatory region of the nucleic acid molecules of the present invention.

The nucleic acid molecules of the invention are also useful for designing ribozymes corresponding to all, or a part, of an mRNA molecule expressed from a SNP- containing nucleic acid molecule described herein.

The nucleic acid molecules of the invention are also useful for constructing host cells expressing a part, or all, of the nucleic acid molecules and variant peptides.

The nucleic acid molecules of the invention are also useful for constructing transgenic animals expressing all, or a part, of the nucleic acid molecules and variant peptides. The production of recombinant cells and transgenic animals having nucleic acid molecules which contain the SNPs disclosed in Table 1 and/or Table 2 allows, for example, effective clinical design of treatment compounds and dosage regimens.

The nucleic acid molecules of the invention are also useful in assays for drug screening to identify compounds that, for example, modulate nucleic acid expression.

The nucleic acid molecules of the invention are also useful in gene therapy in individuals whose cells have aberrant gene expression. Thus, recombinant cells, which include a patient's cells that have been engineered ex vivo and returned to the patient, can be introduced into an individual where the recombinant cells produce the desired protein to treat the individual. SNP Genotyping Methods

The process of determining which nucleotide(s) is/are present at each of one or more SNP positions (such as a SNP position disclosed in Table 1 and/or Table 2), for either or both alleles, may be referred to by such phrases as SNP genotyping, determining the "identity" of a SNP, determining the "content" of a SNP, or determining which nucleotide(s)/allele(s) is/are present at a SNP position. Thus, these terms can refer to detecting a single allele (nucleotide) at a SNP position or can encompass detecting both alleles (nucleotides) at a SNP position (such as to determine the homozygous or heterozygous state of a SNP position). Furthermore, these terms may also refer to detecting an amino acid residue encoded by a SNP (such as alternative amino acid residues that are encoded by different codons created by alternative nucleotides at a missense SNP position, for example).

Certain exemplary embodiments of the invention provide methods of SNP genotyping, such as for use in determing an individual's risk for short stature (such as for a child or adolescent who is below normal height for their age) or for treating an individual (e.g., with GH and/or IGF-1) based on that individual being at increased risk for short stature.

Nucleic acid samples can be genotyped to determine which allele(s) is/are present at any given genetic region {e.g. , SNP position) of interest by methods well known in the art. The neighboring sequence can be used to design SNP detection reagents such as oligonucleotide probes, which may optionally be implemented in a kit format. Exemplary SNP genotyping methods are described in Chen et ah, "Single nucleotide polymorphism genotyping: biochemistry, protocol, cost and throughput," Pharmacogenomics J 3(2):77-96 (2003); Kwok et ah, "Detection of single nucleotide polymorphisms," Curr Issues Mol Biol 5(2):43-60 (Apr. 2003); Shi, "Technologies for individual genotyping: detection of genetic polymorphisms in drug targets and disease genes," Am J Pharmacogenomics 2(3): 197-205 (2002); and Kwok, "Methods for genotyping single nucleotide polymorphisms," Annu Rev Genomics Hum Genet 2:235- 58 (2001). Exemplary techniques for high-throughput SNP genotyping are described in Marnellos, "High-throughput SNP analysis for genetic association studies," Curr Opin Drug Discov Devel 6(3):317-21 (May 2003). Common SNP genotyping methods include, but are not limited to, TaqMan assays, molecular beacon assays, nucleic acid arrays, allele-specific primer extension, allele-specific PCR, arrayed primer extension, homogeneous primer extension assays, primer extension with detection by mass spectrometry, pyrosequencing, multiplex primer extension sorted on genetic arrays, ligation with rolling circle amplification, homogeneous ligation, OLA (U.S. Patent No. 4,988,167), multiplex ligation reaction sorted on genetic arrays, restriction-fragment length polymorphism, single base extension-tag assays, and the Invader assay. Such methods may be used in combination with detection mechanisms such as, for example, luminescence or chemiluminescence detection, fluorescence detection, time-resolved fluorescence detection, fluorescence resonance energy transfer, fluorescence polarization, mass spectrometry, and electrical detection.

Various methods for detecting polymorphisms include, but are not limited to, methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA duplexes (Myers et al, Science 230:1242 (1985); Cotton et al, PNAS 85:4397 (1988); and Saleeba et al. , Meth. Enzymol 217:286-295 (1992)), comparison of the electrophoretic mobility of variant and wild type nucleic acid molecules (Orita et al, PNAS 86:2766 (1989); Cotton et al, MutatRes 285:125-144 (1993); and Hayashi et al, Genet Anal Tech Appl 9:73-79 (1992)), and assaying the movement of polymorphic or wild-type fragments in polyacrylamide gels containing a gradient of denaturant using denaturing gradient gel electrophoresis (DGGE) (Myers et al., Nature 313:495 (1985)). Sequence variations at specific locations can also be assessed by nuclease protection assays such as RNase and S 1 protection or chemical cleavage methods.

In a preferred embodiment, SNP genotyping is performed using the TaqMan assay, which is also known as the 5' nuclease assay (U.S. Patent Nos. 5,210,015 and 5,538,848). The TaqMan assay detects the accumulation of a specific amplified product during PCR. The TaqMan assay utilizes an oligonucleotide probe labeled with a fluorescent reporter dye and a quencher dye. The reporter dye is excited by irradiation at an appropriate wavelength, it transfers energy to the quencher dye in the same probe via a process called fluorescence resonance energy transfer (FRET). When attached to the probe, the excited reporter dye does not emit a signal. The proximity of the quencher dye to the reporter dye in the intact probe maintains a reduced fluorescence for the reporter. The reporter dye and quencher dye may be at the 5' most and the 3' most ends, respectively, or vice versa. Alternatively, the reporter dye may be at the 5 ' or 3 ' most end while the quencher dye is attached to an internal nucleotide, or vice versa. In yet another embodiment, both the reporter and the quencher may be attached to internal nucleotides at a distance from each other such that fluorescence of the reporter is reduced.

During PCR, the 5' nuclease activity of DNA polymerase cleaves the probe, thereby separating the reporter dye and the quencher dye and resulting in increased fluorescence of the reporter. Accumulation of PCR product is detected directly by monitoring the increase in fluorescence of the reporter dye. The DNA polymerase cleaves the probe between the reporter dye and the quencher dye only if the probe hybridizes to the target SNP-containing template which is amplified during PCR, and the probe is designed to hybridize to the target SNP site only if a particular SNP allele is present.

Preferred TaqMan primer and probe sequences can readily be determined using the SNP and associated nucleic acid sequence information provided herein. A number of computer programs, such as Primer Express (Applied Biosystems, Foster City, CA), can be used to rapidly obtain optimal primer/probe sets. Such primers and probes for detecting the SNPs of the present invention are useful in, for example, identifying individuals who are susceptible to short stature. These probes and primers can be readily incorporated into a kit format. The present invention also includes modifications of the Taqman assay well known in the art such as the use of Molecular Beacon probes (U.S. Patent Nos. 5,118,801 and 5,312,728) and other variant formats (U.S. Patent Nos. 5,866,336 and 6,117,635).

Another preferred method for genotyping the SNPs of the present invention is the use of two oligonucleotide probes in an OLA (see, e.g. , U.S. Patent No.

4,988,617). In this method, one probe hybridizes to a segment of a target nucleic acid with its 3 ' most end aligned with the SNP site. A second probe hybridizes to an adjacent segment of the target nucleic acid molecule directly 3' to the first probe. The two juxtaposed probes hybridize to the target nucleic acid molecule, and are ligated in the presence of a linking agent such as a ligase if there is perfect complementarity between the 3' most nucleotide of the first probe with the SNP site. If there is a mismatch, ligation would not occur. After the reaction, the ligated probes are separated from the target nucleic acid molecule, and detected as indicators of the presence of a SNP. The following patents, patent applications, and published international patent applications, which are all hereby incorporated by reference, provide additional information pertaining to techniques for carrying out various types of OLA. The following U.S. patents describe OLA strategies for performing SNP detection: Nos. 6,027,889; 6,268,148; 5,494,810; 5,830,711 and 6,054,564. WO 97/31256 and WO 00/56927 describe OLA strategies for performing SNP detection using universal arrays, wherein a zipcode sequence can be introduced into one of the hybridization probes, and the resulting product, or amplified product, hybridized to a universal zip code array. U.S. application USOl/17329 (and 09/584,905) describes OLA (or LDR) followed by PCR, wherein zipcodes are incorporated into OLA probes, and amplified PCR products are determined by electrophoretic or universal zipcode array readout. U.S. applications 60/427818, 60/445636, and 60/445494 describe SNPlex methods and software for multiplexed SNP detection using OLA followed by PCR, wherein zipcodes are incorporated into OLA probes, and amplified PCR products are hybridized with a zipchute reagent, and the identity of the SNP determined from electrophoretic readout of the zipchute. In some embodiments, OLA is carried out prior to PCR (or another method of nucleic acid amplification). In other

embodiments, PCR (or another method of nucleic acid amplification) is carried out prior to OLA.

Another method for SNP genotyping is based on mass spectrometry. Mass spectrometry takes advantage of the unique mass of each of the four nucleotides of DNA. SNPs can be unambiguously genotyped by mass spectrometry by measuring the differences in the mass of nucleic acids having alternative SNP alleles. MALDI- TOF (Matrix Assisted Laser Desorption Ionization - Time of Flight) mass spectrometry technology is preferred for extremely precise determinations of molecular mass, such as SNPs. Numerous approaches to SNP analysis have been developed based on mass spectrometry. Preferred mass spectrometry-based methods of SNP genotyping include primer extension assays, which can also be utilized in combination with other approaches, such as traditional gel-based formats and microarrays.

Typically, the primer extension assay involves designing and annealing a primer to a template PCR amplicon upstream (5 ') from a target SNP position. A mix of dideoxynucleotide triphosphates (ddNTPs) and/or deoxynucleotide triphosphates (dNTPs) are added to a reaction mixture containing template (e.g. , a SNP-containing nucleic acid molecule which has typically been amplified, such as by PCR), primer, and DNA polymerase. Extension of the primer terminates at the first position in the template where a nucleotide complementary to one of the ddNTPs in the mix occurs. The primer can be either immediately adjacent (i.e., the nucleotide at the 3' end of the primer hybridizes to the nucleotide next to the target SNP site) or two or more nucleotides removed from the SNP position. If the primer is several nucleotides removed from the target SNP position, the only limitation is that the template sequence between the 3' end of the primer and the SNP position cannot contain a nucleotide of the same type as the one to be detected, or this will cause premature termination of the extension primer. Alternatively, if all four ddNTPs alone, with no dNTPs, are added to the reaction mixture, the primer will always be extended by only one nucleotide, corresponding to the target SNP position. In this instance, primers are designed to bind one nucleotide upstream from the SNP position (i. e. , the nucleotide at the 3' end of the primer hybridizes to the nucleotide that is immediately adjacent to the target SNP site on the 5' side of the target SNP site). Extension by only one nucleotide is preferable, as it minimizes the overall mass of the extended primer, thereby increasing the resolution of mass differences between alternative SNP nucleotides. Furthermore, mass-tagged ddNTPs can be employed in the primer extension reactions in place of unmodified ddNTPs. This increases the mass difference between primers extended with these ddNTPs, thereby providing increased sensitivity and accuracy, and is particularly useful for typing heterozygous base positions. Mass-tagging also alleviates the need for intensive sample-preparation procedures and decreases the necessary resolving power of the mass spectrometer.

The extended primers can then be purified and analyzed by MALDI-TOF mass spectrometry to determine the identity of the nucleotide present at the target SNP position. In one method of analysis, the products from the primer extension reaction are combined with light absorbing crystals that form a matrix. The matrix is then hit with an energy source such as a laser to ionize and desorb the nucleic acid molecules into the gas-phase. The ionized molecules are then ejected into a flight tube and accelerated down the tube towards a detector. The time between the ionization event, such as a laser pulse, and collision of the molecule with the detector is the time of flight of that molecule. The time of flight is precisely correlated with the mass-to-charge ratio (m/z) of the ionized molecule. Ions with smaller m/z travel down the tube faster than ions with larger m/z and therefore the lighter ions reach the detector before the heavier ions. The time-of-flight is then converted into a corresponding, and highly precise, m/z. In this manner, SNPs can be identified based on the slight differences in mass, and the corresponding time of flight differences, inherent in nucleic acid molecules having different nucleotides at a single base position. For further information regarding the use of primer extension assays in conjunction with MALDI-TOF mass spectrometry for SNP genotyping, see, e.g., Wise et al. , "A standard protocol for single nucleotide primer extension in the human genome using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry," Rapid Commun Mass Spectrom 17(11): 1195-202 (2003).

The following references provide further information describing mass spectrometry-based methods for SNP genotyping: Bocker, "SNP and mutation discovery using base-specific cleavage and MALDI-TOF mass spectrometry," Bioinformatics 19 Suppl 1:144-153 (Jul. 2003); Storm et al., "MALDI-TOF mass spectrometry-based SNP genotyping," Methods Mol Biol 212:241-62 (2003); Jurinke et al., "The use of Mass ARRAY technology for high throughput genotyping," Adv Biochem Eng Biotechnol 77:57-74 (2002); and Jurinke et al., "Automated genotyping using the DNA MassArray technology," Methods Mol Biol 187: 179-92 (2002).

SNPs can also be scored by direct DNA sequencing. A variety of automated sequencing procedures can be utilized (e.g. Biotechniques 19:448 (1995)), including sequencing by mass spectrometry. See, e.g., PCT International Publication No. WO 94/16101; Cohen et al, Adv Chromatogr 36:127-162 (1996); and Griffin et al., Appl Biochem Biotechnol 38: 147-159 (1993). The nucleic acid sequences of the present invention enable one of ordinary skill in the art to readily design sequencing primers for such automated sequencing procedures. Commercial instrumentation, such as the Applied Biosystems 377, 3100, 3700, 3730, and 3730x1 DNA Analyzers (Foster City, CA), is commonly used in the art for automated sequencing.

Other methods that can be used to genotype the SNPs of the present invention include single-strand conformational polymorphism (SSCP), and denaturing gradient gel electrophoresis (DGGE). Myers et al, Nature 313:495 (1985). SSCP identifies base differences by alteration in electrophoretic migration of single stranded PCR products, as described in Orita et al , Proc. Nat. Acad. Single-stranded PCR products can be generated by heating or otherwise denaturing double stranded PCR products. Single-stranded nucleic acids may refold or form secondary structures that are partially dependent on the base sequence. The different electrophoretic mobilities of single- stranded amplification products are related to base- sequence differences at SNP positions. DGGE differentiates SNP alleles based on the different sequence- dependent stabilities and melting properties inherent in polymorphic DNA and the corresponding differences in electrophoretic migration patterns in a denaturing gradient gel. PCR Technology: Principles and Applications for DNA Amplification Chapter 7, Erlich, ed., W.H. Freeman and Co, N.Y. (1992).

Sequence-specific ribozymes (U.S. Patent No. 5,498,531) can also be used to score SNPs based on the development or loss of a ribozyme cleavage site. Perfectly matched sequences can be distinguished from mismatched sequences by nuclease cleavage digestion assays or by differences in melting temperature. If the SNP affects a restriction enzyme cleavage site, the SNP can be identified by alterations in restriction enzyme digestion patterns, and the corresponding changes in nucleic acid fragment lengths determined by gel electrophoresis.

SNP genotyping can include the steps of, for example, collecting a biological sample from a human subject {e.g. , sample of tissues, cells, fluids, secretions, etc.), isolating nucleic acids {e.g. , genomic DNA, mRNA or both) from the cells of the sample, contacting the nucleic acids with one or more primers which specifically hybridize to a region of the isolated nucleic acid containing a target SNP under conditions such that hybridization and amplification of the target nucleic acid region occurs, and determining the nucleotide present at the SNP position of interest, or, in some assays, detecting the presence or absence of an amplification product (assays can be designed so that hybridization and/or amplification will only occur if a particular SNP allele is present or absent). In some assays, the size of the

amplification product is detected and compared to the length of a control sample; for example, deletions and insertions can be detected by a change in size of the amplified product compared to a normal genotype.

SNP genotyping is useful for numerous practical applications, as described below. Examples of such applications include, but are not limited to, short stature predisposition screening, diagnosis or prognosis of short stature, predicting progression of short stature, determining therapeutic strategies based on an individual's genotype ("pharmacogenomics") such as determining whether an individual (e.g., a child or adolescent) should be treated with GH and/or IGF-1 (and/or other short stature treatments) to alleviate the development of short stature, developing therapeutic agents targeting proteins encoded by genes containing short stature-associated SNPs, and stratifying patient populations for clinical trials of a therapeutic, preventive, or diagnostic agent (e.g., enrolling an individual in a clinical trial, and/or assigning an individual to a particular arm of a clinical trial, of an investigational agent for treating short stature, based on the individual's genotype at one or more short stature- associated SNPs disclosed herein).

Analysis of Genetic Associations between SNPs and Phenotvpic Traits

SNP genotyping for determining risk of short stature, and other uses described herein, typically relies on initially establishing a genetic association between one or more specific SNPs and the particular phenotypic traits of interest (e.g., short stature).

Different study designs may be used for genetic association studies. Modern Epidemiology 609-622, Lippincott, Williams & Wilkins (1998). Observational studies are most frequently carried out in which the response of the patients is not interfered with. The first type of observational study identifies a sample of persons in whom the suspected cause of the disorder is present and another sample of persons in whom the suspected cause is absent, and then the frequency of development of disorder in the two samples is compared. These sampled populations are called cohorts, and the study is a prospective study. The other type of observational study is case-control or a retrospective study. In typical case-control studies, samples are collected from individuals with the phenotype of interest (cases) such as certain manifestations of a disorder, and from individuals without the phenotype (controls) in a population (target population) that conclusions are to be drawn from. Then the possible causes of the disorder are investigated retrospectively. As the time and costs of collecting samples in case-control studies are considerably less than those for prospective studies, case-control studies are the more commonly used study design in genetic association studies, at least during the exploration and discovery stage.

Case-only studies are an alternative to case-control studies when gene- environment interaction is the association of interest (Piegorsch et al., "Non- hierarchical logistic models and case-only designs for assessing susceptibility in population-based case-control studies", Statistics in Medicine 13 (1994) ppl53-162). In a typical case-only study of gene-environment interaction, genotypes are obtained only from cases who are often selected from an existing cohort study. The association between genotypes and the environmental factor is then assessed and a significant association implies that the effect of the environmental factor on the endpoint of interest (the case definition) differs by genotype. The primary assumption underlying the test of association in case-only studies is that the environmental effect of interest is independent of genotype (e.g., allocation to therapy is independent of genotype) and it has been shown that the case-only design has more power than the case-control design to detect gene-environment interaction when this assumption is true in the population (Yang et al., "Sample Size Requirements in Case-Only Designs to Detect Gene-Environment Interaction", American Journal of Epidemiology 146:9 (1997) pp713-720). Selecting cases from a randomized clinical trial may be an ideal setting in which to perform a case-only study since genotypes will be independent of treatment by design.

In observational studies, there may be potential confounding factors that should be taken into consideration. Confounding factors are those that are associated with both the real cause(s) of the disorder and the disorder itself, and they include demographic information such as age, gender, ethnicity as well as environmental factors. When confounding factors are not matched in cases and controls in a study, and are not controlled properly, spurious association results can arise. If potential confounding factors are identified, they should be controlled for by analysis methods explained below.

In a genetic association study, the cause of interest to be tested is a certain allele or a SNP or a combination of alleles or a haplotype from several SNPs. Thus, tissue specimens (e.g., whole blood) from the sampled individuals may be collected and genomic DNA genotyped for the SNP(s) of interest. In addition to the phenotypic trait of interest, other information such as demographic (e.g., age, gender, ethnicity, etc.), clinical, and environmental information that may influence the outcome of the trait can be collected to further characterize and define the sample set. In many cases, these factors are known to be associated with disorders and/or SNP allele frequencies. There are likely gene-environment and/or gene-gene interactions as well. Analysis methods to address gene-environment and gene-gene interactions (for example, the effects of the presence of both susceptibility alleles at two different genes can be greater than the effects of the individual alleles at two genes combined) are discussed below.

After all the relevant phenotypic and genotypic information has been obtained, statistical analyses are carried out to determine if there is any significant correlation between the presence of an allele or a genotype with the phenotypic characteristics of an individual. Preferably, data inspection and cleaning are first performed before carrying out statistical tests for genetic association. Epidemiological and clinical data of the samples can be summarized by descriptive statistics with tables and graphs. Data validation is preferably performed to check for data completion, inconsistent entries, and outliers. Chi-squared tests and t-tests (Wilcoxon rank-sum tests if distributions are not normal) may then be used to check for significant differences between cases and controls for discrete and continuous variables, respectively. To ensure genotyping quality, Hardy- Weinberg disequilibrium tests can be performed on cases and controls separately. Significant deviation from Hardy- Weinberg equilibrium (HWE) in both cases and controls for individual markers can be indicative of genotyping errors. If HWE is violated in a majority of markers, it is indicative of population substructure that should be further investigated. Moreover, Hardy-Weinberg disequilibrium in cases only can indicate genetic association of the markers with the disorder. B. Weir, Genetic Data Analysis, Sinauer (1990).

To test whether an allele of a single SNP is associated with the case or control status of a phenotypic trait, one skilled in the art can compare allele frequencies in cases and controls. Standard chi-squared tests and Fisher exact tests can be carried out on a 2x2 table (2 SNP alleles x 2 outcomes in the categorical trait of interest). To test whether genotypes of a SNP are associated, chi-squared tests can be carried out on a 3x2 table (3 genotypes x 2 outcomes). Score tests are also carried out for genotypic association to contrast the three genotypic frequencies (major homozygotes, heterozygotes and minor homozygotes) in cases and controls, and to look for trends using 3 different modes of inheritance, namely dominant (with contrast coefficients 2, -1, -1), additive or allelic (with contrast coefficients 1, 0, -1) and recessive (with contrast coefficients 1, 1, -2). Odds ratios for minor versus major alleles, and odds ratios for heterozygote and homozygote variants versus the wild type genotypes are calculated with the desired confidence limits, usually 95%.

In order to control for confounders and to test for interaction and effect modifiers, stratified analyses may be performed using stratified factors that are likely to be confounding, including demographic information such as age, ethnicity, and gender, or an interacting element or effect modifier, such as a known major gene (e.g., APOE for Alzheimer's disease or HLA genes for autoimmune diseases), or environmental factors such as smoking in lung cancer. Stratified association tests may be carried out using Cochran- Mantel-Haenszel tests that take into account the ordinal nature of genotypes with 0, 1, and 2 variant alleles. Exact tests by StatXact may also be performed when computationally possible. Another way to adjust for confounding effects and test for interactions is to perform stepwise multiple logistic regression analysis using statistical packages such as SAS or R. Logistic regression is a model-building technique in which the best fitting and most parsimonious model is built to describe the relation between the dichotomous outcome (for instance, developing a certain disorder or not) and a set of independent variables (for instance, genotypes of different associated genes, and the associated demographic and environmental factors). The most common model is one in which the logit transformation of the odds ratios is expressed as a linear combination of the variables (main effects) and their cross-product terms (interactions). Hosmer and Lemeshow, Applied Logistic Regression, Wiley (2000). To test whether a certain variable or interaction is significantly associated with the outcome, coefficients in the model are first estimated and then tested for statistical significance of their departure from zero.

In addition to performing association tests one marker at a time, haplotype association analysis may also be performed to study a number of markers that are closely linked together. Haplotype association tests can have better power than genotypic or allelic association tests when the tested markers are not the disorder- causing mutations themselves but are in linkage disequilibrium with such mutations. The test will even be more powerful if the disorder is indeed caused by a combination of alleles on a haplotype (e.g., APOE is a haplotype formed by 2 SNPs that are very close to each other). In order to perform haplotype association effectively, marker- marker linkage disequilibrium measures, both D' and r ² , are typically calculated for the markers within a gene to elucidate the haplotype structure. Recent studies in linkage disequilibrium indicate that SNPs within a gene are organized in block pattern, and a high degree of linkage disequilibrium exists within blocks and very little linkage disequilibrium exists between blocks. Daly et al, Nature Genetics 29:232-235 (2001). Haplotype association with the disorder status can be performed using such blocks once they have been elucidated.

Haplotype association tests can be carried out in a similar fashion as the allelic and genotypic association tests. Each haplotype in a gene is analogous to an allele in a multi-allelic marker. One skilled in the art can either compare the haplotype frequencies in cases and controls or test genetic association with different pairs of haplotypes. It has been proposed that score tests can be done on haplotypes using the program "haplo.score." Schaid et al, Am J Hum Genet 70:425-434 (2002). In that method, haplotypes are first inferred by EM algorithm and score tests are carried out with a generalized linear model (GLM) framework that allows the adjustment of other factors.

An important decision in the performance of genetic association tests is the determination of the significance level at which significant association can be declared when the P value of the tests reaches that level. In an exploratory analysis where positive hits will be followed up in subsequent confirmatory testing, an unadjusted P value < 0.2 (a significance level on the lenient side), for example, may be used for generating hypotheses for significant association of a SNP with certain phenotypic characteristics of a disorder. It is preferred that a p- value < 0.05 (a significance level traditionally used in the art) is achieved in order for a SNP to be considered to have an association with a disorder. It is more preferred that a p-value <0.01 (a significance level on the stringent side) is achieved for an association to be declared. When hits are followed up in confirmatory analyses in more samples of the same source or in different samples from different sources, adjustment for multiple testing will be performed as to avoid excess number of hits while maintaining the experiment-wide error rates at 0.05. While there are different methods to adjust for multiple testing to control for different kinds of error rates, a commonly used but rather conservative method is Bonferroni correction to control the experiment-wise or family-wise error rate. Westfall et ah, Multiple comparisons and multiple tests, SAS Institute (1999). Permutation tests to control for the false discovery rates, FDR, can be more powerful. Benjamini and Hochberg, Journal of the Royal Statistical Society, Series B 57: 1289-1300 (1995); Westfall and Young, Resampling-based Multiple

Testing, Wiley (1993). Such methods to control for multiplicity would be preferred when the tests are dependent and controlling for false discovery rates is sufficient as opposed to controlling for the experiment-wise error rates.

In replication studies using samples from different populations after statistically significant markers have been identified in the exploratory stage, metaanalyses can then be performed by combining evidence of different studies. Modern Epidemiology 643-673, Lippincott, Williams & Wilkins (1998). If available, association results known in the art for the same SNPs can be included in the metaanalyses. Since both genotyping and disorder status classification can involve errors, sensitivity analyses may be performed to see how odds ratios and p-values would change upon various estimates on genotyping and disorder classification error rates.

It has been well known that subpopulation-based sampling bias between cases and controls can lead to spurious results in case-control association studies when prevalence of the disease is associated with different subpopulation groups. Ewens and Spielman, Am J Hum Genet 62:450-458 (1995). Such bias can also lead to a loss of statistical power in genetic association studies. To detect population stratification, Pritchard and Rosenberg suggested typing markers that are unlinked to the disease and using results of association tests on those markers to determine whether there is any population stratification. Pritchard et al. , Am J Hum Gen 65:220-228 (1999). When stratification is detected, the genomic control (GC) method as proposed by Devlin and Roeder can be used to adjust for the inflation of test statistics due to population stratification. Devlin et al, Biometrics 55 :997-1004 (1999). The GC method is robust to changes in population structure levels as well as being applicable to DNA pooling designs. Devlin et al, Genet Epidem 21 :273-284 (2001).

While Pritchard' s method recommended using 15-20 unlinked micros atellite markers, it suggested using more than 30 biallelic markers to get enough power to detect population stratification. For the GC method, it has been shown that about 60- 70 biallelic markers are sufficient to estimate the inflation factor for the test statistics due to population stratification. Bacanu et al, Am J Hum Genet 66: 1933-1944 (2000). Hence, 70 intergenic SNPs can be chosen in unlinked regions as indicated in a genome scan. Kehoe et al, Hum Mol Genet 8:237-245 (1999).

Once individual risk factors, genetic or non-genetic, have been found for the predisposition to a disorder, the next step is to set up a classification/prediction scheme to predict the category (for instance, presence or absence of a disorder) that an individual will be in depending on their genotypes of associated SNPs and other non- genetic risk factors. Logistic regression for discrete trait and linear regression for continuous trait are standard techniques for such tasks. Draper and Smith, Applied Regression Analysis, Wiley (1998). Moreover, other techniques can also be used for setting up classification. Such techniques include, but are not limited to, MART, CART, neural network, and discriminant analyses that are suitable for use in comparing the performance of different methods. The Elements of Statistical Learning, Hastie, Tibshirani & Friedman, Springer (2002). For further information about genetic association studies, see Balding, "A tutorial on statistical methods for population association studies", Nature Reviews Genetics 7, 781 (2006). Disease/Disorder Diagnosis and Predisposition Screening

Information on association/correlation between genotypes and disorder-related phenotypes can be exploited in several ways. For example, in the case of a highly statistically significant association between one or more SNPs with predisposition to a disorder for which treatment is available, detection of such a genotype pattern in an individual may justify immediate administration of treatment, or at least the institution of regular monitoring of the individual. Detection of the susceptibility alleles associated with a serious disorder in a couple contemplating having children may also be valuable to the couple in their reproductive decisions. In the case of a weaker but still statistically significant association between a SNP and a human disorder, immediate therapeutic intervention or monitoring may not be justified after detecting the susceptibility allele or SNP. Nevertheless, the subject can be motivated to begin simple life-style changes {e.g. , diet, exercise) that can be accomplished at little or no cost to the individual but would confer potential benefits in reducing the risk of developing conditions for which that individual may have an increased risk by virtue of having the risk allele(s).

The SNPs of the invention may contribute to the development of short stature in different ways. Some polymorphisms occur within a protein coding sequence and contribute to a disorder phenotype by affecting protein structure. Other

polymorphisms occur in noncoding regions but may exert phenotypic effects indirectly via influence on, for example, replication, transcription, and/or translation. A single SNP may affect more than one phenotypic trait. Likewise, a single phenotypic trait may be affected by multiple SNPs in different genes.

As used herein, the terms "diagnose," "diagnosis," and "diagnostics" include, but are not limited to, any of the following: assessment of short stature that an individual may presently have, predisposition/susceptibility/predictive screening (i. e. , determining whether an individual, such as a child or adolescent, has an increased or decreased risk of short stature in the future), and prognosing the future course of short stature (e.g., degree/magnitude of short stature) in an individual. Such diagnostic uses can be based on the SNPs individually or in a unique combination or SNP haplotypes of the present invention.

Haplotypes are particularly useful in that, for example, fewer SNPs can be genotyped to determine if a particular genomic region harbors a locus that influences a particular phenotype, such as in linkage disequilibrium-based SNP association analysis.

Linkage disequilibrium (LD) refers to the co-inheritance of alleles (e.g. , alternative nucleotides) at two or more different SNP sites at frequencies greater than would be expected from the separate frequencies of occurrence of each allele in a given population. The expected frequency of co-occurrence of two alleles that are inherited independently is the frequency of the first allele multiplied by the frequency of the second allele. Alleles that co-occur at expected frequencies are said to be in "linkage equilibrium." In contrast, LD refers to any non-random genetic association between allele(s) at two or more different SNP sites, which is generally due to the physical proximity of the two loci along a chromosome. LD can occur when two or more SNPs sites are in close physical proximity to each other on a given chromosome and therefore alleles at these SNP sites will tend to remain unseparated for multiple generations with the consequence that a particular nucleotide (allele) at one SNP site will show a non-random association with a particular nucleotide (allele) at a different SNP site located nearby. Hence, genotyping one of the SNP sites will give almost the same information as genotyping the other SNP site that is in LD.

Various degrees of LD can be encountered between two or more SNPs with the result being that some SNPs are more closely associated (i.e. , in stronger LD) than others. Furthermore, the physical distance over which LD extends along a chromosome differs between different regions of the genome, and therefore the degree of physical separation between two or more SNP sites necessary for LD to occur can differ between different regions of the genome.

For diagnostic purposes and similar uses, if a particular SNP site is found to be useful for, for example, predicting an individual' s susceptibility to short stature, then the skilled artisan would recognize that other SNP sites which are in LD with this SNP site would also be useful for the same purposes. Thus, polymorphisms (e.g. , SNPs and/or haplotypes) that are not the actual disorder-causing (causative) polymorphisms, but are in LD with such causative polymorphisms, are also useful. In such instances, the genotype of the polymorphism(s) that is/are in LD with the causative polymorphism is predictive of the genotype of the causative polymorphism and, consequently, predictive of the phenotype (e.g. , short stature) that is influenced by the causative SNP(s). Therefore, polymorphic markers that are in LD with causative polymorphisms are useful as diagnostic markers, and are particularly useful when the actual causative polymorphism(s) is/are unknown.

Examples of polymorphisms that can be in LD with one or more causative polymorphisms (and/or in LD with one or more polymorphisms that have a significant statistical association with a condition) and therefore useful for diagnosing the same condition that the causative/associated SNP(s) is used to diagnose, include other SNPs in the same gene, protein-coding, or mRNA transcript-coding region as the causative/associated SNP, other SNPs in the same exon or same intron as the causative/associated SNP, other SNPs in the same haplotype block as the

causative/associated SNP, other SNPs in the same intergenic region as the

causative/associated SNP, SNPs that are outside but near a gene (e.g. , within 6kb on either side, 5' or 3', of a gene boundary) that harbors a causative/associated SNP, etc. Such useful LD SNPs can be selected from among the SNPs disclosed in Table 3, for example.

Linkage disequilibrium in the human genome is reviewed in Wall et al. , "Haplotype blocks and linkage disequilibrium in the human genome," Nat Rev Genet 4(8):587-97 (Aug. 2003); Garner et al , "On selecting markers for association studies: patterns of linkage disequilibrium between two and three diallelic loci," Genet Epidemiol 24(l):57-67 (Jan. 2003); Ardlie et al , "Patterns of linkage disequilibrium in the human genome," Nat Rev Genet 3(4):299-309 (Apr. 2002); erratum in Nat Rev Genet 3(7):566 (Jul. 2002); and Remm et al , "High-density genotyping and linkage disequilibrium in the human genome using chromosome 22 as a model," Curr Opin Chem Biol 6(l):24-30 (Feb. 2002); J.B.S. Haldane, "The combination of linkage values, and the calculation of distances between the loci of linked factors," J Genet 8:299-309 (1919); G. Mendel, Versuche iiber Pflanzen-Hybriden. Verhandlungen des naturforschenden Vereines in Briinn (Proceedings of the Natural History Society of BrUnn) (1866); Genes IV, B. Lewin, ed., Oxford University Press, N.Y. (1990); D.L. Hartl and A.G. Clark Principles of Population Genetics 2 ^nd ed., Sinauer Associates, Inc., Mass. (1989); J.H. Gillespie Population Genetics: A Concise Guide.2 ^nd ed., Johns Hopkins University Press (2004) ; R.C. Lewontin, "The interaction of selection and linkage. I. General considerations; heterotic models," Genetics 49:49-67 (1964); P.G. Hoel, Introduction to Mathematical Statistics 2" ed., John Wiley & Sons, Inc., N.Y. (1954); R.R. Hudson, "Two-locus sampling distributions and their application," Genetics 159: 1805-1817 (2001); A.P. Dempster, N.M. Laird, D.B. Rubin, "Maximum likelihood from incomplete data via the EM algorithm," J R Stat Soc 39: 1-38 (1977); L. Excoffier, M. Slatkin, "Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population," Mol Biol Evol 12(5):921-927 (1995); D.A. Tregouet, S. Escolano, L. Tiret, A. Mallet, J.L. Golmard, "A new algorithm for haplotype-based association analysis: the Stochastic-EM algorithm," Ann Hum Genet 68(Pt 2): 165-177 (2004); A.D. Long and C.H. Langley CH, "The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits," Genome Research 9:720-731 (1999); A. Agresti, Categorical Data Analysis, John Wiley & Sons, Inc., N.Y. (1990); K. Lange, Mathematical and Statistical Methods for Genetic Analysis, Springer- Verlag New York, Inc., N.Y. (1997); The International HapMap Consortium, "The International HapMap Project," Nature 426:789-796 (2003); The International HapMap Consortium, "A haplotype map of the human genome," Nature 437: 1299-1320 (2005); G.A. Thorisson, A.V. Smith, L. Krishnan, L.D. Stein, "The International HapMap Project Web Site," Genome Research 15: 1591-1593 (2005); G. McVean, CCA. Spencer, R. Chaix, "Perspectives on human genetic variation from the HapMap project," PLoS Genetics 1(4):413-418 (2005); J.N. Hirschhorn, M.J. Daly, "Genome-wide association studies for common diseases and complex traits," Nat Genet 6:95-108 (2005); S.J. Schrodi, "A

probabilistic approach to large-scale association scans: a semi-Bayesian method to detect disease-predisposing alleles," SAGMB 4(1):31 (2005); W.Y.S. Wang, B.J. Barratt, D.G. Clayton, J.A. Todd, "Genome-wide association studies: theoretical and practical concerns," Nat Rev Genet 6: 109-118 (2005); J.K. Pritchard, M. Przeworski, "Linkage disequilibrium in humans: models and data," Am J Hum Genet 69: 1-14 (2001).

As discussed above, an aspect of the present invention relates to SNPs that are in LD with an interrogated SNP and which can also be used as valid markers for determining whether an individual has an increased or decreased risk for short stature. As used herein, the term "interrogated SNP" refers to SNPs that have been found to be associated with a disorder risk (such as short stature) using genotyping results and analysis, or other appropriate experimental method as exemplified in the working examples described in this application. As used herein, the term "LD SNP" refers to a SNP that has been characterized as a SNP associated with an increased or decreased risk for a disorder (e.g., short stature) due to their being in LD with the "interrogated SNP" under the methods of calculation described in the application. Below, applicants describe the methods of calculation with which one of ordinary skill in the art may determine if a particular SNP is in LD with an interrogated SNP. The parameter r ² is commonly used in the genetics art to characterize the extent of linkage disequilibrium between markers (Hudson, 2001). As used herein, the term "in LD with" refers to a particular SNP that is measured at above the threshold of a parameter such as r ² with an interrogated SNP.

It is now common place to directly observe genetic variants in a sample of chromosomes obtained from a population. Suppose one has genotype data at two genetic markers located on the same chromosome, for the markers A and B . Further suppose that two alleles segregate at each of these two markers such that alleles A _l and A ₂ can be found at marker A and alleles B _l and B ₂ at marker B . Also assume that these two markers are on a human autosome. If one is to examine a specific individual and find that they are heterozygous at both markers, such that their two- marker genotype is A ₁ A ₂ B ₁ B ₂ , then there are two possible configurations: the individual in question could have the alleles A _l B _l on one chromosome and A ₂ B ₂ on the remaining chromosome; alternatively, the individual could have alleles A _l B ₂ on one chromosome and A ₂ B ₁ on the other. The arrangement of alleles on a

chromosome is called a haplotype. In this illustration, the individual could have haplotypes Α _γ Β _γ Ι A ₂ B ₂ or A ₁ B ₂ / A ₂ B ₁ (see Hartl and Clark (1989) for a more complete description). The concept of linkage equilibrium relates the frequency of haplotypes to the allele frequencies.

Assume that a sample of individuals is selected from a larger population.

Considering the two markers described above, each having two alleles, there are four possible haplotypes: A _l B _l , A _l B ₂ , A ₂ B _l and A ₂ B ₂ . Denote the frequencies of these four haplotypes with the following notation.

P = freq(A _l B _l ) (1) P _ii = freq(A _l B ₂ ) (2)

P _2i = freq(A ₂ B _l ) (3) P ₂₂ = freq(A ₂ B ₂ ) (4)

The allele frequencies at the two markers are then the sum of different haplotype frequencies, it is straightforward to write down a similar set of equations relating single-marker allele frequencies to two-marker haplotype frequencies: p ₁ = freq{A ₁ ) = P _n + P ₁₂ (5) p ₂ = freq(A ₂ ) = P _2l + P ₂₂ (6) q ₁ = freq(B ₁ ) = P _u + P ₂₁ (7) q ₂ = freq(B ₂ ) = P ₁₂ + P ₂₂ (8)

Note that the four haplotype frequencies and the allele frequencies at each marker must sum to a frequency of 1.

(10)

q ₁ + q ₂ = l

(11)

If there is no correlation between the alleles at the two markers, one would expect that the frequency of the haplotypes would be approximately the product of the composite alleles. Therefore, P « p _l q _l

(12)

(15)

These approximating equations (12)-(15) represent the concept of linkage equilibrium where there is independent assortment between the two markers - the alleles at the two markers occur together at random. These are represented as approximations because linkage equilibrium and linkage disequilibrium are concepts typically thought of as properties of a sample of chromosomes; and as such they are susceptible to stochastic fluctuations due to the sampling process. Empirically, many pairs of genetic markers will be in linkage equilibrium, but certainly not all pairs.

Having established the concept of linkage equilibrium above, applicants can now describe the concept of linkage disequilibrium (LD), which is the deviation from linkage equilibrium. Since the frequency of the A _l B _l haplotype is approximately the product of the allele frequencies for A ₁ and B ₁ under the assumption of linkage equilibrium as stated mathematically in (12), a simple measure for the amount of departure from linkage equilibrium is the difference in these two quantities, D , D = P _n - p _iqi

(16)

D = 0 indicates perfect linkage equilibrium. Substantial departures from D = 0 indicates LD in the sample of chromosomes examined. Many properties of D are discussed in Lewontin (1964) including the maximum and minimum values that D can take. Mathematically, using basic algebra, it can be shown that D can also be written solely in terms of haplotypes:

D = P P - P P

(17)

If one transforms D by squaring it and subsequently dividing by the product of the allele frequencies of A _l , A ₂ , B _l and B ₂ , the resulting quantity, called r ² , is equivalent to the square of the Pearson' s correlation coefficient commonly used in statistics (e.g., Hoel, 1954). r =

PiPiQiQi

(18) As with D , values of r ² close to 0 indicate linkage equilibrium between the two markers examined in the sample set. As values of r ² increase, the two markers are said to be in linkage disequilibrium. The range of values that r ² can take are from 0 to 1. r ² = 1 when there is a perfect correlation between the alleles at the two markers. In addition, the quantities discussed above are sample-specific. And as such, it is necessary to formulate notation specific to the samples studied. In the approach discussed here, three types of samples are of primary interest: (i) a sample of chromosomes from individuals affected by a disorder-related phenotype (cases), (ii) a sample of chromosomes obtained from individuals not affected by the disorder-related phenotype (controls), and (iii) a standard sample set used for the construction of haplotypes and calculation pairwise linkage disequilibrium. For the allele frequencies used in the development of the method described below, an additional subscript will be added to denote either the case or control sample sets.

Pi,c _S = freq(A _l in cases)

(19)

Pl,c _S = freq(A ₂ in cases)

(20)

= freq(B _l in cases)

(21)

= freq(B ₂ in cases)

(22)

Similarly,

Put = freq(A _l in controls)

(23)

Pl,ct = freq(A ₂ in controls)

(24)

= freq(B _l in controls)

(25)

= freq(B ₂ in controls)

(26) As a well-accepted sample set is necessary for robust linkage disequilibrium calculations, data obtained from the International HapMap project (The International HapMap Consortium 2003, 2005; Thorisson et al, 2005; McVean et al, 2005) can be used for the calculation of pairwise r ² values. Indeed, the samples genotyped for the International HapMap Project were selected to be representative examples from various human sub-populations with sufficient numbers of chromosomes examined to draw meaningful and robust conclusions from the patterns of genetic variation observed. The International HapMap project website (hapmap.org) contains a description of the project, methods utilized and samples examined. It is useful to examine empirical data to get a sense of the patterns present in such data.

Haplotype frequencies were explicit arguments in equation (18) above.

However, knowing the 2-marker haplotype frequencies requires that phase to be determined for doubly heterozygous samples. When phase is unknown in the data examined, various algorithms can be used to infer phase from the genotype data. This issue was discussed earlier where the doubly heterozygous individual with a 2-SNP genotype of A _l A ₂ B _l B ₂ could have one of two different sets of chromosomes:

A _l B _l l A ₂ B ₂ or A _l B ₂ l A ₂ B _l . One such algorithm to estimate haplotype frequencies is the expectation-maximization (EM) algorithm first formalized by Dempster et al.

(1977). This algorithm is often used in genetics to infer haplotype frequencies from genotype data (e.g. Excoffier and Slatkin (1995); Tregouet et al. (2004)). It should be noted that for the two-SNP case explored here, EM algorithms have very little error provided that the allele frequencies and sample sizes are not too small. The impact on r ² values is typically negligible.

As correlated genetic markers share information, interrogation of SNP markers in LD with a disorder-associated SNP marker can also have sufficient power to detect disorder association (Long and Langley (1999)). The relationship between the power to directly find disorder-associated alleles and the power to indirectly detect disorder- association was investigated by Pritchard and Przeworski (2001). In a straightforward derivation, it can be shown that the power to detect disorder association indirectly at a marker locus in linkage disequilibrium with a disorder-association locus is approximately the same as the power to detect disorder-association directly at the disorder- association locus if the sample size is increased by a factor of -^— (the r reciprocal of equation 18) at the marker in comparison with the disorder- association locus.

Therefore, if one calculated the power to detect disorder-association indirectly with an experiment having N samples, then equivalent power to directly detect disorder-association (at the actual disorder-susceptibility locus) would necessitate an experiment using approximately r ² N samples. This elementary relationship between power, sample size and linkage disequilibrium can be used to derive an r ² threshold value useful in determining whether or not genotyping markers in linkage disequilibrium with a SNP marker directly associated with disorder status has enough power to indirectly detect disorder association.

To commence a derivation of the power to detect disorder-associated markers through an indirect process, define the effective chromosomal sample size as

4N _cs N _ct

n =

N„ + N„,

(27) where N _cs and N _ct are the numbers of diploid cases and controls, respectively. This is necessary to handle situations where the numbers of cases and controls are not equivalent. For equal case and control sample sizes, N _cs = N _ct = N , the value of the effective number of chromosomes is simply n = 2N - as expected. Let power be calculated for a significance level a (such that traditional P- values below a will be deemed statistically significant). Define the standard Gaussian distribution function as Φ(·). Mathematically,

(28)

Alternatively, the following error function notation (Erf) may also be used,

(29) For example, φ(ΐ.644854) = 0.95 . The value of r ² may be derived to yield a pre-specified minimum amount of power to detect disorder association though indirect interrogation. Noting that the LD SNP marker could be the one that is carrying the disorder-association allele, therefore that this approach constitutes a lower-bound model where all indirect power results are expected to be at least as large as those interrogated. Denote by β the error rate for not detecting truly disorder-associated markers. Therefore, 1 - β is the classical definition of statistical power. Substituting the Pritchard-Pzreworski result into the sample size, the power to detect disorder associ approximation

(30) where Z _u is the inverse of the standard normal cumulative distribution evaluated at u ( u e (0,1)). Z _u = Φ ^"1 («), where φ(φ-' (uj) = Φ ^~ ' (φ(ιι)) = u . For example, setting a = 0.05 , and therefore 1 - = 0.975 , one obtains Z ₀₉₇₅ = 1.95996. Next, setting power equal to a threshold of a minimum power of T ,

(3D

and solving for r ² , the following threshold r ² is obtained:

(32)

Or,

Z _T + Z /

..2 V 2 ?1 ,« - ) ² + Q e - c ) ² (33)

Suppose that r ² is calculated between an interrogated SNP and a number of other SNPs with varying levels of LD with the interrogated SNP. The threshold value r _r ² is the minimum value of linkage disequilibrium between the interrogated SNP and the potential LD SNPs such that the LD SNP still retains a power greater or equal to T for detecting disorder association. For example, suppose that SNP rs200 is genotyped in a case-control disorder-association study and it is found to be associated with a disorder phenotype. Further suppose that the minor allele frequency in 1 ,000 case chromosomes was found to be 16% in contrast with a minor allele frequency of 10% in 1,000 control chromosomes. Given those measurements one could have predicted, prior to the experiment, that the power to detect disorder association at a significance level of 0.05 was quite high - approximately 98% using a test of allelic association. Applying equation (32) one can calculate a minimum value of r ² to indirectly assess disorder association assuming that the minor allele at SNP rs200 is truly disorder-predisposing for a threshold level of power. If one sets the threshold level of power to be 80%, then r _r ² = 0.489 given the same significance level and chromosome numbers as above. Hence, any SNP with a pairwise r ² value with rs200 greater than 0.489 is expected to have greater than 80% power to detect the disorder association. Further, this is assuming the conservative model where the LD SNP is disorder-associated only through linkage disequilibrium with the interrogated SNP rs200.

The contribution or association of particular SNPs and/or SNP haplotypes with disorder phenotypes, such as short stature, enables the SNPs of the present invention to be used to develop superior diagnostic tests capable of identifying individuals who express a detectable trait, such as short stature, as the result of a specific genotype, or individuals whose genotype places them at an increased or decreased risk of developing a detectable trait at a subsequent time as compared to individuals who do not have that genotype. As described herein, diagnostics may be based on a single SNP or a group of SNPs. Combined detection of a plurality of SNPs (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 48, 50, 64, 96, 100, or any other number in-between, or more, of the SNPs provided in Table 1 and/or Table 2) typically increases the probability of an accurate diagnosis. For example, the presence of a single SNP known to correlate with short stature might indicate a probability of 20% that an individual has or is at risk of developing short stature, whereas detection of five SNPs, each of which correlates with short stature, might indicate a probability of 80% that an individual has or is at risk of developing short stature. To further increase the accuracy of diagnosis or predisposition screening, analysis of the SNPs of the present invention can be combined with that of other polymorphisms or other risk factors of short stature, such as hormone deficits (e.g., growth hormone deficiency), family history, diet (e.g., malnutrition), environmental factors, or various pathological conditions.

It will be understood by practitioners skilled in the treatment or diagnosis of short stature that the present invention generally does not intend to provide an absolute identification of individuals who are at risk (or less at risk) for short stature, but rather to indicate a certain increased (or decreased) degree or likelihood of short stature based on statistically significant association results. However, this information is extremely valuable as it can be used to, for example, initiate preventive treatments (e.g., earlier initiation of treatments such as GH and/or IGF-1 treatments in children or adolescents who are shorter than normal for their age), or to more closely monitor an individual's (e.g., a child's or adolescent's) stature and growth in order to identify and begin treatment of short stature at an early stage (when treatment is more likely to be successful and result in an improved outcome, e.g., increased height). Thus, the knowledge of a potential predisposition for short stature, even if this predisposition is not absolute, would likely contribute significantly to treatment efficacy.

The diagnostic techniques of the present invention may employ a variety of methodologies to determine whether a test subject has a SNP or a SNP pattern associated with an increased or decreased risk of developing short stature as a result of a particular polymorphism/mutation, including, for example, methods which enable the analysis of individual chromosomes for haplotyping, family studies, single sperm DNA analysis, or somatic hybrids.

Another aspect of the present invention relates to a method of determining whether an individual is at risk (or less at risk) of developing one or more traits or whether an individual expresses one or more traits as a consequence of possessing a particular trait-causing or trait-influencing allele. These methods generally involve obtaining a nucleic acid sample from an individual and assaying the nucleic acid sample to determine which nucleotide(s) is/are present at one or more SNP positions, wherein the assayed nucleotide(s) is/are indicative of an increased or decreased risk of developing the trait or indicative that the individual expresses the trait as a result of possessing a particular trait-causing or trait-influencing allele. In another embodiment, the SNP detection reagents of the present invention are used to determine whether an individual has one or more SNP allele(s) affecting the level (e.g., the concentration of mRNA or protein in a sample, etc.) or pattern (e.g., the kinetics of expression, rate of decomposition, stability profile, Km, Vmax, etc.) of gene expression (collectively, the "gene response" of a cell or bodily fluid). Such a determination can be accomplished by screening for mRNA or protein expression (e.g. , by using nucleic acid arrays, RT-PCR, TaqMan assays, or mass spectrometry), identifying genes having altered expression in an individual, genotyping SNPs disclosed in Table 1 and/or Table 2 that could affect the expression of the genes having altered expression (e.g., SNPs that are in and/or around the gene(s) having altered expression, SNPs in regulatory/control regions, SNPs in and/or around other genes that are involved in pathways that could affect the expression of the gene(s) having altered expression, or all SNPs could be genotyped), and correlating SNP genotypes with altered gene expression. In this manner, specific SNP alleles at particular SNP sites can be identified that affect gene expression.

Therapeutics, Pharmacogenomics, and Drug Development

Therapeutic Methods and Compositions

In certain aspects of the invention, there are provided methods of assaying (i.e., testing) one or more SNPs provided by the present invention in an individual's nucleic acids, and administering a therapeutic or preventive agent (e.g., GH and/or IGF-1) to the individual based on the allele(s) present at the SNP(s) having indicated that the individual is at increased risk for short stature.

In further aspects of the invention, there are provided methods of assaying one or more SNPs provided by the present invention in an individual's nucleic acids, and administering a diagnostic agent (e.g., an imaging agent), or otherwise carrying out further diagnostic procedures on the individual, based on the allele(s) present at the SNP(s) having indicated that the diagnostic agents or diagnostics procedures are justified in the individual.

In yet other aspects of the invention, there is provided a pharmaceutical pack comprising a therapeutic agent (e.g. , a small molecule drug, antibody, recombinant protein, antisense or RNAi nucleic acid molecule, etc.) and a set of instructions for administration of the therapeutic agent to an individual who has been tested for one or more SNPs provided by the present invention. Pharmacogenomics

The present invention provides methods for assessing the pharmacogenomics of a subject harboring particular SNP alleles or haplotypes to a particular therapeutic agent (e.g., recombinant protein or pharmaceutical compound), or to a class of such therapeutic agents. Pharmacogenomics deals with the roles which clinically significant hereditary variations (e.g., SNPs) play in the response to drugs due to altered drug disposition and/or abnormal action in affected persons. See, e.g., Roses, Nature 405, 857-865 (2000); Gould Romberg, Nature Biotechnology 19, 209-211 (2001);

Eichelbaum, Clin Exp Pharmacol Physiol 23(10-11):983-985 (1996); and Linder, Clin Chem 43(2):254-266 (1997). The clinical outcomes of these variations can result in severe toxicity of therapeutic drugs in certain individuals or therapeutic failure of drugs in certain individuals as a result of individual variation in metabolism. Thus, the SNP genotype of an individual can determine the way a therapeutic compound acts on the body or the way the body metabolizes the compound. For example, SNPs in drug metabolizing enzymes can affect the activity of these enzymes, which in turn can affect both the intensity and duration of drug action, as well as drug metabolism and clearance.

The discovery of SNPs in drug metabolizing enzymes, drug transporters, proteins for pharmaceutical agents, and other drug targets has explained why some patients do not obtain the expected drug effects, show an exaggerated drug effect, or experience serious toxicity from standard drug dosages. SNPs can be expressed in the phenotype of the extensive metabolizer and in the phenotype of the poor metabolizer. Accordingly, SNPs may lead to allelic variants of a protein in which one or more of the protein functions in one population are different from those in another population. SNPs and the encoded variant peptides thus provide targets to ascertain a genetic

predisposition that can affect treatment modality. For example, in a ligand-based treatment, SNPs may give rise to amino terminal extracellular domains and/or other ligand-binding regions of a receptor that are more or less active in ligand binding, thereby affecting subsequent protein activation. Accordingly, ligand dosage would necessarily be modified to maximize the therapeutic effect within a given population containing particular SNP alleles or haplotypes.

As an alternative to genotyping, specific variant proteins containing variant amino acid sequences encoded by alternative SNP alleles could be identified. Thus, pharmacogenomic characterization of an individual permits the selection of effective compounds and effective dosages of such compounds for prophylactic or therapeutic uses based on the individual's SNP genotype, thereby enhancing and optimizing the effectiveness of the therapy. Furthermore, the production of recombinant cells and transgenic animals containing particular SNPs/haplotypes allow effective clinical design and testing of treatment compounds and dosage regimens. For example, transgenic animals can be produced that differ only in specific SNP alleles in a gene that is orthologous to a human disorder susceptibility gene.

Pharmacogenomic uses of the SNPs of the present invention provide several significant advantages for patient care, particularly in predicting an individual's predisposition to short stature. Pharmacogenomic characterization of an individual, based on an individual's SNP genotype, can identify those individuals unlikely to respond to treatment with a particular medication and thereby allows physicians to avoid prescribing the ineffective medication to those individuals. On the other hand, SNP genotyping of an individual may enable physicians to select the appropriate medication and dosage regimen that will be most effective based on an individual's SNP genotype. This information increases a physician's confidence in prescribing medications and motivates patients to comply with their drug regimens. Furthermore, pharmacogenomics may identify patients predisposed to toxicity and adverse reactions to particular drugs or drug dosages. Adverse drug reactions lead to more than 100,000 avoidable deaths per year in the United States alone and therefore represent a significant cause of

hospitalization and death, as well as a significant economic burden on the healthcare system (Pfost et al, Trends in Biotechnology, Aug. 2000.). Thus, pharmacogenomics based on the SNPs disclosed herein has the potential to both save lives and reduce healthcare costs substantially.

Pharmacogenomics in general is discussed further in Rose et al. ,

"Pharmacogenetic analysis of clinically relevant genetic polymorphisms," Methods Mol Med 85:225-37 (2003). Pharmacogenomics as it relates to Alzheimer's disease and other neurodegenerative disorders is discussed in Cacabelos, "Pharmacogenomics for the treatment of dementia," Ann Med 34(5):357-79 (2002); Maimone et al. , "Pharmacogenomics of neurodegenerative diseases," Eur J Pharmacol 413(l): l l-29 (Feb. 2001); and Poirier, "Apolipoprotein E: a pharmacogenetic target for the treatment of Alzheimer's disease," Mol Diagn 4(4):335-41 (Dec.1999).

Pharmacogenomics as it relates to cardiovascular disorders is discussed in Siest et al., "Pharmacogenomics of drugs affecting the cardiovascular system," Clin Chem Lab Med 41(4):590-9 (Apr. 2003); Mukherjee et al, "Pharmacogenomics in

cardiovascular diseases," Prog Cardiovasc Dis 44(6):479-98 (May-Jun. 2002); and Mooser et al. , "Cardiovascular pharmacogenetics in the SNP era," J Thromb Haemost l(7): 1398-402 (Jul. 2003). Pharmacogenomics as it relates to cancer is discussed in McLeod et al, "Cancer pharmacogenomics: SNPs, chips, and the individual patient," Cancer Invest 21(4):630-40 (2003); and Watters et al., "Cancer pharmacogenomics: current and future applications," Biochim Biophys Acta 1603(2):99-111 (Mar. 2003).

Clinical Trials

In certain aspects of the invention, there are provided methods of using the

SNPs disclosed herein to identify or stratify patient populations for clinical trials of a therapeutic, preventive, or diagnostic agent. For instance, an aspect of the present invention includes selecting individuals for clinical trials based on their SNP genotype, such as selecting individuals for inclusion in a clinical trial and/or assigning individuals to a particular group within a clinical trial (e.g., an "arm" or "cohort" of the trial). For example, individuals with SNP genotypes that indicate that they are at increased risk for short stature can be included in the trials, whereas those individuals whose SNP genotypes indicate that they are not at increased risk for short stature can be excluded from the clinical trials. Thus, certain embodiments of the invention provide methods for conducting a clinical trial of a therapeutic agent in which a human is selected for inclusion in the clinical trial (enrolled in a clinical trial) and/or assigned to a particular arm (group) within a clinical trial based on the presence or absence of one or more SNP alleles disclosed herein. In certain embodiments, the therapeutic agent is a type of GH or IGF- 1.

Identification, Screening, and Use of Therapeutic Agents

The SNPs of the present invention also can be used to identify novel therapeutic targets for short stature. For example, genes containing the disorder- associated variants ("variant genes") or their products, as well as genes or their products that are directly or indirectly regulated by or interacting with these variant genes or their products, can be targeted for the development of therapeutics that, for example, treat the disorder or prevent or delay disorder onset. The therapeutics may be composed of, for example, small molecules, proteins, protein fragments or peptides, antibodies, nucleic acids, or their derivatives or mimetics which modulate the functions or levels of the target genes or gene products.

The invention further provides methods for identifying a compound or agent that can be used to treat short stature. The SNPs disclosed herein are useful as targets for the identification and/or development of therapeutic agents. A method for identifying a therapeutic agent or compound typically includes assaying the ability of the agent or compound to modulate the activity and/or expression of a SNP-containing nucleic acid or the encoded product and thus identifying an agent or a compound that can be used to treat a disorder characterized by undesired activity or expression of the SNP-containing nucleic acid or the encoded product. The assays can be performed in cell-based and cell- free systems. Cell-based assays can include cells naturally expressing the nucleic acid molecules of interest or recombinant cells genetically engineered to express certain nucleic acid molecules.

Variant gene expression in a short stature individual can include, for example, either expression of a SNP-containing nucleic acid sequence (for instance, a gene that contains a SNP can be transcribed into an mRNA transcript molecule containing the SNP, which can in turn be translated into a variant protein) or altered expression of a normal/wild-type nucleic acid sequence due to one or more SNPs (for instance, a regulatory/control region can contain a SNP that affects the level or pattern of expression of a normal transcript).

Assays for variant gene expression can involve direct assays of nucleic acid levels (e.g. , mRNA levels), expressed protein levels, or of collateral compounds involved in a signal pathway. Further, the expression of genes that are up- or down- regulated in response to the signal pathway can also be assayed. In this embodiment, the regulatory regions of these genes can be operably linked to a reporter gene such as luciferase.

Modulators of variant gene expression can be identified in a method wherein, for example, a cell is contacted with a candidate compound/agent and the expression of mRNA determined. The level of expression of mRNA in the presence of the candidate compound is compared to the level of expression of mRNA in the absence of the candidate compound. The candidate compound can then be identified as a modulator of variant gene expression based on this comparison and be used to treat a disorder such as short stature that is characterized by variant gene expression (e.g. , either expression of a SNP-containing nucleic acid or altered expression of a normal/wild-type nucleic acid molecule due to one or more SNPs that affect expression of the nucleic acid molecule) due to one or more SNPs of the present invention. When expression of mRNA is statistically significantly greater in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of nucleic acid expression. When nucleic acid expression is statistically significantly less in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of nucleic acid expression.

The invention further provides methods of treatment, with the SNP or associated nucleic acid domain (e.g., catalytic domain, ligand/substrate-binding domain, regulatory/control region, etc.) or gene, or the encoded mRNA transcript, as a target, using a compound identified through drug screening as a gene modulator to modulate variant nucleic acid expression. Modulation can include either up-regulation (i.e., activation or agonization) or down-regulation (i.e. , suppression or antagonization) of nucleic acid expression.

Expression of mRNA transcripts and encoded proteins, either wild type or variant, may be altered in individuals with a particular SNP allele in a

regulatory/control element, such as a promoter or transcription factor binding domain, that regulates expression. In this situation, methods of treatment and compounds can be identified, as discussed herein, that regulate or overcome the variant

regulatory/control element, thereby generating normal, or healthy, expression levels of either the wild type or variant protein.

Pharmaceutical Compositions and Administration Thereof

Any of the short stature-associated proteins, and encoding nucleic acid molecules, disclosed herein can be used as therapeutic targets (or directly used themselves as therapeutic compounds) for treating or preventing short stature or related pathologies, and the present disclosure enables therapeutic compounds (e.g., small molecules, antibodies, therapeutic proteins, RNAi and antisense molecules, etc.) to be developed that target (or are comprised of) any of these therapeutic targets.

In general, a therapeutic compound will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the therapeutic compound of this invention, i.e. , the active ingredient, will depend upon numerous factors such as the severity of the disorder to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.

Therapeutically effective amounts of therapeutic compounds may range from, for example, approximately 0.01-50 mg per kilogram body weight of the recipient per day; preferably about 0.1-20 mg/kg/day. Thus, as an example, for administration to a 70-kg person, the dosage range would most preferably be about 7 mg to 1.4g per day.

In general, therapeutic compounds will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g. , transdermal, intranasal, or by suppository), or parenteral (e.g. , intramuscular, intravenous, or subcutaneous) administration. The preferred manner of administration is oral or parenteral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Oral compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules are preferred) and the bioavailability of the drug substance.

Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1 ,000 nm in which the active material is supported on a cross-linked matrix of macromolecules. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.

Pharmaceutical compositions are comprised of, in general, a therapeutic compound in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the therapeutic compound. Such excipients may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one skilled in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g. , peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.

Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences 18 ^th ed., E.W. Martin, ed., Mack Publishing Company (1990).

The amount of the therapeutic compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of the therapeutic compound based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80% wt.

Therapeutic compounds can be administered alone or in combination with other therapeutic compounds or in combination with one or more other active ingredient(s). For example, an inhibitor or stimulator of a short stature-associated protein can be administered in combination with another agent that inhibits or stimulates the activity of the same or a different short stature-associated protein to thereby counteract the effects of short stature.

For further information regarding pharmacology, see Current Protocols in Pharmacology, John Wiley & Sons, Inc., N.Y.

Nucleic Acid-Based Therapeutic Agents

The SNP-containing nucleic acid molecules disclosed herein, and their complementary nucleic acid molecules, may be used as antisense constructs to control gene expression in cells, tissues, and organisms. Antisense technology is well established in the art and extensively reviewed in Antisense Drug Technology:

Principles, Strategies, and Applications, Crooke, ed., Marcel Dekker, Inc., N.Y. (2001). An antisense nucleic acid molecule is generally designed to be

complementary to a region of mRNA expressed by a gene so that the antisense molecule hybridizes to the mRNA and thereby blocks translation of mRNA into protein. Various classes of antisense oligonucleotides are used in the art, two of which are cleavers and blockers. Cleavers, by binding to target RNAs, activate intracellular nucleases (e.g. , RNaseH or RNase L) that cleave the target RNA.

Blockers, which also bind to target RNAs, inhibit protein translation through steric hindrance of ribosomes. Exemplary blockers include peptide nucleic acids, morpholinos, locked nucleic acids, and methylphosphonates. See, e.g. , Thompson, Drug Discovery Today 7(17): 912-917 (2002). Antisense oligonucleotides are directly useful as therapeutic agents, and are also useful for determining and validating gene function (e.g. , in gene knock-out or knock-down experiments).

Antisense technology is further reviewed in: Lavery et al. , "Antisense and RNAi: powerful tools in drug target discovery and validation," Curr Opin Drug Discov Devel 6(4):561-9 (Jul. 2003); Stephens et al , "Antisense oligonucleotide therapy in cancer," Curr Opin Mol Ther 5(2): 118-22 (Apr. 2003); Kurreck,

"Antisense technologies. Improvement through novel chemical modifications," Eur J Biochem 270(8): 1628-44 (Apr. 2003); Dias et al. , "Antisense oligonucleotides: basic concepts and mechanisms," Mol Cancer Ther l(5):347-55 (Mar. 2002); Chen, "Clinical development of antisense oligonucleotides as anti-cancer therapeutics," Methods Mol Med 75:621-36 (2003); Wang et al. , "Antisense anticancer

oligonucleotide therapeutics," Curr Cancer Drug Targets l(3): 177-96 (Nov. 2001); and Bennett, "Efficiency of antisense oligonucleotide drug discovery," Antisense Nucleic Acid Drug Dev 12(3):215-24 (Jun. 2002).

The SNPs of the present invention are particularly useful for designing antisense reagents that are specific for particular nucleic acid variants. Based on the SNP information disclosed herein, antisense oligonucleotides can be produced that specifically target mRNA molecules that contain one or more particular SNP nucleotides. In this manner, expression of mRNA molecules that contain one or more undesired polymorphisms (e.g. , SNP nucleotides that lead to a defective protein such as an amino acid substitution in a catalytic domain) can be inhibited or completely blocked. Thus, antisense oligonucleotides can be used to specifically bind a particular polymorphic form (e.g. , a SNP allele that encodes a defective protein), thereby inhibiting translation of this form, but which do not bind an alternative polymorphic form (e.g. , an alternative SNP nucleotide that encodes a protein having normal function).

Antisense molecules can be used to inactivate mRNA in order to inhibit gene expression and production of defective proteins. Accordingly, these molecules can be used to treat a disorder, such as short stature, characterized by abnormal or undesired gene expression or expression of certain defective proteins. This technique can involve cleavage by means of ribozymes containing nucleotide sequences complementary to one or more regions in the mRNA that attenuate the ability of the mRNA to be translated. Possible mRNA regions include, for example, protein-coding regions and particularly protein-coding regions corresponding to catalytic activities, substrate/ligand binding, or other functional activities of a protein.

The SNPs of the present invention are also useful for designing RNA interference reagents that specifically target nucleic acid molecules having particular SNP variants. RNA interference (RNAi), also referred to as gene silencing, is based on using double-stranded RNA (dsRNA) molecules to turn genes off. When introduced into a cell, dsRNAs are processed by the cell into short fragments (generally about 21, 22, or 23 nucleotides in length) known as small interfering RNAs (siRNAs) which the cell uses in a sequence- specific manner to recognize and destroy complementary RNAs. Thompson, Drug Discovery Today 7(17): 912-917 (2002). Accordingly, an aspect of the present invention specifically contemplates isolated nucleic acid molecules that are about 18-26 nucleotides in length, preferably 19-25 nucleotides in length, and more preferably 20, 21 , 22, or 23 nucleotides in length, and the use of these nucleic acid molecules for RNAi. Because RNAi molecules, including siRNAs, act in a sequence-specific manner, the SNPs of the present invention can be used to design RNAi reagents that recognize and destroy nucleic acid molecules having specific SNP alleles/nucleotides (such as deleterious alleles that lead to the production of defective proteins), while not affecting nucleic acid molecules having alternative SNP alleles (such as alleles that encode proteins having normal function). As with antisense reagents, RNAi reagents may be directly useful as therapeutic agents (e.g. , for turning off defective, disorder-causing genes), and are also useful for characterizing and validating gene function (e.g. , in gene knock-out or knock-down experiments).

The following references provide a further review of RNAi: Reynolds et ah, "Rational siRNA design for RNA interference," Nat Biotechnol 22(3):326-30 (Mar. 2004); Epub Feb. 1, 2004; Chi et al , "Genomewide view of gene silencing by small interfering RNAs," PNAS 100(11):6343-6346 (2003); Vickers et al , "Efficient Reduction of Target RNAs by Small Interfering RNA and RNase H-dependent Antisense Agents," J Biol Chem 278:7108-7118 (2003); Agami, "RNAi and related mechanisms and their potential use for therapy," Curr Opin Chem Biol 6(6):829-34 (Dec. 2002); Lavery et al , "Antisense and RNAi: powerful tools in drug target discovery and validation," Curr Opin Drug Discov Devel 6(4):561-9 (Jul. 2003); Shi, "Mammalian RNAi for the masses," Trends Genet 19(1):9-12 (Jan. 2003); Shuey et al, "RNAi: gene-silencing in therapeutic intervention," Drug Discovery Today 7(20): 1040-1046 (Oct. 2002); McManus et al , Nat Rev Genet 3(10):737-47 (Oct. 2002); Xia et al. , Nat Biotechnol 20(10): 1006-10 (Oct. 2002); Plasterk et al, Curr Opin Genet Dev 10(5):562-7 (Oct. 2000); Bosher et al, Nat Cell Biol 2(2):E31-6 (Feb. 2000); and Hunter, Curr Biol 17; 9(12):R440-2 (Jun. 1999). Other Therapeutic Aspects

SNPs have many important uses in drug discovery, screening, and

development, and thus the SNPs of the present invention are useful for improving many different aspects of the drug development process.

For example, a high probability exists that, for any gene/protein selected as a potential drug target, variants of that gene/protein will exist in a patient population.

Thus, determining the impact of gene/protein variants on the selection and delivery of a therapeutic agent should be an integral aspect of the drug discovery and

development process. Jazwinska, A Trends Guide to Genetic Variation and Genomic Medicine S30-S36 (Mar. 2002).

Knowledge of variants (e.g. , SNPs and any corresponding amino acid polymorphisms) of a particular therapeutic target (e.g. , a gene, mRNA transcript, or protein) enables parallel screening of the variants in order to identify therapeutic candidates (e.g., small molecule compounds, antibodies, antisense or RNAi nucleic acid compounds, etc.) that demonstrate efficacy across variants. Rothberg, Nat Biotechnol 19(3):209-11 (Mar. 2001). Such therapeutic candidates would be expected to show equal efficacy across a larger segment of the patient population, thereby leading to a larger potential market for the therapeutic candidate.

Furthermore, identifying variants of a potential therapeutic target enables the most common form of the target to be used for selection of therapeutic candidates, thereby helping to ensure that the experimental activity that is observed for the selected candidates reflects the real activity expected in the largest proportion of a patient population. Jazwinska, A Trends Guide to Genetic Variation and Genomic Medicine S30-S36 (Mar. 2002).

Additionally, screening therapeutic candidates against all known variants of a target can enable the early identification of potential toxicities and adverse reactions relating to particular variants. For example, variability in drug absorption, distribution, metabolism and excretion (ADME) caused by, for example, SNPs in therapeutic targets or drug metabolizing genes, can be identified, and this information can be utilized during the drug development process to minimize variability in drug disposition and develop therapeutic agents that are safer across a wider range of a patient population. The SNPs of the present invention, including the variant proteins and encoding polymorphic nucleic acid molecules provided in Tables 1 and 2, are useful in conjunction with a variety of toxicology methods established in the art, such as those set forth in Current Protocols in Toxicology, John Wiley & Sons, Inc., N.Y.

Furthermore, therapeutic agents that target any art-known proteins (or nucleic acid molecules, either RNA or DNA) may cross-react with the variant proteins (or polymorphic nucleic acid molecules) disclosed in Table 1 , thereby significantly affecting the pharmacokinetic properties of the drug. Consequently, the protein variants and the SNP-containing nucleic acid molecules disclosed in Tables 1 and 2 are useful in developing, screening, and evaluating therapeutic agents that target corresponding art-known protein forms (or nucleic acid molecules). Additionally, as discussed above, knowledge of all polymorphic forms of a particular drug target enables the design of therapeutic agents that are effective against most or all such polymorphic forms of the drug target.

A subject having a disorder ascribed to a SNP, such as short stature, may be treated so as to correct the genetic defect. See Kren et ah, Proc Natl Acad Sci USA 96: 10349-10354 (1999). Such a subject can be identified by any method that can detect the polymorphism in a biological sample drawn from the subject. Such a genetic defect may be permanently corrected by administering to such a subject a nucleic acid fragment incorporating a repair sequence that supplies the normal/wild- type nucleotide at the position of the SNP. This site-specific repair sequence can encompass an RNA/DNA oligonucleotide that operates to promote endogenous repair of a subject's genomic DNA. The site-specific repair sequence is administered in an appropriate vehicle, such as a complex with polyethylenimine, encapsulated in anionic liposomes, a viral vector such as an adenovirus, or other pharmaceutical composition that promotes intracellular uptake of the administered nucleic acid. A genetic defect leading to an inborn pathology may then be overcome, as the chimeric oligonucleotides induce incorporation of the normal sequence into the subject's genome. Upon incorporation, the normal gene product is expressed, and the replacement is propagated, thereby engendering a permanent repair and therapeutic enhancement of the clinical condition of the subject.

In cases in which a cSNP results in a variant protein that is ascribed to be the cause of, or a contributing factor to, a pathological condition, a method of treating such a condition can include administering to a subject experiencing the pathology the wild-type/normal cognate of the variant protein. Once administered in an effective dosing regimen, the wild-type cognate provides complementation or remediation of the pathological condition.

VARIANT PROTEINS, ANTIBODIES, VECTORS, HOST CELLS, & USES THEREOF

Variant Proteins Encoded by SNP-Containing Nucleic Acid Molecules

The present invention provides SNP-containing nucleic acid molecules, many of which encode proteins having variant amino acid sequences as compared to the art- known (i.e., wild- type) proteins. Amino acid sequences encoded by the polymorphic nucleic acid molecules of the present invention are referred to as SEQ ID NOS:40-78 in Table 1 and provided in the Sequence Listing. These variants will generally be referred to herein as variant proteins/peptides/polypeptides, or polymorphic

proteins/peptides/polypeptides of the present invention. The terms "protein," "peptide," and "polypeptide" are used herein interchangeably.

A variant protein of the present invention may be encoded by, for example, a nonsynonymous nucleotide substitution at any one of the cSNP positions disclosed herein. In addition, variant proteins may also include proteins whose expression, structure, and/or function is altered by a SNP disclosed herein, such as a SNP that creates or destroys a stop codon, a SNP that affects splicing, and a SNP in control/regulatory elements, e.g. promoters, enhancers, or transcription factor binding domains. As used herein, a protein or peptide is said to be "isolated" or "purified" when it is substantially free of cellular material or chemical precursors or other chemicals. The variant proteins of the present invention can be purified to homogeneity or other lower degrees of purity. The level of purification will be based on the intended use. The key feature is that the preparation allows for the desired function of the variant protein, even if in the presence of considerable amounts of other components.

As used herein, "substantially free of cellular material" includes preparations of the variant protein having less than about 30% (by dry weight) other proteins (i.e., contaminating protein), less than about 20% other proteins, less than about 10% other proteins, or less than about 5% other proteins. When the variant protein is

recombinantly produced, it can also be substantially free of culture medium, i.e. , culture medium represents less than about 20% of the volume of the protein preparation.

The language "substantially free of chemical precursors or other chemicals" includes preparations of the variant protein in which it is separated from chemical precursors or other chemicals that are involved in its synthesis. In one embodiment, the language "substantially free of chemical precursors or other chemicals" includes preparations of the variant protein having less than about 30% (by dry weight) chemical precursors or other chemicals, less than about 20% chemical precursors or other chemicals, less than about 10% chemical precursors or other chemicals, or less than about 5% chemical precursors or other chemicals.

An isolated variant protein may be purified from cells that naturally express it, purified from cells that have been altered to express it (recombinant host cells), or synthesized using known protein synthesis methods. For example, a nucleic acid molecule containing SNP(s) encoding the variant protein can be cloned into an expression vector, the expression vector introduced into a host cell, and the variant protein expressed in the host cell. The variant protein can then be isolated from the cells by any appropriate purification scheme using standard protein purification techniques. Examples of these techniques are described in detail below. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).

The present invention provides isolated variant proteins that comprise, consist of or consist essentially of amino acid sequences that contain one or more variant amino acids encoded by one or more codons that contain a SNP of the present invention. Accordingly, the present invention provides variant proteins that consist of amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein consists of an amino acid sequence when the amino acid sequence is the entire amino acid sequence of the protein.

The present invention further provides variant proteins that consist essentially of amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein consists essentially of an amino acid sequence when such an amino acid sequence is present with only a few additional amino acid residues in the final protein.

The present invention further provides variant proteins that comprise amino acid sequences that contain one or more amino acid polymorphisms (or truncations or extensions due to creation or destruction of a stop codon, respectively) encoded by the SNPs provided in Table 1 and/or Table 2. A protein comprises an amino acid sequence when the amino acid sequence is at least part of the final amino acid sequence of the protein. In such a fashion, the protein may contain only the variant amino acid sequence or have additional amino acid residues, such as a contiguous encoded sequence that is naturally associated with it or heterologous amino acid residues. Such a protein can have a few additional amino acid residues or can comprise many more additional amino acids. A brief description of how various types of these proteins can be made and isolated is provided below.

The variant proteins of the present invention can be attached to heterologous sequences to form chimeric or fusion proteins. Such chimeric and fusion proteins comprise a variant protein operatively linked to a heterologous protein having an amino acid sequence not substantially homologous to the variant protein.

"Operatively linked" indicates that the coding sequences for the variant protein and the heterologous protein are ligated in-frame. The heterologous protein can be fused to the N-terminus or C-terminus of the variant protein. In another embodiment, the fusion protein is encoded by a fusion polynucleotide that is synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and re-amplified to generate a chimeric gene sequence. See Ausubel et al , Current Protocols in Molecular Biology (1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety {e.g. , a GST protein). A variant protein-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the variant protein.

In many uses, the fusion protein does not affect the activity of the variant protein. The fusion protein can include, but is not limited to, enzymatic fusion proteins, for example, beta-galactosidase fusions, yeast two-hybrid GAL fusions, poly-His fusions, MYC-tagged, HI-tagged and Ig fusions. Such fusion proteins, particularly poly-His fusions, can facilitate their purification following recombinant expression. In certain host cells {e.g., mammalian host cells), expression and/or secretion of a protein can be increased by using a heterologous signal sequence. Fusion proteins are further described in, for example, Terpe, "Overview of tag protein fusions: from molecular and biochemical fundamentals to commercial systems," Appl Microbiol Biotechnol

60(5):523-33 (Jan. 2003); Epub Nov. 07, 2002; Graddis et al, "Designing proteins that work using recombinant technologies," Curr Pharm Biotechnol 3(4):285-97 (Dec. 2002); and Nilsson et al. , "Affinity fusion strategies for detection, purification, and immobilization of recombinant proteins," Protein Expr Purif 11(1): 1-16 (Oct. 1997).

In certain embodiments, novel compositions of the present invention also relate to further obvious variants of the variant polypeptides of the present invention, such as naturally-occurring mature forms {e.g., allelic variants), non-naturally occurring recombinantly-derived variants, and orthologs and paralogs of such proteins that share sequence homology. Such variants can readily be generated using art-known techniques in the fields of recombinant nucleic acid technology and protein biochemistry.

Further variants of the variant polypeptides disclosed in Table 1 can comprise an amino acid sequence that shares at least 70-80%, 80-85%, 85-90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence disclosed in Table 1 (or a fragment thereof) and that includes a novel amino acid residue (allele) disclosed in Table 1 (which is encoded by a novel SNP allele). Thus, an aspect of the present invention that is specifically contemplated are polypeptides that have a certain degree of sequence variation compared with the polypeptide sequences shown in Table 1 , but that contain a novel amino acid residue (allele) encoded by a novel SNP allele disclosed herein. In other words, as long as a polypeptide contains a novel amino acid residue disclosed herein, other portions of the polypeptide that flank the novel amino acid residue can vary to some degree from the polypeptide sequences shown in Table 1.

Full-length pre-processed forms, as well as mature processed forms, of proteins that comprise one of the amino acid sequences disclosed herein can readily be identified as having complete sequence identity to one of the variant proteins of the present invention as well as being encoded by the same genetic locus as the variant proteins provided herein.

Orthologs of a variant peptide can readily be identified as having some degree of significant sequence homology/identity to at least a portion of a variant peptide as well as being encoded by a gene from another organism. Preferred orthologs will be isolated from non-human mammals, preferably primates, for the development of human therapeutic targets and agents. Such orthologs can be encoded by a nucleic acid sequence that hybridizes to a variant peptide-encoding nucleic acid molecule under moderate to stringent conditions depending on the degree of relatedness of the two organisms yielding the homologous proteins.

Variant proteins include, but are not limited to, proteins containing deletions, additions and substitutions in the amino acid sequence caused by the SNPs of the present invention. One class of substitutions is conserved amino acid substitutions in which a given amino acid in a polypeptide is substituted for another amino acid of like characteristics. Typical conservative substitutions are replacements, one for another, among the aliphatic amino acids Ala, Val, Leu, and He; interchange of the hydroxyl residues Ser and Thr; exchange of the acidic residues Asp and Glu; substitution between the amide residues Asn and Gin; exchange of the basic residues Lys and Arg; and replacements among the aromatic residues Phe and Tyr. Guidance concerning which amino acid changes are likely to be phenotypically silent are found, for example, in Bowie et al, Science 247:1306-1310 (1990).

Variant proteins can be fully functional or can lack function in one or more activities, e.g. ability to bind another molecule, ability to catalyze a substrate, ability to mediate signaling, etc. Fully functional variants typically contain only

conservative variations or variations in non-critical residues or in non-critical regions. Functional variants can also contain substitution of similar amino acids that result in no change or an insignificant change in function. Alternatively, such substitutions may positively or negatively affect function to some degree. Non-functional variants typically contain one or more non-conservative amino acid substitutions, deletions, insertions, inversions, truncations or extensions, or a substitution, insertion, inversion, or deletion of a critical residue or in a critical region.

Amino acids that are essential for function of a protein can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis, particularly using the amino acid sequence and polymorphism information provided in Table 1. Cunningham et al, Science 244:1081-1085 (1989). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity such as enzyme activity or in assays such as an in vitro proliferative activity. Sites that are critical for binding partner/substrate binding can also be determined by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling. Smith et al, J Mol Biol 224:899-904 (1992); de Vos et al, Science 255:306-312 (1992).

Polypeptides can contain amino acids other than the 20 amino acids commonly referred to as the 20 naturally occurring amino acids. Further, many amino acids, including the terminal amino acids, may be modified by natural processes, such as processing and other post-translational modifications, or by chemical modification techniques well known in the art. Accordingly, the variant proteins of the present invention also encompass derivatives or analogs in which a substituted amino acid residue is not one encoded by the genetic code, in which a substituent group is included, in which the mature polypeptide is fused with another compound, such as a compound to increase the half-life of the polypeptide {e.g., polyethylene glycol), or in which additional amino acids are fused to the mature polypeptide, such as a leader or secretory sequence or a sequence for purification of the mature polypeptide or a pro-protein sequence.

Known protein modifications include, but are not limited to, acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation,

demethylation, formation of covalent crosslinks, formation of cystine, formation of pyroglutamate, fonnylation, gamma carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination.

Such protein modifications are well known to those of skill in the art and have been described in great detail in the scientific literature. Particularly common modifications, for example glycosylation, lipid attachment, sulfation, gamma- carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation, are described in most basic texts, such as Proteins - Structure and Molecular Properties 2nd Ed., T.E. Creighton, W.H. Freeman and Company, N.Y. (1993); F. Wold,

Posttranslational Covalent Modification of Proteins 1-12, B.C. Johnson, ed., Academic Press, N.Y. (1983); Seifter et al, Meth Enzymol 182:626-646 (1990); and Rattan et al , Ann NY Acad Sci 663:48-62 (1992).

The present invention further provides fragments of the variant proteins in which the fragments contain one or more amino acid sequence variations (e.g. , substitutions, or truncations or extensions due to creation or destruction of a stop codon) encoded by one or more SNPs disclosed herein. The fragments to which the invention pertains, however, are not to be construed as encompassing fragments that have been disclosed in the prior art before the present invention.

As used herein, a fragment may comprise at least about 4, 8, 10, 12, 14, 16, 18, 20, 25, 30, 50, 100 (or any other number in-between) or more contiguous amino acid residues from a variant protein, wherein at least one amino acid residue is affected by a SNP of the present invention, e.g. , a variant amino acid residue encoded by a nonsynonymous nucleotide substitution at a cSNP position provided by the present invention. The variant amino acid encoded by a cSNP may occupy any residue position along the sequence of the fragment. Such fragments can be chosen based on the ability to retain one or more of the biological activities of the variant protein or the ability to perform a function, e.g. , act as an immunogen. Particularly important fragments are biologically active fragments. Such fragments will typically comprise a domain or motif of a variant protein of the present invention, e.g. , active site, transmembrane domain, or ligand/substrate binding domain. Other fragments include, but are not limited to, domain or motif-containing fragments, soluble peptide fragments, and fragments containing immunogenic structures. Predicted domains and functional sites are readily identifiable by computer programs well known to those of skill in the art (e.g., PROSITE analysis). Current Protocols in Protein Science, John Wiley & Sons, N.Y. (2002). Uses of Variant Proteins

The variant proteins of the present invention can be used in a variety of ways, including but not limited to, in assays to determine the biological activity of a variant protein, such as in a panel of multiple proteins for high-throughput screening; to raise antibodies or to elicit another type of immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the variant protein (or its binding partner) in biological fluids; as a marker for cells or tissues in which it is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disorder state); as a target for screening for a therapeutic agent; and as a direct therapeutic agent to be administered into a human subject. Any of the variant proteins disclosed herein may be developed into reagent grade or kit format for commercialization as research products. Methods for performing the uses listed above are well known to those skilled in the art. See, e.g. , Molecular Cloning: A Laboratory Manual, Sambrook and Russell, Cold Spring Harbor Laboratory Press, N.Y. (2000), and Methods in Enzymology: Guide to

Molecular Cloning Techniques, S.L. Berger and A.R. Kimmel, eds., Academic Press (1987).

In a specific embodiment of the invention, the methods of the present invention include detection of one or more variant proteins disclosed herein. Variant proteins are disclosed in Table 1 and in the Sequence Listing as SEQ ID NOS:40-78. Detection of such proteins can be accomplished using, for example, antibodies, small molecule compounds, aptamers, ligands/substrates, other proteins or protein fragments, or other protein-binding agents. Preferably, protein detection agents are specific for a variant protein of the present invention and can therefore discriminate between a variant protein of the present invention and the wild-type protein or another variant form. This can generally be accomplished by, for example, selecting or designing detection agents that bind to the region of a protein that differs between the variant and wild-type protein, such as a region of a protein that contains one or more amino acid substitutions that is/are encoded by a non- synonymous cSNP of the present invention, or a region of a protein that follows a nonsense mutation-type SNP that creates a stop codon thereby leading to a shorter polypeptide, or a region of a protein that follows a read-through mutation-type SNP that destroys a stop codon thereby leading to a longer polypeptide in which a portion of the polypeptide is present in one version of the polypeptide but not the other. In another aspect of the invention, variant proteins of the present invention can be used as targets for diagnosing short stature or for determining predisposition to short stature in a human, for treating and/or preventing short stature, etc. Accordingly, the invention provides methods for detecting the presence of, or levels of, one or more variant proteins of the present invention in a cell, tissue, or organism. Such methods typically involve contacting a test sample with an agent (e.g., an antibody, small molecule compound, or peptide) capable of interacting with the variant protein such that specific binding of the agent to the variant protein can be detected. Such an assay can be provided in a single detection format or a multi-detection format such as an array, for example, an antibody or aptamer array (arrays for protein detection may also be referred to as "protein chips"). The variant protein of interest can be isolated from a test sample and assayed for the presence of a variant amino acid sequence encoded by one or more SNPs disclosed by the present invention. The SNPs may cause changes to the protein and the corresponding protein function/activity, such as through non-synonymous substitutions in protein coding regions that can lead to amino acid substitutions, deletions, insertions, and/or rearrangements; formation or destruction of stop codons; or alteration of control elements such as promoters. SNPs may also cause inappropriate post-translational modifications .

One preferred agent for detecting a variant protein in a sample is an antibody capable of selectively binding to a variant form of the protein (antibodies are described in greater detail in the next section). Such samples include, for example, tissues, cells, and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject.

In vitro methods for detection of the variant proteins associated with short stature that are disclosed herein and fragments thereof include, but are not limited to, enzyme linked immunosorbent assays (ELISAs), radioimmunoassays (RIA), Western blots, immunoprecipitations, immunofluorescence, and protein arrays/chips (e.g., arrays of antibodies or aptamers). For further information regarding immunoassays and related protein detection methods, see Current Protocols in Immunology, John Wiley & Sons, N.Y., and Hage, "Immunoassays," Anal Chem 15;71(12):294R-304R (Jun. 1999).

Additional analytic methods of detecting amino acid variants include, but are not limited to, altered electrophoretic mobility, altered tryptic peptide digest, altered protein activity in cell-based or cell-free assay, alteration in ligand or antibody-binding pattern, altered isoelectric point, and direct amino acid sequencing. Alternatively, variant proteins can be detected in vivo in a subject by introducing into the subject a labeled antibody (or other type of detection reagent) specific for a variant protein. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

Other uses of the variant peptides of the present invention are based on the class or action of the protein. For example, proteins isolated from humans and their mammalian orthologs serve as targets for identifying agents (e.g. , small molecule drugs or antibodies) for use in therapeutic applications, particularly for modulating a biological or pathological response in a cell or tissue that expresses the protein. Pharmaceutical agents can be developed that modulate protein activity.

As an alternative to modulating gene expression, therapeutic compounds can be developed that modulate protein function. For example, many SNPs disclosed herein affect the amino acid sequence of the encoded protein (e.g. , non-synonymous cSNPs and nonsense mutation- type SNPs). Such alterations in the encoded amino acid sequence may affect protein function, particularly if such amino acid sequence variations occur in functional protein domains, such as catalytic domains, ATP-binding domains, or ligand/substrate binding domains. It is well established in the art that variant proteins having amino acid sequence variations in functional domains can cause or influence pathological conditions. In such instances, compounds (e.g. , small molecule drugs or antibodies) can be developed that target the variant protein and modulate (e.g., up- or down-regulate) protein function/activity.

The therapeutic methods of the present invention further include methods that target one or more variant proteins of the present invention. Variant proteins can be targeted using, for example, small molecule compounds, antibodies, aptamers, ligands/substrates, other proteins, or other protein-binding agents. Additionally, the skilled artisan will recognize that the novel protein variants (and polymorphic nucleic acid molecules) disclosed in Table 1 may themselves be directly used as therapeutic agents by acting as competitive inhibitors of corresponding art-known proteins (or nucleic acid molecules such as mRNA molecules).

The variant proteins of the present invention are particularly useful in drug screening assays, in cell-based or cell-free systems. Cell-based systems can utilize cells that naturally express the protein, a biopsy specimen, or cell cultures. In one embodiment, cell-based assays involve recombinant host cells expressing the variant protein. Cell-free assays can be used to detect the ability of a compound to directly bind to a variant protein or to the corresponding SNP-containing nucleic acid fragment that encodes the variant protein.

A variant protein of the present invention, as well as appropriate fragments thereof, can be used in high-throughput screening assays to test candidate compounds for the ability to bind and/or modulate the activity of the variant protein. These candidate compounds can be further screened against a protein having normal function (e.g., a wild-type/non- variant protein) to further determine the effect of the compound on the protein activity. Furthermore, these compounds can be tested in animal or invertebrate systems to determine in vivo activity/effectiveness. Compounds can be identified that activate (agonists) or inactivate (antagonists) the variant protein, and different compounds can be identified that cause various degrees of activation or inactivation of the variant protein.

Further, the variant proteins can be used to screen a compound for the ability to stimulate or inhibit interaction between the variant protein and a target molecule that normally interacts with the protein. The target can be a ligand, a substrate or a binding partner that the protein normally interacts with (for example, epinephrine or

norepinephrine). Such assays typically include the steps of combining the variant protein with a candidate compound under conditions that allow the variant protein, or fragment thereof, to interact with the target molecule, and to detect the formation of a complex between the protein and the target or to detect the biochemical consequence of the interaction with the variant protein and the target, such as any of the associated effects of signal transduction.

Candidate compounds include, for example, 1) peptides such as soluble peptides, including Ig-tailed fusion peptides and members of random peptide libraries (see, e.g. , Lam et al, Nature 354:82-84 (1991); Houghten et al, Nature 354:84-86 (1991)) and combinatorial chemistry-derived molecular libraries made of D- and/or L- configuration amino acids; 2) phosphopeptides (e.g., members of random and partially degenerate, directed phosphopeptide libraries, see, e.g., Songyang et al , Cell 72:767-778 (1993)); 3) antibodies (e.g. , polyclonal, monoclonal, humanized, anti-idiotypic, chimeric, and single chain antibodies as well as Fab, F(ab') ₂ , Fab expression library fragments, and epitope- binding fragments of antibodies); and 4) small organic and inorganic molecules (e.g., molecules obtained from combinatorial and natural product libraries). One candidate compound is a soluble fragment of the variant protein that competes for ligand binding. Other candidate compounds include mutant proteins or appropriate fragments containing mutations that affect variant protein function and thus compete for ligand. Accordingly, a fragment that competes for ligand, for example with a higher affinity, or a fragment that binds ligand but does not allow release, is encompassed by the invention.

The invention further includes other end point assays to identify compounds that modulate (stimulate or inhibit) variant protein activity. The assays typically involve an assay of events in the signal transduction pathway that indicate protein activity. Thus, the expression of genes that are up or down-regulated in response to the variant protein dependent signal cascade can be assayed. In one embodiment, the regulatory region of such genes can be operably linked to a marker that is easily detectable, such as luciferase. Alternatively, phosphorylation of the variant protein, or a variant protein target, could also be measured. Any of the biological or biochemical functions mediated by the variant protein can be used as an endpoint assay. These include all of the biochemical or biological events described herein, in the references cited herein, incorporated by reference for these endpoint assay targets, and other functions known to those of ordinary skill in the art.

Binding and/or activating compounds can also be screened by using chimeric variant proteins in which an amino terminal extracellular domain or parts thereof, an entire transmembrane domain or subregions, and/or the carboxyl terminal intracellular domain or parts thereof, can be replaced by heterologous domains or subregions. For example, a substrate-binding region can be used that interacts with a different substrate than that which is normally recognized by a variant protein. Accordingly, a different set of signal transduction components is available as an end-point assay for activation. This allows for assays to be performed in other than the specific host cell from which the variant protein is derived.

The variant proteins are also useful in competition binding assays in methods designed to discover compounds that interact with the variant protein. Thus, a compound can be exposed to a variant protein under conditions that allow the compound to bind or to otherwise interact with the variant protein. A binding partner, such as ligand, that normally interacts with the variant protein is also added to the mixture. If the test compound interacts with the variant protein or its binding partner, it decreases the amount of complex formed or activity from the variant protein. This type of assay is particularly useful in screening for compounds that interact with specific regions of the variant protein. Hodgson, Bio/technology, 10(9), 973-80 (Sept. 1992).

To perform cell-free drug screening assays, it is sometimes desirable to immobilize either the variant protein or a fragment thereof, or its target molecule, to facilitate separation of complexes from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. Any method for immobilizing proteins on matrices can be used in drug screening assays. In one embodiment, a fusion protein containing an added domain allows the protein to be

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bound to a matrix. For example, glutathione-S-transferase/ I fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, MO) or glutathione derivatized microtitre plates, which are then combined with the cell lysates (e.g. , ³⁵ S-labeled) and a candidate compound, such as a drug candidate, and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads can be washed to remove any unbound label, and the matrix immobilized and radiolabel determined directly, or in the supernatant after the complexes are dissociated. Alternatively, the complexes can be dissociated from the matrix, separated by SDS-PAGE, and the level of bound material found in the bead fraction quantitated from the gel using standard electrophoretic techniques.

Either the variant protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Alternatively, antibodies reactive with the variant protein but which do not interfere with binding of the variant protein to its target molecule can be derivatized to the wells of the plate, and the variant protein trapped in the wells by antibody conjugation. Preparations of the target molecule and a candidate compound are incubated in the variant protein-presenting wells and the amount of complex trapped in the well can be quantitated. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the protein target molecule, or which are reactive with variant protein and compete with the target molecule, and enzyme-linked assays that rely on detecting an enzymatic activity associated with the target molecule.

Modulators of variant protein activity identified according to these drug screening assays can be used to treat a subject with a disorder mediated by the protein pathway, such as short stature. These methods of treatment typically include the steps of administering the modulators of protein activity in a pharmaceutical composition to a subject in need of such treatment.

The variant proteins, or fragments thereof, disclosed herein can themselves be directly used to treat a disorder characterized by an absence of, inappropriate, or unwanted expression or activity of the variant protein. Accordingly, methods for treatment include the use of a variant protein disclosed herein or fragments thereof.

In yet another aspect of the invention, variant proteins can be used as "bait proteins" in a two-hybrid assay or three-hybrid assay to identify other proteins that bind to or interact with the variant protein and are involved in variant protein activity. See, e.g., U.S. Patent No. 5,283,317; Zervos et al, Cell 72:223-232 (1993); Madura et al, J Biol Chem 268: 12046-12054 (1993); Bartel et al, Biotechniques 14:920-924 (1993); Iwabuchi et al, Oncogene 8:1693-1696 (1993); and Brent, WO 94/10300. Such variant protein-binding proteins are also likely to be involved in the propagation of signals by the variant proteins or variant protein targets as, for example, elements of a protein- mediated signaling pathway. Alternatively, such variant protein-binding proteins are inhibitors of the variant protein.

The two-hybrid system is based on the modular nature of most transcription factors, which typically consist of separable DNA-binding and activation domains. Briefly, the assay typically utilizes two different DNA constructs. In one construct, the gene that codes for a variant protein is fused to a gene encoding the DNA binding domain of a known transcription factor {e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein ("prey" or "sample") is fused to a gene that codes for the activation domain of the known transcription factor. If the "bait" and the "prey" proteins are able to interact, in vivo, forming a variant protein-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene {e.g., LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected, and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein that interacts with the variant protein. Antibodies Directed to Variant Proteins

The present invention also provides antibodies that selectively bind to the variant proteins disclosed herein and fragments thereof. Such antibodies may be used to quantitatively or qualitatively detect the variant proteins of the present invention. As used herein, an antibody selectively binds a target variant protein when it binds the variant protein and does not significantly bind to non- variant proteins, i.e. , the antibody does not significantly bind to normal, wild-type, or art-known proteins that do not contain a variant amino acid sequence due to one or more SNPs of the present invention (variant amino acid sequences may be due to, for example, nonsynonymous cSNPs, nonsense SNPs that create a stop codon, thereby causing a truncation of a polypeptide or SNPs that cause read-through mutations resulting in an extension of a polypeptide).

As used herein, an antibody is defined in terms consistent with that recognized in the art: they are multi-subunit proteins produced by an organism in response to an antigen challenge. The antibodies of the present invention include both monoclonal antibodies and polyclonal antibodies, as well as antigen-reactive proteolytic fragments of such antibodies, such as Fab, F(ab)' ₂ , and Fv fragments. In addition, an antibody of the present invention further includes any of a variety of engineered antigen-binding molecules such as a chimeric antibody (U.S. Patent Nos. 4,816,567 and 4,816,397; Morrison et al, Proc Natl Acad Sci USA 81 :6851 (1984); Neuberger et al., Nature 312:604 (1984)), a humanized antibody (U.S. Patent Nos. 5,693,762; 5,585,089 and 5,565,332), a single-chain Fv (U.S. Patent No. 4,946,778; Ward et al., Nature 334:544 (1989)), a bispecific antibody with two binding specificities (Segal et al, J Immunol Methods 248:1 (2001); Carter, J Immunol Method 248:7 (2001)), a diabody, a triabody, and a tetrabody (Todorovska et al, J Immunol Methods 248:47 (2001)), as well as a Fab conjugate (dimer or trimer), and a minibody.

Many methods are known in the art for generating and/or identifying antibodies to a given target antigen. Harlow, Antibodies, Cold Spring Harbor Press, N.Y. (1989). In general, an isolated peptide (e.g., a variant protein of the present invention) is used as an immunogen and is administered to a mammalian organism, such as a rat, rabbit, hamster or mouse. Either a full-length protein, an antigenic peptide fragment (e.g. , a peptide fragment containing a region that varies between a variant protein and a corresponding wild-type protein), or a fusion protein can be used. A protein used as an immunogen may be naturally-occurring, synthetic or recombinantly produced, and may be administered in combination with an adjuvant, including but not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substance such as lysolecithin, pluronic polyols, poly anions, peptides, oil emulsions, keyhole limpet hemocyanin, dinitrophenol, and the like.

Monoclonal antibodies can be produced by hybridoma technology, which immortalizes cells secreting a specific monoclonal antibody. Kohler and Milstein, Nature 256:495 (1975). The immortalized cell lines can be created in vitro by fusing two different cell types, typically lymphocytes, and tumor cells. The hybridoma cells may be cultivated in vitro or in vivo. Additionally, fully human antibodies can be generated by transgenic animals. He et al , J Immunol 169:595 (2002). Fd phage and Fd phagemid technologies may be used to generate and select recombinant antibodies in vitro. Hoogenboom and Chames, Immunol Today 21 :371 (2000); Liu et al., J Mol Biol 315: 1063 (2002). The complementarity-determining regions of an antibody can be identified, and synthetic peptides corresponding to such regions may be used to mediate antigen binding. U.S. Patent No. 5,637,677.

Antibodies are preferably prepared against regions or discrete fragments of a variant protein containing a variant amino acid sequence as compared to the corresponding wild-type protein (e.g., a region of a variant protein that includes an amino acid encoded by a nonsynonymous cSNP, a region affected by truncation caused by a nonsense SNP that creates a stop codon, or a region resulting from the destruction of a stop codon due to read- through mutation caused by a SNP).

Furthermore, preferred regions will include those involved in function/activity and/or protein/binding partner interaction. Such fragments can be selected on a physical property, such as fragments corresponding to regions that are located on the surface of the protein, e.g., hydrophilic regions, or can be selected based on sequence uniqueness, or based on the position of the variant amino acid residue(s) encoded by the SNPs provided by the present invention. An antigenic fragment will typically comprise at least about 8-10 contiguous amino acid residues in which at least one of the amino acid residues is an amino acid affected by a SNP disclosed herein. The antigenic peptide can comprise, however, at least 12, 14, 16, 20, 25, 50, 100 (or any other number in-between) or more amino acid residues, provided that at least one amino acid is affected by a SNP disclosed herein.

Detection of an antibody of the present invention can be facilitated by coupling (i.e. , physically linking) the antibody or an antigen-reactive fragment thereof to a detectable substance. Detectable substances include, but are not limited to, various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin;

examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and

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examples of suitable radioactive material include I, I, S or H.

Antibodies, particularly the use of antibodies as therapeutic agents, are reviewed in: Morgan, "Antibody therapy for Alzheimer's disease," Expert Rev Vaccines (l):53-9 (Feb. 2003); Ross et al, "Anticancer antibodies," Am J Clin Pathol 119(4):472-85 (Apr. 2003); Goldenberg, "Advancing role of radiolabeled antibodies in the therapy of cancer," Cancer Immunol Immunother 52(5):281-96 (May 2003); Epub Mar. 11, 2003; Ross et al , "Antibody-based therapeutics in oncology," Expert Rev Anticancer Ther 3(1): 107-21 (Feb. 2003); Cao et al., "Bispecific antibody conjugates in therapeutics," Adv Drug Deliv Rev 55(2): 171-97 (Feb. 2003); von Mehren et al. , "Monoclonal antibody therapy for cancer," Annu Rev Med 54:343-69 (2003); Epub Dec. 3, 2001 ; Hudson et al. , "Engineered antibodies," Nat Med 9(1): 129-34 (Jan. 2003); Brekke et al. , "Therapeutic antibodies for human diseases at the dawn of the twenty-first century," Nat Rev Drug Discov 2(l):52-62 (Jan. 2003); Erratum in: Nat Rev Drug Discov 2(3):240 (Mar. 2003); Houdebine, "Antibody manufacture in transgenic animals and comparisons with other systems," Curr Opin Biotechnol 13(6):625-9 (Dec. 2002); Andreakos et al., "Monoclonal antibodies in immune and inflammatory diseases," Curr Opin Biotechnol 13(6):615-20 (Dec. 2002); Kellermann et al. , "Antibody discovery: the use of transgenic mice to generate human monoclonal antibodies for therapeutics," Curr Opin Biotechnol 13(6):593-7 (Dec. 2002); Pini et al., "Phage display and colony filter screening for high- throughput selection of antibody libraries," Comb Chem High Throughput Screen 5(7):503-10 (Nov. 2002); Batra et al., "Pharmacokinetics and biodistribution of genetically engineered antibodies," Curr Opin Biotechnol 13(6):603-8 (Dec. 2002); and Tangri et al. , "Rationally engineered proteins or antibodies with absent or reduced immunogenicity," Curr Med Chem 9(24):2191-9 (Dec. 2002). Uses of Antibodies

Antibodies can be used to isolate the variant proteins of the present invention from a natural cell source or from recombinant host cells by standard techniques, such as affinity chromatography or immunoprecipitation. In addition, antibodies are useful for detecting the presence of a variant protein of the present invention in cells or tissues to determine the pattern of expression of the variant protein among various tissues in an organism and over the course of normal development or disorder progression. Further, antibodies can be used to detect variant protein in situ, in vitro, in a bodily fluid, or in a cell lysate or supernatant in order to evaluate the amount and pattern of expression. Also, antibodies can be used to assess abnormal tissue distribution, abnormal expression during development, or expression in an abnormal condition, such as in short stature. Additionally, antibody detection of circulating fragments of the full-length variant protein can be used to identify turnover.

Antibodies to the variant proteins of the present invention are also useful in pharmacogenomic analysis. Thus, antibodies against variant proteins encoded by alternative SNP alleles can be used to identify individuals that require modified treatment modalities.

Further, antibodies can be used to assess expression of the variant protein in a disorder or in an individual with a predisposition to a disorder related to the protein's function, such as short stature, or during the course of a treatment regime. Antibodies specific for a variant protein encoded by a SNP-containing nucleic acid molecule of the present invention can be used to assay for the presence of the variant protein, such as to diagnose short stature or to predict an individual's predisposition/susceptibility to short stature, as indicated by the presence of the variant protein.

Antibodies are also useful as diagnostic tools for evaluating the variant proteins in conjunction with analysis by electrophoretic mobility, isoelectric point, tryptic peptide digest, and other physical assays well known in the art.

Antibodies are also useful for tissue typing. Thus, where a specific variant protein has been correlated with expression in a specific tissue, antibodies that are specific for this protein can be used to identify a tissue type.

Antibodies can also be used to assess aberrant subcellular localization of a variant protein in cells in various tissues. The diagnostic uses can be applied, not only in genetic testing, but also in monitoring a treatment modality. Accordingly, where treatment is ultimately aimed at correcting the expression level or the presence of variant protein or aberrant tissue distribution or developmental expression of a variant protein, antibodies directed against the variant protein or relevant fragments can be used to monitor therapeutic efficacy.

The antibodies are also useful for inhibiting variant protein function, for example, by blocking the binding of a variant protein to a binding partner. These uses can also be applied in a therapeutic context in which treatment involves inhibiting a variant protein's function. An antibody can be used, for example, to block or competitively inhibit binding, thus modulating (agonizing or antagonizing) the activity of a variant protein. Antibodies can be prepared against specific variant protein fragments containing sites required for function or against an intact variant protein that is associated with a cell or cell membrane. For in vivo administration, an antibody may be linked with an additional therapeutic payload such as a radionuclide, an enzyme, an immunogenic epitope, or a cytotoxic agent. Suitable cytotoxic agents include, but are not limited to, bacterial toxin such as diphtheria, and plant toxin such as ricin. The in vivo half-life of an antibody or a fragment thereof may be lengthened by pegylation through conjugation to polyethylene glycol. Leong et al, Cytokine 16:106 (2001).

The invention also encompasses kits for using antibodies, such as kits for detecting the presence of a variant protein in a test sample. An exemplary kit can comprise antibodies such as a labeled or labelable antibody and a compound or agent for detecting variant proteins in a biological sample; means for determining the amount, or presence/absence of variant protein in the sample; means for comparing the amount of variant protein in the sample with a standard; and instructions for use.

Vectors and Host Cells

The present invention also provides vectors containing the SNP-containing nucleic acid molecules described herein. The term "vector" refers to a vehicle, preferably a nucleic acid molecule, which can transport a SNP-containing nucleic acid molecule. When the vector is a nucleic acid molecule, the SNP-containing nucleic acid molecule can be covalently linked to the vector nucleic acid. Such vectors include, but are not limited to, a plasmid, single or double stranded phage, a single or double stranded RNA or DNA viral vector, or artificial chromosome, such as a BAC, PAC, YAC, or MAC.

A vector can be maintained in a host cell as an extrachromosomal element where it replicates and produces additional copies of the SNP-containing nucleic acid molecules. Alternatively, the vector may integrate into the host cell genome and produce additional copies of the SNP-containing nucleic acid molecules when the host cell replicates.

The invention provides vectors for the maintenance (cloning vectors) or vectors for expression (expression vectors) of the SNP-containing nucleic acid molecules. The vectors can function in prokaryotic or eukaryotic cells or in both (shuttle vectors).

Expression vectors typically contain cis-acting regulatory regions that are operably linked in the vector to the SNP-containing nucleic acid molecules such that transcription of the SNP-containing nucleic acid molecules is allowed in a host cell. The SNP-containing nucleic acid molecules can also be introduced into the host cell with a separate nucleic acid molecule capable of affecting transcription. Thus, the second nucleic acid molecule may provide a trans-acting factor interacting with the cis- regulatory control region to allow transcription of the SNP-containing nucleic acid molecules from the vector. Alternatively, a trans-acting factor may be supplied by the host cell. Finally, a trans-acting factor can be produced from the vector itself. It is understood, however, that in some embodiments, transcription and/or translation of the nucleic acid molecules can occur in a cell-free system.

The regulatory sequences to which the SNP-containing nucleic acid molecules described herein can be operably linked include promoters for directing mRNA transcription. These include, but are not limited to, the left promoter from bacteriophage λ, the lac, TRP, and TAC promoters from E. coli, the early and late promoters from SV40, the CMV immediate early promoter, the adenovirus early and late promoters, and retrovirus long-terminal repeats.

In addition to control regions that promote transcription, expression vectors may also include regions that modulate transcription, such as repressor binding sites and enhancers. Examples include the SV40 enhancer, the cytomegalovirus immediate early enhancer, polyoma enhancer, adenovirus enhancers, and retrovirus LTR enhancers.

In addition to containing sites for transcription initiation and control, expression vectors can also contain sequences necessary for transcription termination and, in the transcribed region, a ribosome-binding site for translation. Other regulatory control elements for expression include initiation and termination codons as well as polyadenylation signals. A person of ordinary skill in the art would be aware of the numerous regulatory sequences that are useful in expression vectors. See, e.g., Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).

A variety of expression vectors can be used to express a SNP-containing nucleic acid molecule. Such vectors include chromosomal, episomal, and virus-derived vectors, for example, vectors derived from bacterial plasmids, from bacteriophage, from yeast episomes, from yeast chromosomal elements, including yeast artificial chromosomes, from viruses such as baculoviruses, papovaviruses such as SV40, Vaccinia viruses, adenoviruses, poxviruses, pseudorabies viruses, and retroviruses. Vectors can also be derived from combinations of these sources such as those derived from plasmid and bacteriophage genetic elements, e.g., cosmids and phagemids. Appropriate cloning and expression vectors for prokaryotic and eukaryotic hosts are described in Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).

The regulatory sequence in a vector may provide constitutive expression in one or more host cells (e.g. , tissue specific expression) or may provide for inducible expression in one or more cell types such as by temperature, nutrient additive, or exogenous factor, e.g., a hormone or other ligand. A variety of vectors that provide constitutive or inducible expression of a nucleic acid sequence in prokaryotic and eukaryotic host cells are well known to those of ordinary skill in the art.

A SNP-containing nucleic acid molecule can be inserted into the vector by methodology well-known in the art. Generally, the SNP-containing nucleic acid molecule that will ultimately be expressed is joined to an expression vector by cleaving the SNP-containing nucleic acid molecule and the expression vector with one or more restriction enzymes and then ligating the fragments together. Procedures for restriction enzyme digestion and ligation are well known to those of ordinary skill in the art.

The vector containing the appropriate nucleic acid molecule can be introduced into an appropriate host cell for propagation or expression using well-known techniques. Bacterial host cells include, but are not limited to, Escherichia coli, Streptomyces spp. , and Salmonella typhimurium. Eukaryotic host cells include, but are not limited to, yeast, insect cells such as Drosophila spp. , animal cells such as COS and CHO cells, and plant cells.

As described herein, it may be desirable to express the variant peptide as a fusion protein. Accordingly, the invention provides fusion vectors that allow for the production of the variant peptides. Fusion vectors can, for example, increase the expression of a recombinant protein, increase the solubility of the recombinant protein, and aid in the purification of the protein by acting, for example, as a ligand for affinity purification. A proteolytic cleavage site may be introduced at the junction of the fusion moiety so that the desired variant peptide can ultimately be separated from the fusion moiety.

Proteolytic enzymes suitable for such use include, but are not limited to, factor Xa, thrombin, and enterokinase. Typical fusion expression vectors include pGEX (Smith et al, Gene 67:31-40 (1988)), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein. Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amann et al. , Gene 69:301-315 (1988)) and pET l id (Studier et al. , Gene Expression Technology: Methods in Enzymology 185:60-89 (1990)).

Recombinant protein expression can be maximized in a bacterial host by providing a genetic background wherein the host cell has an impaired capacity to proteolytically cleave the recombinant protein (S. Gottesman, Gene Expression

Technology: Methods in Enzymology 185:119-128, Academic Press, Calif. (1990)). Alternatively, the sequence of the SNP-containing nucleic acid molecule of interest can be altered to provide preferential codon usage for a specific host cell, for example, E. coli. Wada et al., Nucleic Acids Res 20:2111-2118 (1992).

The SNP-containing nucleic acid molecules can also be expressed by expression vectors that are operative in yeast. Examples of vectors for expression in yeast (e.g., S. cerevisiae) include pYepSecl (Baldari et al. , EMBO J 6:229-234 (1987)), pMFa (Kurjan et al , Cell 30:933-943 (1982)), pJRY88 (Schultz et al. , Gene 54:113-123 (1987)), and pYES2 (Invitrogen Corporation, San Diego, Calif.).

The SNP-containing nucleic acid molecules can also be expressed in insect cells using, for example, baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g. , Sf 9 cells) include the pAc series (Smith et al. , Mol Cell Biol 3:2156-2165 (1983)) and the pVL series (Lucklow et al. , Virology 170:31-39 (1989)).

In certain embodiments of the invention, the SNP-containing nucleic acid molecules described herein are expressed in mammalian cells using mammalian expression vectors. Examples of mammalian expression vectors include pCDM8 (B. Seed, Nature 329:840(1987)) and pMT2PC (Kaufman et al, EMBO J 6:187-195 (1987)). The invention also encompasses vectors in which the SNP-containing nucleic acid molecules described herein are cloned into the vector in reverse orientation, but operably linked to a regulatory sequence that permits transcription of antisense RNA. Thus, an antisense transcript can be produced to the SNP-containing nucleic acid sequences described herein, including both coding and non-coding regions. Expression of this antisense RNA is subject to each of the parameters described above in relation to expression of the sense RNA (regulatory sequences, constitutive or inducible expression, tissue- specific expression).

The invention also relates to recombinant host cells containing the vectors described herein. Host cells therefore include, for example, prokaryotic cells, lower eukaryotic cells such as yeast, other eukaryotic cells such as insect cells, and higher eukaryotic cells such as mammalian cells.

The recombinant host cells can be prepared by introducing the vector constructs described herein into the cells by techniques readily available to persons of ordinary skill in the art. These include, but are not limited to, calcium phosphate transfection, DEAE- dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, lipofection, and other techniques such as those described in Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, N.Y. (2000).

Host cells can contain more than one vector. Thus, different SNP-containing nucleotide sequences can be introduced in different vectors into the same cell. Similarly, the SNP-containing nucleic acid molecules can be introduced either alone or with other nucleic acid molecules that are not related to the SNP-containing nucleic acid molecules, such as those providing trans-acting factors for expression vectors. When more than one vector is introduced into a cell, the vectors can be introduced independently, co- introduced, or joined to the nucleic acid molecule vector.

In the case of bacteriophage and viral vectors, these can be introduced into cells as packaged or encapsulated virus by standard procedures for infection and transduction. Viral vectors can be replication-competent or replication-defective. In the case in which viral replication is defective, replication can occur in host cells that provide functions that complement the defects.

Vectors generally include selectable markers that enable the selection of the subpopulation of cells that contain the recombinant vector constructs. The marker can be inserted in the same vector that contains the SNP-containing nucleic acid molecules described herein or may be in a separate vector. Markers include, for example, tetracycline or ampicillin-resistance genes for prokaryotic host cells, and dihydrofolate reductase or neomycin resistance genes for eukaryotic host cells. However, any marker that provides selection for a phenotypic trait can be effective.

While the mature variant proteins can be produced in bacteria, yeast, mammalian cells, and other cells under the control of the appropriate regulatory sequences, cell-free transcription and translation systems can also be used to produce these variant proteins using RNA derived from the DNA constructs described herein.

Where secretion of the variant protein is desired, which is difficult to achieve with multi-transmembrane domain containing proteins such as G-protein-coupled receptors (GPCRs), appropriate secretion signals can be incorporated into the vector. The signal sequence can be endogenous to the peptides or heterologous to these peptides.

Where the variant protein is not secreted into the medium, the protein can be isolated from the host cell by standard disruption procedures, including freeze/thaw, sonication, mechanical disruption, use of lysing agents, and the like. The variant protein can then be recovered and purified by well-known purification methods including, for example, ammonium sulfate precipitation, acid extraction, anion or cationic exchange chromatography, phosphocellulose chromatography, hydrophobic-interaction chromatography, affinity chromatography, hydroxylapatite chromatography, lectin chromatography, or high performance liquid chromatography.

It is also understood that, depending upon the host cell in which recombinant production of the variant proteins described herein occurs, they can have various glycosylation patterns, or may be non-glycosylated, as when produced in bacteria. In addition, the variant proteins may include an initial modified methionine in some cases as a result of a host-mediated process.

For further information regarding vectors and host cells, see Current Protocols in Molecular Biology, John Wiley & Sons, N.Y.

Uses of Vectors and Host Cells, and Transgenic Animals

Recombinant host cells that express the variant proteins described herein have a variety of uses. For example, the cells are useful for producing a variant protein that can be further purified into a preparation of desired amounts of the variant protein or fragments thereof. Thus, host cells containing expression vectors are useful for variant protein production. Host cells are also useful for conducting cell-based assays involving the variant protein or variant protein fragments, such as those described above as well as other formats known in the art. Thus, a recombinant host cell expressing a variant protein is useful for assaying compounds that stimulate or inhibit variant protein function. Such an ability of a compound to modulate variant protein function may not be apparent from assays of the compound on the native/wild-type protein, or from cell-free assays of the compound. Recombinant host cells are also useful for assaying functional alterations in the variant proteins as compared with a known function.

Genetically-engineered host cells can be further used to produce non-human transgenic animals. A transgenic animal is preferably a non-human mammal, for example, a rodent, such as a rat or mouse, in which one or more of the cells of the animal include a transgene. A transgene is exogenous DNA containing a SNP of the present invention which is integrated into the genome of a cell from which a transgenic animal develops and which remains in the genome of the mature animal in one or more of its cell types or tissues. Such animals are useful for studying the function of a variant protein in vivo, and identifying and evaluating modulators of variant protein activity. Other examples of transgenic animals include, but are not limited to, non-human primates, sheep, dogs, cows, goats, chickens, and amphibians. Transgenic non-human mammals such as cows and goats can be used to produce variant proteins which can be secreted in the animal' s milk and then recovered.

A transgenic animal can be produced by introducing a SNP-containing nucleic acid molecule into the male pronuclei of a fertilized oocyte, e.g., by microinjection or retroviral infection, and allowing the oocyte to develop in a pseudopregnant female foster animal. Any nucleic acid molecules that contain one or more SNPs of the present invention can potentially be introduced as a transgene into the genome of a non-human animal.

Any of the regulatory or other sequences useful in expression vectors can form part of the transgenic sequence. This includes intronic sequences and polyadenylation signals, if not already included. A tissue-specific regulatory sequence(s) can be operably linked to the transgene to direct expression of the variant protein in particular cells or tissues.

Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Patent Nos. 4,736,866 and 4,870,009, both by Leder et al. ; U.S. Patent No. 4,873,191 by Wagner et al. , and in B. Hogan, Manipulating the Mouse Embryo, Cold Spring Harbor Laboratory Press, N.Y. (1986). Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the transgene in its genome and/or expression of transgenic mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene can further be bred to other transgenic animals carrying other transgenes. A transgenic animal also includes a non-human animal in which the entire animal or tissues in the animal have been produced using the homologously recombinant host cells described herein.

In another embodiment, transgenic non-human animals can be produced which contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage PI. Lakso et al., PNAS 89:6232-6236 (1992). Another example of a recombinase system is the FLP recombinase system of S. cerevisiae. O'Gorman et al, Science 251: 1351-1355 (1991). If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are generally needed. Such animals can be provided through the construction of "double" transgenic animals, e.g. , by mating two transgenic animals, one containing a transgene encoding a selected variant protein and the other containing a transgene encoding a recombinase.

Clones of the non-human transgenic animals described herein can also be produced according to the methods described, for example, in I. Wilmut et al. , Nature 385:810-813 (1997) and PCT International Publication Nos. WO 97/07668 and WO 97/07669. In brief, a cell (e.g. , a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter G ₀ phase. The quiescent cell can then be fused, e.g. , through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyst and then transferred to pseudopregnant female foster animal. The offspring born of this female foster animal will be a clone of the animal from which the cell (e.g. , a somatic cell) is isolated.

Transgenic animals containing recombinant cells that express the variant proteins described herein are useful for conducting the assays described herein in an in vivo context. Accordingly, the various physiological factors that are present in vivo and that could influence ligand or substrate binding, variant protein activation, signal transduction, or other processes or interactions, may not be evident from in vitro cell-free or cell-based assays. Thus, non-human transgenic animals of the present invention may be used to assay in vivo variant protein function as well as the activities of a therapeutic agent or compound that modulates variant protein function/activity or expression. Such animals are also suitable for assessing the effects of null mutations (i.e., mutations that substantially or completely eliminate one or more variant protein functions).

For further information regarding transgenic animals, see Houdebine, "Antibody manufacture in transgenic animals and comparisons with other systems," Curr Opin Biotechnol 13(6):625-9 (Dec. 2002); Petters et al , "Transgenic animals as models for human disease," Transgenic Res 9(4-5):347-51, discussion 345-6 (2000); Wolf et al., "Use of transgenic animals in understanding molecular mechanisms of toxicity," J Pharm Pharmacol 50(6):567-74 (Jun. 1998); Echelard, "Recombinant protein production in transgenic animals," Curr Opin Biotechnol 7(5):536-40 (Oct. 1996); Houdebine, "Transgenic animal bioreactors," Transgenic Res 9(4-5):305-20 (2000); Pirity et al. , "Embryonic stem cells, creating transgenic animals," Methods Cell Biol 57:279-93 (1998); and Robl et al., "Artificial chromosome vectors and expression of complex proteins in transgenic animals," Theriogenology 59(1): 107-13 (Jan. 2003). EXAMPLES

The following examples are offered to illustrate, but not limit, the claimed invention.

EXAMPLE 1 : POLYMORPHISMS ASSOCIATED WITH SHORT

STATURE

Overview

The Epigrow study, which is a prospective epidemiological study of insulinlike growth factor- 1 (IGF-1) status in idiopathic short stature (ISS) children conducted in nine European countries, was analyzed to identify genetic polymorphisms that are associated with idiopathic short stature. Short children were included provided they had a normal GH level and no identified cause of short stature (SS). Re-sequencing was performed on 1.35 Mb of genomic DNA (with a focus on exons, exon-intron junctions, and promoter regions) of 232 genes in 263 Epigrow short stature subjects and 263 matched normal controls from the general population, which lead to the identification of 22,052 SNPs and 4,006 single base insertion or deletion polymorphisms (indels). Of these, 21 SNPs from eight genes were below an allelic p- value threshold <10 ^"4 and <20% False Discovery Rate. These eight genes and the corresponding highest odds ratios were ZBTB38 (OR=1.96), PRKAR1B (OR=17.64, the largest effect size in the study), KRAS (OR=2.13), SOS2 (OR=2.13), PRKCH (OR=2.08), BBS4 (OR=2.72), FANCA (OR=1.82), and MAPK1 (OR=2.87). 10 of the 12 SNPs in FANCA and the 2 SNPs in MAPK1 share high LD, and the two most significant SNPs in FANCA share moderate LD. Two SNPs in ZBTB38 (OR=1.96), one indel in NFKB1 (OR=2.32), and one indel in IGF1 (OR=0.33) showed particularly significant association with ISS after applying a stringent Bonferroni multiple testing correction for the 22,052 SNPs and 4,006 indels.

Materials and Methods

Characteristics ofEpigrow study population

The study population included 263 Epigrow short stature subjects and 263 matched normal controls. The 263 Epigrow short stature subjects were children with idiopathic short stature who did not have growth hormone deficiency (GHD) or any other identified cause of short stature and who were not treated with recombinant growth hormone (GH) or IGF-1.

Specific inclusion criteria for the 263 Epigrow short stature subjects were as follows: height at or below -2.5 standard deviations (SD) of population mean height, age > 2 years, peak GH > 7 ng/mL, and pre-pubertal.

Specific exclusion criteria for the 263 Epigrow short stature subjects were as follows: GHD; hypothyroidism, Cushing's, parathyroid hormone (PTH) or vitamin D disorders, or hypogandism; identified syndromes with genetic abnormalities (Turner, Noonan, Russel-Silver); chronic diseases (malnutritian, coeliac disease, chronic inflammation, muscular dystrophy, thalassaemia, blood disorders, severe liver or kidney disease, sever cyanotic heart disease); skeletal dysplasia; psychosocial short stature; patients receiving GH or IGF-1 therapy or having received therapy during the last 12 months; chronic diseases requiring treatment with chronically administered corticosteroids; patients having received irradiation, including total body irradiation; and any mental condition that prevents both parents or legally authorized representatives and the child when applicable from understanding the nature, scope and possible consequences of the study, or any evidence of an uncooperative attitude.

Samples utilized in this analysis

DNA for Epigrow subject was obtained. Additionally, for controls, one milliliter aliquots of whole blood from 500 de-identified individuals were obtained from Berkeley Heart Lab (BHL) (Alameda, CA) and stored at -20°C. DNA was extracted from 900ul of each sample on a Qiagen Symphony SP automated sample preparation instrument following the manufacturer' s standard midi kit protocol. DNA was quantitated by PicoGreen fluorescence and standardized to 25ng/ul. The BHL samples were used to select a convenience control group equal in size to the Epigrow group.

Population structure analysis

95 SNPs that map across all autosomes and cluster HapMap samples into the main continental groups (European, African, Asian ancestry) were selected to match 263 Epigrow cases and an equal number of controls, using the program Structure (Pritchard et al., Human Genetics. 2000, 67: 170-181). In addition all samples were genotyped with a Y-chromosome specific marker. Genotyping was done by allele- specific real-time PCR using assays designed and validated at Celera. Genotyping accuracy on this platform has been found to be greater than 99% (Grupe et al., Am J Hum Genet. 2006;78:78-88).

The program Structure was used to assess the population structure in the Epigrow and BHL sample sets using the above 95 SNPs. The Structure analyses were run with the SNP genotype data for 263 Epigrow subjects, 500 BHL subjects, and publicly available genotype data from four HapMap populations (JPT [Asian, n=89], CNB [Asian, n=86], YRI [African, n=176], CEU [Caucasian, n=169]). The Structure runs were done with settings for K = 3 populations, burn in = 10,000, cycles = 30,000 and the admixture setting set to on. Probabilities (PI , P2, P3) were estimated for each sample to assess clustering with each of the three possible populations.

Target enrichment Agilent Sureselect bait design

Agilent's eArray platform, which accepts only hgl9 coordinates, was used for the bait design. Using hgl9 coordinates, the chromosome, exon start/stop positions and transcriptional direction were identified for all selected 234 candidate genes. To calculate the hgl9 coordinates for the bait design, the exon coordinates were extended by 60bp in each direction for added coverage of the exon/intron boundaries. The coordinates of the most 5' exon of each gene were extended upstream by 460bp for added coverage of the putative promoter region. The resulting coordinates were entered into Agilent's eArray application and submitted for bait design, using Agilent's recommended optimized parameters for single-end Illumina sequencing of long reads (75bp or more). The parameters were (i) centered baits, (ii) 120bp bait length, (iii) lx bait tiling frequency, (iv) overlap of 20bp or less into avoided regions (i.e. repeats from RepeatMasker and Tandem Repeats Finder), and (v) sense strand. The design yielded 11,061 baits that map to 232 of the 234 target genes. Two miRNA genes, MIR320dl and MIR320e, yielded no bait designs.

Sureselect target enrichment for Illumina multiplexed sequencing

3ug of each DNA sample was sheared to an average of 150 to 200 nucleotides on a S2 High Performance UltraSonicator (Covaris, Woburn, MA) following the Agilent SureSelect protocol "SureSelect Target Enrichment for Illumina Paired-End Multiplexed Sequencing (Version 1.0, May 2010).

The initial 24 samples, all BHL controls, were processed in individual 1.5ml Eppendorf tubes as specified in the Agilent protocol. All subsequent samples were processed in groups of 96 in MicroAmp Optical 96-well ReactionPlates (Applied Biosystems, Foster City, CA). There was no observed reduction in sample recovery, as measured by Agilent Bioanalyzer 2100 DNA 1000 Lab-on-a-Chip gel electrophoresis, across all enrichment steps performed in 96-well plates versus Eppendorf tubes. Other deviations from the Agilent protocol were as follows: a) indexed samples were pooled at 2 to 4-fold higher concentration than the recommended target concentration to allow for, b) the inclusion of a second quantitative PCR step (Kapa Biosystems, Woburn, MA) after pooling to allow for fine-tune adjustment of pool concentration to a final 20nM (concentration requested by the Illumina Sequencing Service Lab). To minimize possible introduction of sequence bias yet maximizing product yield, 5 cycles of PCR were performed to amplify the adapter- ligated libraries and 14 PCR cycles to add the index barcode tags and amplify the final libraries. The recommended 24 hour hybridization period at 65°C was employed for all samples and baits. A total of 617 individual target enrichment reactions were conducted on the 526 unique samples, including 91 repeat enrichments employed to increase sequence depth of coverage on those samples with adequate remaining DNA.

Sequencing A total of eight sample sets were generated and delivered to Illumina for sequencing. Each of these sample sets contained up to 8 pools each consisting of 12 individual case and/or control samples indexed with a unique 6-base DNA sequence. The inclusion of the index barcode allows for multiplexing 12 samples in each lane of an 8-lane flow cell, effectively increasing sample capacity from 8 to 96 per sequencing run. The pipeline data analysis software identifies the index sequence from each sequence read and assigns the sample ID associated with that index to all data from that read.

All sample pools were delivered to Illumina at 20nM. Cluster generation was performed on a cBot instrument (Illumina, San Diego, CA) using 1.5fmol of pool. All samples were sequenced on an Illumina Genome Analyzer IIx using TruSeq SBS kit v5 reagents. 75bp to 125bp sequence reads were generated on either single-end or paired-end flow cells.

In order to increase average sequence coverage depth to greater than 6 reads per nucleotide for 80% of the baits employed, a number of samples were sequenced multiple times. 107 Epigrow samples were sequenced twice and 17 were sequenced three times. For the BHL controls, 73 were sequenced twice and 2 were sequenced three times. This resulted in a total of 744 sequencing lanes run to assemble sequence data on 526 unique samples.

Sequence analysis pipeline Sequence analysis was performed in the Linux environment using Illumina' s

CASAVA 1.7 software for the de-multiplexing, alignment and SNP calls algorithms. SAM/BAM tools were employed for pile-up and coverage reports.

Sequencing reads from the Illumina platform were aligned to the reference genome B36 using the CASAVA 1.7 software suite from Illumina. Standard variables were maintained throughout the runs and the flag DenseAlleleCall was used. With this flag set to on, only bases where a nucleotide was identified were

accumulated and bases without information were eliminated. The alignment proceeded without chromosome Y to ensure that the pseudo-autosomal X region was mapped uniquely to the X chromosome.

The next sections describe six steps to identify variants and call genotypes for these variants. Most of these steps are embedded in the CASAVA process. 1) The SNP variant is detected using CASAVA software. 2) The SNP variants are annotated using the Celera annotation engine onto the B36 assembly. 3) The CASAVA process uses a BACON quality score to generate a SNP genotype call for heterozygotes and non-reference allele homozygotes. 4) The reference allele homozygotes are collected from coverage data (PILE-UPs). 5) The Indel variations are detected using the coverage alignments (PILE-UPs) of the sequence reads. 6) The minor alleles for the Indels are collapsed to a single minor allele.

SNP variant detection

CASAVA Variation Discovery was run with DenseAlleleCall flag set to on to identify all bases in the genome which could be called (CASAVA Software 1.7 User Guide, Illumina March 2010). As expected from the SureSelect hybridization method, SNPs were discovered inside and outside of the target areas. Final genotypes were only collected for target genes and the agreed upon +/-5kb of the surrounding sequence.

Variant annotation All variants were catalogued on B36 assembly (hgl8). The SNP variants were collected for the target gene plus or minus 5kb. Several of the target genes are close to other genes which are either target or non-target. The SNPs were annotated in the PLINK result file according to target gene. Some SNPs are thus annotated as "Intergenic/unknown" for a target although they map to a non-target gene as a different variant type. Regarding the miRNA genes, these are very small, usually 70- 80 bp whereas their target region encompasses approximately lOkb. Some of the target regions for miRNAs overlap each other, some miRNA target regions overlap target genes and some miRNA target regions overlap other non-target genes. There is no annotation on miRNA target gene SNPs other than inside or outside the miRNA. To simplify miRNA annotation, the miRNA SNPs which are inside an miRNA were listed separately. The annotation in the PLINK "SNP only" analysis shows the SNP annotation according to the B36 genome. The annotation of SNPs and Indels has a hierarchy, with preference given to the Indel annotation when Indels overlap with a SNP. Thus, some SNPs may be annotated as Indels in the tables herein in Example 1. This preference is merely to alert one to the dual nature of these variations. SNP genotype calls

Heterozygotes and non-reference allele homozygotes

Heterozygous and minor allele homozygous genotypes were assigned according to the BACON score at the nucleotide position. The BACON score is a quality measure that Illumina implemented in CASAVA for making a heterozygous or non-reference allele homozygous genotype call. This score combines the number of sequence reads at a given position with the quality of the base call in each read (the Q-score). A Q-score of 30 is equivalent to the base being miscalled one in 1000 times. To assign a heterozygous genotype, a BACON score of >10 for the reference allele and >6 for the non-reference allele (BACON = (∑Qi)/10) was required; the ratio of the reference to non-reference allele BACON scores needed to be <3. A BACON score of >10 was required to assign a non-reference allele homozygote genotype.

Herein in Example 1 , the reference allele was the nucleotide recorded in the B36 reference genome sequence (which was most often equivalent to the major allele). Also herein in Example 1, the terms "non-reference allele" and "variant allele" are used interchangeably.

Reference allele homozygotes

CASAVA assigns a reference allele homozygous genotype if the previous process that uses the BACON score did not assign a non-reference allele homozygous or heterozygous genotype. The PILE-UP results, an intermediate result from the CASAVA run, were also examined to determine if the base was covered with >1 reference allele read before designating the genotype as reference allele homozygote. A 'no call' was assigned when the PILE-UP base differed from the reference allele or no read for the reference allele existed. This ensured that the genotypes from PILE- UP do not over-ride the BACON score genotypes for heterozygotes and non-reference allele homozygotes.

Indel calls An Indel calling procedure was implemented and the PILE-UP results were used to identify Indels and call the genotypes because Indel identification is not implemented in the CASAVA 1.7 software package for single end sequence reads. To assign Indel genotypes, the quality score (Q-score) was used for non-reference allele calls and coverage (i.e., presence of the reference allele) for the reference allele. Since Indels may be multi-allelic and have different non-reference alleles in different subjects, Oracle database procedures were used to collapse non-reference alleles to generate biallelic Indel variants. The base preceding the start of the Indel becomes the reference allele and the insertion/deletion becomes the non-reference allele.

Consecutive base collapse is held as long as there is another Indel one base away.

The position of an Indel is the position of the base preceding either the deletion or the insertion on the B36 genome. This position itself can be polymorphic and harbor a SNP. Thus a SNP and Indel can share the same position and the same hCV/hDV identifier. SNPs and Indels are analyzed separately, but the annotation herein in Example 1 gives precedence to the Indel annotation over the SNP annotation. Indel genotypes are coded as the reference allele and "I". The "I" can stand for either an insertion or a deletion; the non-reference alleles of some Indels are both (deletions and insertions). A simple case is a microsatellite in which the reference genome, for example, has 8 repeats and other individuals have either 4 or 12 repeats. Collapse of non-reference alleles is used for the statistical analysis methods employed herein in Example 1. Quality of the Indel was assessed from the PILE_UP results. To increase the quality of the Indels, Indels were removed for which the SNP-quality score was 0 or the number of covering reads was one AND the number of individuals was one. A small number of 57 Indels were identified where only the non-reference alleles were detected (i.e., the B36 reference sequence was never observed).

Indel genotypes and allele collapse

Many methods exist to collapse Indel genotypes. Space based positions were used herein in Example 1 for the Indels. In this method, the insertions/deletions are positioned between the B36 mapping coordinates. Furthermore, most statistical software packages will require that the Indel (which are less than 20 bases) be collapsed into 3 basic genotypes, the major reference allele, and the variation allele(s), either in combination with a reference allele (heterozygous) or variation alleles alone (minor allele variants). This has implications for the Hardy-Weinberg equilibrium (HWE) test. In heterozygous or minor homozygous individuals there can be a large number of compound alleles contributing to the Indel call and count. For example, a single Indel position may have multiple variant Indel alleles (e.g., an Indel may have "A" as a reference allele, and -aaag, +G, +AAG, and +AG as variant Indel alleles). Other Indels could be more complex and may not be accurately de-convoluted. For example, PILE-UP may place Indels at consecutive positions but further processing merges them into one polymorphism with multiple variations of the indel, such as may happen with compound-complex microsatellites. Rather than analyzing the different compound alleles separately, the alleles were collapsed instead (e.g., multiple variant Indel alleles are collectively represented as "I"). Non-reference allele homozygotes are also complex counts of alleles and are not limited to a specific compound-complex allele. This has implications for the HWE analysis since the collapsed alleles and no individual alleles were used in the calculations. Thus, multiple variant indel alleles may be represented by "I" for the variant allele(s), such as in Table 8 herein in Example 1. For example, if an indel has "A" as a reference allele and one or more variant indel alleles, the "Ref/Var Allele" column of Table 8 would indicate "A/I" (and individuals who are heterozygous for the "A' allele and one of the indel alleles would be coded "A/I" for the statistical framework and analysis).

PolyPhen2 analysis

The PolyPhen2 scores were calculated using the PolyPhen2 web site for version 2.0.22 in November 2010, Adzhubei et al., Nat Methods 2010; 7:248-249. Only missense SNPs were submitted and the settings used were for hgl8 (B36 assembly), humDIV, and canonical transcripts. Missense SNPs which could not produce a PolyPhen2 score were given a default score of 0.2 (the boundary between "benign" and "possibly damaging"). Nonsense SNPs and frame-shift Indels were assigned a default score of 1 , and acceptor and donor splice site SNPs were assigned a default score of 0.8. Sample tracking

Sequencing of 199 samples was repeated. Three samples were repeated because they failed completely on their initial runs, 22 samples had been pre-specified for repeated runs, and the remainder were repeated to increase coverage. To assess tracking accuracy, a "twin" analysis was performed to determine if the sample genotypes matched only to the same subject. Genotypes from identical samples with multiple runs were compared to assess genotyping accuracy by identifying the percentage of changing genotypes.

Statistical methods Sample size and power

The study contains 263 ISS patients and 263 controls. Controls were matched to patients according to estimated fractions of Asian, African, and European ancestry on the basis of an analysis of population structure of genotypes from 95 autosomal SNPs. The power of Fisher's exact test to detect varying differences in proportions of minor alleles carried by case and control samples for single variants was estimated by simulation. The power to detect association of case status with the combined effect of multiple SNPs within a gene will typically depend on the number and functional types of SNPs found within the gene and their corresponding allele frequencies. Single marker tests

Single marker tests were implemented in PLINK 1.07 (Purcell et al., American Journal of Human Genetics. 2007; 81). For each variant, the following statistics were reported:

- Number and proportion of missing genotypes in cases, controls and overall - Fisher's exact test for association between missing genotype and case/control status

- Genotype counts in cases and controls

- Counts of minor allele in cases and controls

- Minor allele frequency in cases, controls and overall

- Exact Test for Hardy-Weinberg equilibrium in cases, controls and overall

The following tests for association of variants and case/controls status were performed:

- Fisher's exact test (allelic association)

- Additive test for association (Cochran-Armitage trend test)

- Dominant test (Fisher's exact)

- Recessive test (Fisher's exact)

- Genotypic (2 df) test (Fisher's exact)

- False discovery rate (FDR) (Benjamini and Yekutieli, Annals of Statistics.

2001 ; 29: 1165-1188). Most existing methods of estimating false discovery rates assume the p-values have a continuous uniform distribution under the null hypothesis. Due to the extreme discrete nature of the distribution of p-values from exact tests of association involving variants with very rare allele frequencies, the FDR was applied only to variants with minor allele frequency greater than 1% and greater than 75% coverage (percent of subjects with non-missing genotypes). Since variants within a gene may be in linkage disequilibrium, the Benjamini and Yekutieli FDR method, which accounts for dependency between the test statistics, was applied to the p-values from Fisher's exact test of allelic association. In addition, SNPs having p-values which are significant after applying a Bonferroni correction considering the total number of analyzed SNPs (22,052) are noted.

Haplotype and linkage disequilibrium calculations

Pairwise measures of linkage disequilibrium (r ² ) were calculated using GOLD software (Abecasis and Cookson, "GOLD-Graphical overview of linkage disequilibrium", Bioinformatics. 2000; 16: 182-3). Estimates of haplotype frequencies and corresponding tests of association with disease status were performed using version 1.4.4 of the haplo. stats package (Schaid and Sinwell J, "Haplo Stats: Statistical analysis of haplotypes with traits and covariates when linkage phase is ambiguous. Version 1.4.4." 2009; Schaid et al., Am J Hum Genet. 2002; 70:425-34) for R. A haplotype specific odds ratio and p-value assessing the association of haplotype frequency with case status was determined for each common haplotype (> 1% frequency among all subjects). In addition, a global score statistic and p-value were determined which assess the overall association of the haplotype frequencies with case status. Under the null hypothesis of no association, the global score statistic has a chi-square distribution with n-1 degrees of freedom where n is the number of distinct haplotypes (haplotypes with frequency of < 1 % are pooled into one "rare" haplotype). The Price method has been implemented in publicly available software in the R programming language. Other summary measures were also calculated using R.

Results Population structure analysis - Epigrow cases and controls

To match the 263 Epigrow subjects with an equal number of BHL controls of similar continental distribution, 95 SNPs were genotyped in 263 Epigrow cases and 500 BHL control samples and analyzed in the program Structure by clustering them with Caucasian, African, and Asian HapMap samples. The Structure analysis shows that good matching of Epigrow cases and controls can be achieved for 260 Epigrow cases according to the analyzed 95 SNPs.

Sequencing coverage

The average coverage in bait regions across all 526 samples is 88% for a sequencing depth of 6x or higher. Only two Epigrow cases have a 6x average sequencing depth of less than 80%. The average and the between- sample variability differ by chromosome and correlate with GC content of the directly targeted sequences. Coding sequence variants (missense, nonsense, and silent variants) are covered on average between 92% and 93% at the 6x level. Variation in sequencing depth was also assessed by gene. For that purpose, the percentage of baits per gene that show greater than 50% average coverage at 6x was determined across all samples. Out of 1.33Mbp of total targeted sequence (11,061 baits x 120bp), approximately 1.19Mbp (89.2%) showed an average above 50% and approximately l.HMbp (83.3%) showed an average above 80%. Accuracy of SNP calls

A total of 199 samples were sequenced at least twice. None showed similarity beyond itself, confirming accurate sample tracking. An extremely small fraction of SNP genotypes changed between the reruns, suggesting a high level of genotype accuracy. Only 0.11% of genotypes in the bait regions changed between reruns (2,864 of 2,547,190) and 0.28% of all accumulated genotypes (13,479 of 4,885,274).

Annotation of identified variants

27,648 SNPs were identified that are polymorphic in the 526 sequenced samples and map within +/-5kb of a target gene. Filters were set up to identify a set of SNPs that meet certain quality criteria. First, SNPs were removed that had genotypes in less than 75% of subjects in this study, which eliminated 4,943 SNPs from consideration (17.9%). Next SNPs were removed that showed deviation from HWE in controls at p<0.0001, which removed another 653 SNPs (2.9%), leaving 22,052 SNPs in the final set. This set includes 1,835 missense and nonsense SNPs. The 22,052 SNPs contain 3,924 SNPs with a minor allele frequency of 1% or higher, including 219 missense and nonsense SNPs. The set of 22,052 SNPs includes 16,168 SNPs that have not been recorded in dbSNP (rs identifier) and the set of 3,924 SNPs include 729 SNPs without an rs-identifier. Single marker analysis - SNPs

The allelic association test for the 22,052 SNPs with short stature yielded 654 SNPs with an allelic p-value < 0.05. Applying a very conservative Bonferroni testing correction for 22,052 tests at p<0.05 yields a p-value threshold of p<2.3 E-6, which is met by allelic p-values for 2 SNPs, rs724016 and rs6764769, both in ZBTB38. The risk alleles of both SNPs are common in controls (frequency: 0.443 and 0.525, respectively) and their frequency is increased in cases to 0.607 and 0.683, respectively. The allelic odds ratio of each SNP is approximately 2. Both SNPs are in high linkage disequilibrium (r ² =0.97). In order to identify additional SNPs that don't meet the conservative

Bonferroni corrected p-value, p<l E-4 was selected as cutoff, which is also bound by a false discovery rate (FDR) threshold of FDR<0.2 (FDR calculated on SNPs as described above in the "Materials and Methods" section of Example 1). Twenty-one SNPs from eight genes meet this allelic p-value threshold of p<l E-4 (Table 4). These eight genes and the corresponding highest odds ratios are ZBTB38 (OR=1.96),

PRKAR1B (OR=17.64), KRAS (OR=2.13), SOS2 (OR=2.13), PRKCH (OR=2.08), BBS4 (OR=2.72), FANCA (OR=1.82), and MAPK1 (OR=2.87). The intronic SNP hDV88213973 in PRKAR1B, a novel SNP not recorded in dbSNP, stands out from the other SNPs due to its large effect size (OR=17.64) and low frequency (0.034 cases / 0.002 controls). Ten of the 12 SNPs in FANCA and the 2 SNPs in MAPK1 share high LD. The two most significant SNPs in FANCA share moderate LD. The r ² of hCV3275471 in FANCA (p=0.0000146) with the FANCA top hit hCV3020887 (p=0.0000142) is 0.58.

Table 5 shows analysis results of the above dataset after it was filtered for missense and nonsense SNPs that meet a threshold of p(allelic) <0.05. This filter yields 24 missense SNPs. These missense SNPs were further filtered to identify those missense SNPs where the minor allele represents the risk allele. Six SNPs in the following genes met these criteria: SPAG17 (p=0.0073, OR=3.24), LRP5 (p=0.020, OR=2.02), FGFR3 (p=0.021 , OR=9.07), LEPR (p=0.029, OR=1.43), CENPW (p=0.031, OR=NA) and PCNT (p=0.043, OR=2.32).

This analysis also identified SNP hCV25995019 (rs9282731), which is a missense SNP in the IGFALS gene, as being present at significantly different frequencies in individuals with idiopathic short stature (cases) as compared to control individuals (see Table 6). As shown in Table 6, the major allele (G) of IGFALS SNP hCV25995019 is more common in idiopathic short stature cases relative to controls and thus is associated with increased risk for short stature, whereas the minor allele (A) is more common in controls relative to idiopathic short stature cases and thus is associated with a protective (non-risk) effect.

GRUPE, Andrew et al. Attorney Docket #: CD000031PCT

Date of Filing: May 2, 2012

TABLE 4 Var Allele Freq

SNP Ref/Var HWE Allelic P- Allelic FDR-

Gene SNP SEQ ID NO Type Allele Case Control HWE (Cs) (Co) Value OR BY ^** r2

ZBTB38 hCV29279566/rs6764769 ^* 333 UTR5 A/G 0.393 0.557 0.89 0.081 0.000001473 0.52 0.02 0.97

ZBTB38 hCV2416397/rs724016 332 Intron A/G 0.317 0.475 0.12 0.00078 2.081 E-07 0.51 0.004

PRKAR1 B hDV88213973 392 Intron G/A 0.034 0.002 0.0014 1 0.00006535 17.64 0.12

KRAS hDV75942727/rs34719539 ^* 285 UTR3 T/C 0.177 0.092 0.83 0.24 0.00008763 2.13 0.15

SOS2 hCV30550339/rs10483598 327 Intron T/C 0.220 0.1 17 9.771 E-08 0.0018 0.00002692 2.13 0.10

PRKCH hCV7600023/rs1092331 315 Intron A/G 0.891 0.796 0.15 0.020 0.00009482 0.48 0.16

BBS4 hCV25628122/rs3759870 358 Intron A/G 0.117 0.047 7.542E-12 0.001 0.00005877 2.72 0.12

FANCA hCV3020887/rs1230 ^* 232 UTR3 C/T 0.341 0.473 0.34 0.048 0.00001415 0.58 0.08

FANCA hC V12112567/rs7195906 ^* 228 Intron A/T 0.344 0.473 0.41 0.048 0.00001954 0.58 0.08 0.98

FANCA hCV26871795/rs6500441 236 Intron C/G 0.336 0.469 0.00040 0.005 0.00004226 0.57 0.1 1 0.86

FANCA hCV3275471 /rs3785275 233 Intron C/G 0.246 0.373 0.092 0.14 0.0000146 0.55 0.08 0.58

FANCA hCV31692807/rs7187436 238 Intron A/T 0.346 0.472 0.50 0.064 0.00004459 0.59 0.1 1 0.94

FANCA hCV11951343/rs1800337 ^* 226 Intron A/G 0.345 0.472 0.49 0.064 0.0000341 1 0.59 0.1 1 0.94

FANCA hCV2590886/rs8049660 ^* 235 Intron A/G 0.281 0.400 0.28 0.029 0.00006363 0.59 0.12 0.67

FANCA hCV2590883/rs6500450 ^* 231 Intron A/G 0.344 0.475 0.34 0.013 0.0000176 0.58 0.08 0.89

FANCA hCV1211271 1/rs6500452 ^* 229 Intron T/C 0.260 0.378 0.87 0.90 0.00003962 0.58 0.1 1 0.62

FANCA hCV12112715/rs1800287 ^* 230 Intron C/G 0.347 0.477 0.49 0.047 0.00001932 0.58 0.08 0.91

FANCA hCV11951344/rs1800285 ^* 227 Intron C/T 0.345 0.466 0.41 0.14 0.00007312 0.60 0.13 0.88

FANCA hCV2590841/rs1 1859183 234 Intron C/T 0.315 0.441 0.0019 0.025 0.00005252 0.58 0.12 0.69

MAPK1 hCV7626903/rs13058 ^* 304 UTR3 A/C 0.120 0.048 1 1 0.00001926 2.74 0.08

MAPK1 hCV25922338/rs3729910 ^* 303 Silent A/G 0.1 16 0.044 1 1 0.00001935 2.87 0.08 0.95

Table 4. Single SNP analysis. Allelic p-value < 0.0001. FDR-BY < 0.2.

r2: r-squared to most significant SNP in the same gene

*: SNP is in sequence targeted by bait; **: FDR calculation included SNPs with HWE<0.0001 in controls

GRUPE, Andrew et al. Attorney Docket #: CD000031PCT

Date of Filing: May 2, 2012

In Table 4, the column labeled "SEQ ID NO" provides a genomic context sequence for each SNP from Table 2 and the Sequence Listing of the instant application. Each genomic context sequence is an exemplary sequence which presents the SNP at position 101, with 100 nucleotides upstream and downstream of the SNP position.

GRUPE, Andrew et al. Attorney Docket #: CD000031PCT

Date of Filing: May 2, 2012

TABLE 5 Var Allele Freq

Ref/Var HWE HWE Allelic P- Allelic FDR-

Gene SNP SEQ ID NO SNP Type Allele Case Control (Cs) (Co) Value OR BY ^**

LEPR hCV8722378/rs8179183* 286 Missense G/C 0.221 0.165 0.15 1 0.029 1.43 1

SPAG17 hCV25750081 /rs35290515* 328 Missense T/C 0.042 0.013 0.37 1 0.0073 3.24 1

FANCL hDV81424415/rs55849827 ^* 277 Missense G/A 0.000 0.01 1 1 1 0.031 0.00 NA

NHEJ1 hCV25636054/rs34689457 ^* 310 Missense C/T 0.002 0.019 1 0.083 0.01 1 0.10 1

FGFR3 hDV71078050/rs17881656* 278 Missense T/C 0.017 0.002 1 1 0.021 9.07 NA

CENPW hDV88213803* 223 Missense C/T 0.011 0.000 1 1 0.031 NA NA

IGFBP3 hCV29670713/rs9282734 ^* 281 Missense T/G 0.000 0.01 1 1 1 0.031 0.00 NA

PEX2 hDV88202422 ^* 324 Missense A/G 0.002 0.021 1 0.10 0.0061 0.09 1

PEX2 hDV88214691 ^* 325 Missense C/T 0.004 0.019 1 0.083 0.038 0.20 1

NBN hCV7566051/rs769420 ^* 309 Missense G/A 0.000 0.01 1 1 1 0.031 0.00 NA

LRP5 hCV25604912/rs4988321 * 302 Missense G/A 0.063 0.032 0.071 0.23 0.020 2.02 1

CEP290 hCV29120804/rs 7307793 ^* 224 Missense C/T 0.004 0.023 1 0.005 0.012 0.16 1

CEP290 hCV31 193798/rs1 1 104738 ^* 225 Missense T/C 0.030 0.057 0.21 0.58 0.049 0.52 1

SOS2 hCV25598905/rs17122201 ^* 326 Missense C/T 0.000 0.013 1 1 0.015 0.00 NA

BUB1 B hDV81584461 /rs56079734 ^* 21 1 Missense C/T 0.000 0.013 1 0.040 0.015 0.00 NA

BUB1 B hCV8868138/rs1801528 ^* 210 Missense T/C 0.006 0.032 1 0.024 0.0024 0.17 0.85

ACAN hCV25473397/rs35430524 ^* 180 Missense C/A 0.074 0.1 13 0.16 0.55 0.043 0.63 1

FANCA hCV30590701/rs7190823 ^* 237 Missense T/C 0.351 0.466 0.50 0.084 0.00017 0.62 0.22

ATAD5 hCV27849348/rs9910051 ^* 181 Missense A/T 0.1 10 0.158 0.75 0.06 0.030 0.66 1

BCAS3 hCV25962833/rs34712615 ^* 209 Missense A/G 0.002 0.023 1 1 0.003 0.08 1

PTPN1 hDV88320149 ^* 323 Missense T/G 0.006 0.025 1 1 0.020 0.23 1

PC NT hCV2446917/rs7279204* 313 Missense C/T 0.046 0.021 0.00059 0.080 0.043 2.32 1

PCNT hCV25474258/rs8131693 ^* 314 Missense G/A 0.006 0.027 1 0.00030 0.012 0.21 1

ELK1 hCV8938091 /rs 1059579 ^* 368 Missense C/T 0.002 0.033 1 0.002 0.00051 0.07 0.41

GRUPE, Andrew et al. Attorney Docket #: CD000031PCT

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Table 5. Single SNP analysis of missense and nonsense SNPs. Allelic p-value < 0.05.

*: SNP is in sequence targeted by bait; **: FDR calculation included SNPs with HWE<0.0001 in controls; bold: minor allele is risk allele

In Table 5, the column labeled "SEQ ID NO" provides a genomic context sequence for each SNP from Table 2 and the Sequence Listing of the instant application. Each genomic context sequence is an exemplary sequence which presents the SNP at position 101, with 100 nucleotides 5 upstream and downstream of the SNP position.

TABLE 6

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In Table 6, an exemplary genomic context sequence for hCV25995019 is SEQ ID NO:280. This genomic context sequence is provided in Table 2 and the Sequence Listing of the instant application, and presents the SNP at position 101, with 100 nucleotides upstream and downstream of the SNP position.

Haplotype analysis

Since there was only moderate LD between the two most significant SNPs in FANCA (hCV3275471 and hCV3020887), haplotype analysis of these two SNPs was performed. The CC haplotype was the most common and was associated with a higher frequency (p=4.6E-05) in cases (65%) than in controls (52%) and an Odds ratio of OR=1.73 (Table 7).

TABLE 7. FANCA Haplotype Analysis

hCV3275471 hCV3020887 control. hf case.hf p-value OR

T G 0.364 0.237 1 .50E-05 0.54

T C 0.109 0.103 0.66 0.94

c G 0.01 1 0.013 0.79 1 .18

c C 0.516 0.648 4.60E-05 1 .73

global-stat = 20, df = 3, p-val = 0.00016

Table 7: Case.hf: case haplotype frequency; control.hf: control haplotype frequency

OR: Odds Ratio (reference: all other haplotypes)

In Table 7, exemplary genomic context sequences for hCV3275471 and hCV3020887 are SEQ ID NO:233 and SEQ ID NO:232, respectively (these two FANCA SNPs are also provided in Table 4 above). These genomic context sequences are each provided in Table 2 and the Sequence Listing of the instant application, and present each SNP at position 101, with 100 nucleotides upstream and downstream of the SNP position.

Single marker analysis - indels

After collapsing multiple alleles that start at the same position or at consecutive positions (see "Indel calls" section above within the "Materials and Methods" section of Example 1) 11,821 Indels were recorded that mapped within 5kb of the candidate genes. Indels were further limited to those with genotype information in at least 75% of subjects (4,448 Indels). Next, the same HWE filter was

implemented in control samples (p>0.0001) as for the SNP analysis, resulting in 4,006 remaining Indels (HWE was calculated for the collapsed Indels and not for each Indel allele). 110 Indels met a p-value threshold of p(allelic)<0.05. The statistical analysis results for two Indels that are p(allelic)<0.01 are shown in Table 8. These two Indels meet a conservative Bonferroni correction for p<0.05 and 4,006 tests (p<1.25E-5). These two Indels map to an intron of NFKBl (p=1.36E-10, OR=2.32) and the 3' UTR of IGF1 (p=1.2E-5, OR=0.33). The individual allele counts of the NFKBl and IGF1 Indels is provided in Table 9 (NFKB 1 ) and Table 10 (IGF1 ).

The risk allele of the NFKB 1 Indel is of high frequency in controls and further increased in cases (frequency: 0.272 and 0.464, respectively). This Indel shows a strong deviation from HWE in cases (p=2.08E-15) and not in controls (p=0.76). This deviation in cases is the result of an increase in heterozygotes, which is also reflected in a very significant dominant p-value (p=1.45E-16) and dominant odds ratio

(OR=5.50; counts maj hom/het/min horn, cases: 44/194/25, controls: 138/107/18).

The IGF1 Indel has an allele frequency of 0.112 in controls and 0.04 in cases, thus the minor allele is protective. Only heterozygous and no homozygous Indel alleles have been found in cases (n=21) and in controls (n=59).

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TABLE 8

Var Allele Freq

Ref/Var HWE HWE Allelic P- Allelic FDR-

Gene SNP SEQ I D NO Indel Type Allele Case Control (Cs) (Co) Value OR BY ^**

NFKB1 hDV893651 67 ^* 374 Intronic T/l 0.464 0.272 2.08E-15 0.76 1 .36E-1 0 2.32 7.36E-06

IGF1 hDV89345868 279 UTR3 A/I 0.040 0.1 1 2 1 0.055 0.000012 0.33 0.075

Table 8. Single Indel analysis. Allelic p-value < 0.01.

*: Indel is in sequence targeted by bait; **: FDR calculation included SNPs with HWE<0.0001 in controls

In Table 8, the column labeled "SEQ ID NO" provides a genomic context sequence for each Indel from Table 2 and the Sequence Listing of the instant application. Each genomic context sequence is an exemplary sequence which presents the SNP at position 101, with 100 nucleotides upstream and downstream of the SNP position.

TABLE 9. NFKBl Indel (hDV89365167) Allele Counts

(NFKBl Indel hDV89365167 is also listed in Table 8 above.)

TABLE 10. IGFl Indel (hDV89345868) Allele Counts

(IGFl Indel hDV89345868 is also listed in Table 8 above.)

Discussion This study used deep re-sequencing of 232 candidate genes in 263 Epigrow patients and

263 control samples on the Illumina platform to identify variants associated with short stature. Agilent's SureSelect bait enrichment strategy was used to enrich exons, exon/intron boundaries, and putative promoter regions immediately upstream of the most 5 ' exons of the candidate genes for sequencing. 27,648 SNPs and 11,821 Indels that are polymorphic in the 526 sequenced samples and map within +/-5kb of a target gene were identified. After implementing additional quality filters (< 25% missing subjects, HWE _controls > 0.0001), 22,052 high quality SNPs and 4,006 Indels were counted in this dataset. These variants were tested for association with short stature using a single marker analysis.

Among the polymorphisms identified as being associated with short stature, the single marker analysis led to the identification of two SNPs (rs724016 and rs6764769, which are both common variants in the ZBTB38 gene) and two Indels (hDV89365167 in the NFKB1 gene, and hDV89345868 in the IGFl gene) that meet a stringent Bonferroni testing correction for 22,052 SNPs and 4,006 Indels, respectively. The effect size of ZBTB38 SNP rs724016 in the analysis herein in Example 1 was OR of 1.96 per each copy of the rare allele and OR=2.78 under a recessive mode, indicating that this variant has a significant impact on height in the short stature population. The increase in risk in the recessive model over the allelic model for ZBTB38 SNP rs724016 shows that carriers of two risk alleles are at a greater growth disadvantage than carriers of one risk allele.

Two Indels, one mapping to NFKBl (hDV89365167) and the other mapping to IGF1 (hDV89345868), show strong associations with short stature. The NFKBl variant hDV89365167 is present at a high frequency in the general population and shows a substantial increase of heterozygotes in cases. The strongest effect size for the association of the NFKBl variant with short stature is observed under a dominant model (OR(dominant) = 5.5). In contrast to the NFKBl Indel, the minor allele of the IGF1 Indel hDV89345868 has a higher frequency in controls, thus the minor allele is associated with a protective effect and the major allele is associated with increased risk for short stature.

The low frequency variant hDV88213973 in PRKAR1B has the largest effect size of all identified low frequency variants in the analysis herein in Example 1 (OR=17.64). PRKAR1B forms one of the regulatory subunits for protein kinase A, an essential enzyme in the signaling pathway of cAMP.

Sequences and other information provided in Tables 1-2

Sequences, SNP information, and associated gene/transcript/protein information for each of the SNPs listed in Tables 4-10 above is provided in Tables 1-2 (Table 1 is based on transcript and protein sequences, whereas Table 2 is based on genomic sequences). Thus, for any SNP listed in Tables 4-10 herein in Example 1, sequences or other information can be found by searching Tables 1-2 using the hCV (or hDV) or rs identification number of the SNP of interest. Furthermore, SEQ ID NOs of genomic context sequences have been provided above with respect to each of Tables 4-8 and the SNPs listed therein.

EXAMPLE 2: ADDITIONAL LP SNPS ASSOCIATED WITH SHORT STATURE Another investigation was conducted to identify additional SNPs that are in high linkage disequilibrium (LD) with certain "interrogated SNPs" that have been found to be associated with short stature (particularly idiopathic short stature). The "interrogated SNPs" were those SNPs provided in Tables 4-10 in Example 1 above (the interrogated SNPs are shown in columns 1 and 2 of Table 3, which indicates the hCV and rs identification numbers of each interrogated SNP), and the LD SNPs which were identified as being in high LD are provided in Table 3 (in the columns labeled "LD SNP", which indicate the hCV and rs identification numbers of each LD SNP).

Specifically, Table 3 provides LD SNPs from the HapMap database (NCBI, NLM, NIH) that have linkage disequilibrium r ² values of at least 0.9 (the threshold r ² value, which may also be designated as r _r ² ) with an interrogated SNP. Each of these LD SNPs from the HapMap database is within 500 kb of its respective interrogated SNP, and the r ² values are calculated based on genotypes of HapMap Caucasian subjects. If an interrogated SNP is not in the HapMap database, then there will not be any LD SNPs listed in Table 3 for that interrogated SNP.

As an example in Table 3, the interrogated SNP rs 1800337 (hC VI 1951343) was calculated to be in LD with rsl800335 (hCVl 1951325) at an r ² value of 1 (which is above the threshold r ² value of 0.9), thus establishing the latter SNP as a marker associated with short stature as well.

In this example, the threshold r ² value was set at 0.9. However, the threshold r ² value can be set at other values such that one of ordinary skill in the art would consider that any two SNPs having an r ² value greater than or equal to the threshold r ² value would be in sufficient LD with each other such that either SNP is useful for the same utilities, such as determining an individual's risk for short stature. For example, in various embodiments, the threshold r ² value used to classify SNPs as being in sufficient LD with an interrogated SNP (such that these LD SNPs can be used for the same utilities as the interrogated SNP, for example) can be set at, for example, 0.7, 0.75, 0.8, 0.85, 0.95, 0.96, 0.97, 0.98, 0.99, 1, etc. (or any other threshold r ² value in-between these values). Threshold r ² values may be utilized with or without considering power or other calculations.

Sequences, SNP information, and associated gene/transcript/protein information for each of the LD SNPs listed in Table 3 is provided in Tables 1-2 (Tables 1-2 also provide sequences and information for each of the "interrogated SNPs", which are listed in Tables 4-10 in Example 1 above). Thus, for any LD SNP listed in Table 3, sequence and allele information (or other information) can be found by searching Tables 1-2 using the hCV (or hDV) or rs identification number of the LD SNP of interest. All publications and patents cited in this specification are herein incorporated by reference in their entirety. Modifications and variations of the described compositions, methods and systems of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments and certain working examples, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described modes for carrying out the invention that are obvious to those skilled in the field of molecular biology, genetics and related fields are intended to be within the scope of the following claims.

Gene Symbol ACAN - 176

Gene Name: aggrecan

Public Transcript Accession: NM_001135

Public Protein Accession: NP_001126

Chromosome: 15

OMIM NUMBER:

OMIM Information:

Transcript Sequence (SEQ ID NO: 1)

Protein Sequence (SEQ ID NO:

SNP Information

Context (SEQ ID NO: 79):

CTTGACTTCAGTGGGCAGCTGTCAGGGGACAGGGCAAGTGGACTGCCCTCTGGAGACCTG GACTCCAGTGGTCTTACTTCC

ACAGTGGGCTCAGGCCTGC

M

TGTGGAAAGTGGACTACCCTCAGGGGATGAAGAGAGAATTGAGTGGCCCAGCACTCC TACGGTTGGTGAACTGCCCTCTGG AGCTGAGATCCTAGAGGGC

Celera SNP ID: hCV25473397

Public SNP ID: rs35430524

SNP Chromosome Position: 87199557

SNP in Transcript Sequence SEQ ID NO: 1

SNP Position Transcript: 3112

SNP Source: Appl era

Population (Allele, Count) : Caucasian (A,3|C,35) African American (A,0|C,36) total (A, 3 IC, 71)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 40, at position 913,(P,CCT) (T , ACT) SNP Source: Appl era

Population (Allele, Count) : Caucasian (A,7|C,33) African American (A,0|C,32) total (A, 7IC, 65)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 40, at position 913,(P,CCT) (T , ACT) SNP Source: dbSNP

Population (Allele, Count) : no_pop (A,-|C,-)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 40, at position 913,(P,CCT) (T , ACT)

Gene Number: 2

Gene Symbol ATAD5 - 79915

Gene Name: ATPase family, AAA domain containing 5

Public Transcript Accession: NM_024857

Public Protein Accession: NP_079133

Chromosome : 17

OMIM NUMBER:

OMIM Information:

Transcript Sequence (SEQ ID NO: 2 )

Protein Sequence (SEQ ID NO:

SNP Information

Context (SEQ ID NO: 80)

GGGGTCCTGGCCATGGCGGCTGCAGCTGCTCCGCCTCCCGTGAAGGACTGCGAGATTGAG CCATGCAAAAAGCGAAAGAAA

GATGATGACACATCTACCT

W

CAAAACAATTACAAAATATTTATCACCACTAGGGAAGACTAGAGACAGGGTTTTTGC TCCACCAAAACCTAGTAATATTCT GGATTATTTTAGAAAGACT

Celera SNP ID: hCV27849348

Public SNP ID: rs9910051

SNP Chromosome Position: 26185328

SNP in Transcript Sequence SEQ ID NO: 2

SNP Position Transcript: 453

SNP Source: Appl era

Population (Allele, Count) : Caucasian (A,21|T,3) African American (A,1|T,5) SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 41, at position 35,(S,TCT) (T , ACT) SNP Source: dbSNP; HapMap; HGBASE

Popul ati on (Al 1 el e , Count) Caucasian (A, 106 |T, 14)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 41, at position 35,(S,TCT) (T , ACT)

Context (SEQ ID NO: 81):

AAATCTAAGAAAAAATCTAACAAAAGATCTGAGAAATCTGAAGCAACTGATGGAGGTTTT ACTTCTCAGATTAGAAAGGCA

AGCAATACTTCAAAAAACA

M

ATCAAAAGCAAAACAATTGATTGAAAAAGCAAAAGCTTTACACATCAGTAGGTCAAA GGTGACTGAAGAAATAGCGATACC CTTAAGGCGCTCCTCTAGA

Celera SNP ID: hCVl955740

Public SNP ID: rs3764421

SNP Chromosome Position: 26191779

SNP in Transcript Sequence SEQ ID NO: 2

SNP Position Transcript: 2445

Related interrogated SNP: hCV27849348

SNP Source: Appl era

Popul ati on (Allele, Count) : Caucasian (A, 35 C,3) African American (A,35|C,3) total (A, 701C, 6)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 41, at position 699, (K, AAA) (Q, CAA) SNP Source: dbSNP; Celera; HapMap; ABI_Val ; HGBASE

Popul ati on (Allele, Count) : Caucasian (A, 202 |C, 24)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 41, at position 699, (K, AAA) (Q, CAA)

Context (SEQ ID NO: 82):

ACAGGTTCACCCTATTCCGCCCAAAAAGACAGGGAAAATACCCCGAATTTTCTTGAAACA AAAGCAATTTGAAATGGAAAA

TAGTTTATCTGATCCTGAG

Y

ATGAACAGACAGTTCAGAAAAGAAAATCTAATGTTGTTATACAGGAGGAAGAATTAG AATTGGCTGTTTTGGAAGCTGGAA GTTCTGAAGCTGTGAAACC

Celera SNP ID: hCVl955744

Public SNP ID: rsll655623

SNP Chromosome Position: 26186299

SNP in Transcript Sequence SEQ ID NO: 2

SNP Position Transcript: 1424

Related interrogated SNP: hCV27849348

SNP Source: Appl era

Popul ati on (Allele, Count) : Caucasian (C, 3 IT , 37) African American (C,7|T,31) total (C,10|T,68)

SNP Type: Silent Mutation

Protein Coding: SEQ ID NO: 41, at position 358, (D, GAT) (D , GAC) SNP Source: dbSNP; Celera; HapMap

Popul ati on (Allele, Count) : Caucasian (T,200|C,24)

SNP Type: Silent Mutation

Protein Coding: SEQ ID NO: 41, at position 358, (D, GAT) (D , GAC)

Context (SEQ ID NO: 83):

GCTCCACCAAAACCTAGTAATATTCTGGATTATTTTAGAAAGACTTCACCCACAAATGAG AAGACACAATTAGGGAAAGAG

TGCAAGATAAAGTCACCTG

Y

ATCAGTACCTGTTGACAGCAACAAAGACTGTACGACACCTTTGGAAATGTTCTCAAA TGTAGAGTTTAAGAAGAAAAGAAA GAGGGTTAATTTATCTCAT

Celera SNP ID: hCV27493873

Public SNP ID: rs3816780

SNP Chromosome Position: 26185484

SNP in Transcript Sequence SEQ ID NO: 2

SNP Position Transcript: 609

Related interrogated SNP: hCV27849348

SNP Source: Appl era

Popul ati on (Allele, Count) : Caucasian (C,33|T,3) African American (C,23|T,7) total (C,56|T,10)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 41, at position 87,(S,TCA) (P,CCA) Popul ati on (Al 1 el e , Count) Caucasian (C,37|T,3) African American (C,17|T,5) total (C,54|T,8)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 41, at position 87,(S,TCA) (P,CCA) SNP Source: dbSNP; HapMap; ABI_Val ; HGBASE

Popul ati on (Al 1 el e , Count) Caucasian (C,200|T,24)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 41, at position 87,(S,TCA) (P,CCA)

Context (SEQ ID NO: 84):

ACTGCAAATACTTGTGATATCAGAAAAAGTATCCTTTACTTACAATTCTGGATTAGAAGT GGAGGTGGAGTTTTAGAAGAA

CGACCATTAACCCTTTATC

Y

TGGAAATAGCAGAAATGTACAACTAGTTTGCTCTGAACATGGCCTTGATAACAAAAT TTACCCTAAAAATACTAAAAAGAA ACGTGTAGACCTTCCAAAA

Celera SNP ID: hCV30686611

Public SNP ID: rsll657270

SNP Chromosome Position: 26238513

SNP in Transcript Sequence SEQ ID NO: 2

SNP Position Transcript: 4605

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap; ABI_Val

Popul ati on (Allele, Count) : Caucasian (T,202|C,24)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 41, at position 1419,(L,CTT) (F , TTT)

Gene Number: 3

Gene Symbol BCAS3 - 54828

Gene Name: breast carcinoma amplified sequence 3

Public Transcript Accession: NM_017679

Public Protein Accession: NP_060149

Chromosome : 17

OMIM NUMBER:

OMIM Information:

Transcript Sequence (SEQ ID NO: 3) :

Protein Sequence (SEQ ID NO: 42):

SNP Information

Context (SEQ ID NO: 85):

TCTAACAGAAGAAAAGGAGAAAATAGTCTGGGTCAGATTTGAAAATGCAGATTTAAATGA TACATCAAGAAATCTGGAATT

TCATGAAATACATAGTACT

R

GGAATGAACCGCCTTTGTTGATTATGATTGGCTACAGTGATGGAATGCAGGTCTGGA GCATCCCTATCAGTGGCGAAGCAC AAGAGCTCTTCTCTGTTCG

Celera SNP ID: hCV25962833

Public SNP ID: rs34712615

SNP Chromosome Position: 56141463

SNP in Transcript Sequence SEQ ID NO: 3

SNP Position Transcript: 365

SNP Source: Appl era

Popul ati on (Allele, Count) : Caucasian (A,40|G, 0) African American (A,27|G,9) total (A, 67IG, 9)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 42, at position 106,(I,ATC) (V,GTC) SNP Source: dbSNP

Popul ati on (Allele, Count) : no_pop (A,-|G,-)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 42, at position 106,(I,ATC) (V,GTC)

Gene Number: 4

Gene Symbol BUBlB - 701

Gene Name: BUBl budding uninhibited by benzimidazoles homolog beta (yeast)

Public Transcript Accession: NM_001211

Public Protein Accession: NP_001202 OMIM NUMBER: 602860

OMIM Information: Colorectal cancer, 114500 (3)

Transcript Sequence (SEQ ID NO: 4):

Protein Sequence (SEQ ID NO: 43) :

SNP Information

Context (SEQ ID NO: 86):

GATGTTTGTGATGAATTTACAGGAATTGAACCCTTGAGCGAGGATGCCATTATCACAGGC TTCAGAAATGTAACAATTTGT

CCTAACCCAGAAGACACTT

Y

TGACTTTGCCAGAGCAGCTCGTTTTGTATCCACTCCTTTTCATGAGATAATGTCCTT GAAGGATCTCCCTTCTGATCCTGA GAGACTGTTACCGGAAGAA

Celera SNP ID: hCV8868138

Public SNP ID: rsl801528

SNP Chromosome Position: 38285795

SNP in Transcript Sequence SEQ ID NO: 4

SNP Position Transcript: 2038

SNP Source: Appl era

Population (Allele, Count) : Caucasian (C,0|T,36) African American (C,10|T,26) total (C,10|T,62)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 43, at position 618,(V,GTA) (A, GCA) SNP Source: HGBASE ; HapMap ; dbSNP

Population (Allele, Count) : no_pop (C,-|T,-)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 43, at position 618,(V,GTA) (A, GCA)

Context (SEQ ID NO: 87):

GAATGCAGGATGGCGGCGGTGAAGAAGGAAGGGGGTGCTCTGAGTGAAGCCATGTCCCTG GAGGGAGATGAATGGGAACTG

AGTAAAGAAAATGTACAAC

Y

TTTAAGGCAAGGGCGGATCATGTCCACGCTTCAGGGAGCACTGGCACAAGAATCTGC CTGTAACAATACTCTTCAGCAGCA GAAACGGGCATTTGAATAT

Celera SNP ID: hDV81584461

Public SNP ID:

SNP Chromosome Position: 38244629

SNP in Transcript Sequence SEQ ID NO: 4

SNP Position Transcript: 304

SNP Source: dbSNP

Population (Allele, Count) : no_pop (C,-|T,-)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 43, at position 40,(T,ACG) (M , ATG)

Gene Number:

Gene Symbol Cl7orf42 - 79736

Gene Name: chromosome 17 open reading frame 42

Public Transcript Accession: NM_024683

Public Protein Accession: NP_078959

Chromosome : 17

OMIM NUMBER:

OMIM Information:

Transcript Sequence (SEQ ID NO: 5) :

Protein Sequence (SEQ ID NO: 44)

SNP Information

Context (SEQ ID NO: 88) :

GTGTTCTTCCCATCAGATAAAATAGTTCACTACAGACAGATGTTTTTATCTACTGAACTA CAAAGAGTAGAAGAGCTTTAT

GATTCATTATTACAAGCTA

R

TGCCTTCTATGAATTAGCAGTGTTTGACTCTCAGCCTTAGAATTCTGAGGTTAACGT GCTAAAGTATAATTATTAGCTCTA ACGTAACACCAACTGTTGT

Celera SNP ID: hCVll413173 SNP Chromosome Position: 26250354

SNP in Transcript Sequence SEQ ID NO: 5

SNP Position Transcript: 1113

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap; ABI_Val ; HGBASE

Population (Allele, Count) : Gaucasian (A, 202 |G, 24)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 44, at position 348, (I, ATT) (V , GTT)

Gene Number: 6

Gene Symbol CENPW - 387103

Gene Name: chromosome 6 open reading frame 173

Public Transcript Accession: NM_001012507

Public Protein Accession: NP_001012525

Chromosome : 6

OMIM NUMBER:

OMIM Information:

Transcript Sequence (SEQ ID NO: 6):

Protein Sequence (SEQ ID NO: 45) :

SNP Information

Context (SEQ ID NO: 89):

TGGAGAAAAGTGGTGACTTATTGGTCCATCTGAACTGTTTACTGTTTGTTCATCGATTAG CAGAAGAGTCCAGGACAAACG

CTTGTGCGAGTAAATGTAG

Y

GTCATTAACAAGGAGCATGTACTGGCCGCAGCAAAGGTAATTCTAAAGAAGAGCAGA GGTTAGAAGTCAAAGAACATATTC TTGAAAGTTATGATGCATT

Celera SNP ID: hDV88213803

Public SNP ID:

SNP Chromosome Position: 126709108

SNP in Transcript Sequence SEQ ID NO: 6

SNP Position Transcript: 358

SNP Source: CDX

Population (Allele, Count) : no_pop (C,-|T,-)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 45, at position 64,(T,ACA) (I, ATA)

Gene Number: 7

Gene Symbol CEP290 - 80184

Gene Name: centrosomal protein 290kDa

Public Transcript Accession: NM_025114

Public Protein Accession: NP_079390

Chromosome : 12

OMIM NUMBER:

OMIM Information:

Transcript Sequence (SEQ ID NO: 7):

Protein Sequence (SEQ ID NO: 46):

SNP Information

Context (SEQ ID NO: 90):

CTCTTCAACTGAGTGAGGCTACTGCTCTTGGTAAGTTGGAGTCAATTACATCTAAACTGC AGAAGATGGAGGCCTACAACT

TGCGCTTAGAGCAGAAACT

R

GATGAAAAAGAACAGGCTCTCTATTATGCTCGTTTGGAGGGAAGAAACAGAGCAAAA CATCTGCGCCAAACAATTCAGTCT CTACGACGACAGTTTAGTG

Celera SNP ID: hCV29120804

Public SNP ID: rs7307793

SNP Chromosome Position: 87007259

SNP in Transcript Sequence SEQ ID NO: 7

SNP Position Transcript: 4070

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Gaucasian (G,120|A,-) Protein Coding: SEQ ID NO: 46, at position 1242,(R,CGC) (H,CAC)

Context (SEQ ID NO: 91):

AGAAAATTTGCTGTAATTCGTCATCAACAAAGTTTGTTGTATAAAGAATACCTAAGTGAA AAGGAGACCTGGAAAACAGAA

TCTAAAACAATAAAAGAGG

R

AAAGAGAAAACTTGAGGATCAAGTCCAACAAGATGCTATAAAAGTAAAAGAATATAA TAATTTGCTCAATGCTCTTCAGAT GGATTCGGATGAAATGAAA

Celera SNP ID: hCV31193798

Public SNP ID: rslll04738

SNP Chromosome Position: 87024978

SNP in Transcript Sequence SEQ ID NO: 7

SNP Position Transcript: 2872

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Gaucasian (A,215|G,9)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 46, at position 843, (K, AAA) (E , GAA)

Gene Number:

Gene Symbol FANCA - 2175

Gene Name: Fanconi anemia, complementation group A

Public Transcript Accession: NM_000135

Public Protein Accession: NP_000126

Chromosome : 16

OMIM NUMBER: 607139

OMIM Information: Fanconi anemia, complementation group A, 227650 (3)

Transcript Sequence (SEQ ID NO: 8) :

Protein Sequence (SEQ ID NO: 47):

SNP Information

Context (SEQ ID NO: 92):

GCATAACATGGAGCTCTTGTTGCACTAAAAAGTGGATTACAAATCTCCTCGACTGCTTTA GTGGGGAAAGGAATCAATTAT

TTATGAACTGTCCGGCCCC

R

AGTCACTCAGCGTTTGCGGGAAAATAAACCACTGGTCCCAGAGCAGAGGAAGGCTAC TTGAGCCGGACACCAAGCCCGCCT CCAGCACCAAGGGCGGGCA

Celera SNP ID: hCV3020887

Public SNP ID: rsl230

SNP Chromosome Position: 88332356

SNP in Transcript Sequence SEQ ID NO:

SNP Position Transcript: 4564

SNP Source: Appl era

Population (Allele, Count) : Gaucasi an (G,23|A,17) African American (G,8|A,28) total (G,31|A,45)

SNP Type: UTR3

SNP Source: dbSNP; HapMap; HGBASE

Population (Allele, Count) : Gaucasian (G,133|A,93)

SNP Type: UTR3

Context (SEQ ID NO: 93):

GCCATGCTTTCTGATTTTGTTCAAATGTTTGTTTTGAGGGGATTTCAGAAAAACTCAGAT CTGAGAAGAACTGTGGAGCCT

GAAAAAATGCCGCAGGTCA

R

GGTTGATGTACTGCAGAGAATGCTGATTTTTGCACTTGACGCTTTGGCTGCTGGAGT ACAGGAGGAGTCCTCCACTCACAA GATCGTGAGGTGCTGGTTC

Celera SNP ID: hCV30590701

Public SNP ID: rs7190823

SNP Chromosome Position: 88393544

SNP in Transcript Sequence SEQ ID NO: 8

SNP Position Transcript: 839

SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Gaucasian (A, 132 |G, 94)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 47, at position 266,(T,ACG) (A, GCG) Gene Symbol FANCA - 2175

Gene Name: Fanconi anemia, complementation group A

Public Transcript Accession: NM_001018112

Public Protein Accession: NP_001018122

Chromosome: 16

OMIM NUMBER: 607139

OMIM Information: Fanconi anemia, complementation group A, 227650 (3)

Transcript Sequence (SEQ ID NO: 9):

Protein Sequence (SEQ ID NO: 48):

SNP Information

Context (SEQ ID NO: 94):

GCCATGCTTTCTGATTTTGTTCAAATGTTTGTTTTGAGGGGATTTCAGAAAAACTCAGAT CTGAGAAGAACTGTGGAGCCT

GAAAAAATGCCGCAGGTCA

R

GGTTGATGTACTGCAGAGAATGCTGATTTTTGCACTTGACGCTTTGGCTGCTGGAGT ACAGGAGGAGTCCTCCACTCACAA GATCGTGAGGTGCTGAGCT

Celera SNP ID: hCV30590701

Public SNP ID: rs7190823

SNP Chromosome Position: 88393544

SNP in Transcript Sequence SEQ ID NO: 9

SNP Position Transcript: 839

SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Gaucasian (A, 132 |G, 94)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 48, at position 266,(T,ACG) (A, GCG)

Context (SEQ ID NO: 95):

ATCCTGTTCCGCCTCTGGAAGTCCTGCACCAATGTTTGTCCCACTCACTGTGACCTCCTC CTGTGTGGAGTCTCCCCTTGC

TCCTCCTTCCCTGGGTGTG

R

TTCAGGCTCTAGAGCTGGCCCTGCCTCTCAGCCCCCCACATTTCTAGAACACACTGT AGCTGTGCCTCTACAGACTCCCGC TGCCTGGCCTCCACAGATC

Celera SNP ID: hCV31692777

Public SNP ID: rsl0852623

SNP Chromosome Position: 88392743

SNP in Transcript Sequence SEQ ID NO: 9

SNP Position Transcript: 1181

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Gaucasian (A, 132 |G, 94)

SNP Type: UTR3

Context (SEQ ID NO: 96):

CATTTCTAGAACACACTGTAGCTGTGCCTCTACAGACTCCCGCTGCCTGGCCTCCACAGA TCCTGCTCAGATTCACCAGTA

GGCAAAGCTTGGCCCTATT

W

GCTTTTTCTCTCCATGGCTCTGTGGAGATGTGCGGAGACCCTTACAGGTCGGGAGGC GGAAGCTGAGGAGTGGGGGCTGGG TGGAAGGTGGACATCGGGG

Celera SNP ID: hCV31692778

Public SNP ID: rsll076626

SNP Chromosome Position: 88392604

SNP in Transcript Sequence SEQ ID NO: 9

SNP Position Transcript: 1320

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795 Related interrogated SNP: hCV30590701

Related interrogated SNP: hCV31692807

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (A,69|T,51)

SNP Type: UTR3

Gene Number: 9

Gene Symbol FANCL - 55120

Gene Name: Fanconi anemia, complementation group L

Public Transcript Accession: NM_018062

Public Protein Accession: NP_060532

Chromosome : 2

OMIM NUMBER: 608111

OMIM Information: Fanconi anemia, complementation group L (3)

Transcript Sequence (SEQ ID NO: 10):

Protein Sequence (SEQ ID NO: 49):

SNP Information

Context (SEQ ID NO: 97):

GGAAGCGAGCCTGTTGCGCCAGTGCCCCCTGCTTCTGCCCCAGAACCGGTCGAAAACCGT GTATGAGGGATTCATCTCGGC

TCAGGGAAGAGACTTCCAC

Y

TTAGGATAGTGTTGCCTGAAGATTTACAACTGAAGAATGCAAGATTATTATGTAGTT GGCAGCTGAGAACAATACTTAGTG GATACCATCGAATAGTACA

Celera SNP ID: hDV81424415

Public SNP ID:

SNP Chromosome Position: 58312736

SNP in Transcript Sequence SEQ ID NO: 10

SNP Position Transcript: 179

SNP Source: dbSNP

Population (Allele, Count) : no_pop (T,-|C,-)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 49, at position 38,(L,CTT) (F , TTT)

Gene Number: 10

Gene Symbol FGFR3 - 2261

Gene Name: fibroblast growth factor receptor 3

(achondroplasia, thanatophoric dwa

rfi sm)

Public Transcript Accession: NM_000142

Public Protein Accession: NP_000133

Chromosome : 4

OMIM NUMBER: 134934

OMIM Information: Achondroplasia, 100800 (3); Hypochondropl asi a, 146000 (3) ;/Thanatophor

ic dysplasia, types I and II, 187600 (3); Crouzon syndrome with acanthosis nigricans (3); Muenke syn

drome, 602849 (3); Bladder cancer , /109800 (3); Colorectal cancer, somatic, 109800

(3); Cervical cane

er, somatic, 603956 (3)

Transcript Sequence (SEQ ID NO: 11):

Protein Sequence (SEQ ID NO: 50):

SNP Information

Context (SEQ ID NO: 98):

TCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGAGGAGCTGGTGGAGGCTGACGAGGCGGGC AGTGTGTATGCAGGCATCCTC

AGCTACGGGGTGGGCTTCT

Y

CCTGTTCATCCTGGTGGTGGCGGCTGTGACGCTCTGCCGCCTGCGCAGCCCCCCCAA GAAAGGCCTGGGCTCCCCCACCGT GCACAAGATCTCCCGCTTC Public SNP ID: rsl7881656

SNP Chromosome Position: 1775929

SNP in Transcript Sequence SEQ ID NO: 11

SNP Position Transcript: 1407

SNP Source: ABI_Val ;Celera;HGBASE;dbSNP

Population (Allele, Count) : no_pop (C,-|T,-)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 50, at position 384,(F,TTC) (L,CTC)

Gene Number: 11

Gene Symbol IGFl - 3479

Gene Name: insulin-like growth factor 1 (somatomedin C)

Public Transcript Accession: NM_000618

Public Protein Accession: NP_000609

Chromosome : 12

OMIM NUMBER: 147440

OMIM Information: Growth retardation with deafness and mental retardation due to/lGFl de

ficiency, 608747 (3)

Transcript Sequence (SEQ ID NO: 12):

Protein Sequence (SEQ ID NO: 51) :

SNP Information

Context (SEQ ID NO: 99) :

TCTACTGATAAAGAAAGAATTTATGAGAAATTGTTGAAAGAGATGGCTAACAATCTGTGA AGATTTTTTGTTTCTTGTTTT

TGTTTTTTTTTTTTTTTTA

C

TTTATACAGTCTTTATGAATTTCTTAATGTTCAAAATGACTTGGTTCTTTTCTTCTT TTTTTATATCAGAATGAGGAATAA TAAGTTAAACCCACATAGA

Celera SNP ID: hDV89345868

Public SNP ID:

SNP Chromosome Position: 101315993

SNP in Transcript Sequence SEQ ID NO: 12

SNP Position Transcript: 5103

SNP Source: CDX

Population (Allele, Count) : no_pop (C,-| ,-)

SNP Type: UTR3 Indel

Gene Number: 12

Gene Symbol IGFALS - 3483

Gene Name: insulin-like growth factor binding protein, acid labile subunit

Public Transcript Accession NM_004970

Public Protein Accession: NP_004961

Chromosome : 16

OMIM NUMBER: 601489

OMIM Information: Acid-labile subunit, deficiency of (3)

Transcript Sequence (SEQ ID NO: 13):

Protein Sequence (SEQ ID NO: 52):

SNP Information

Context (SEQ ID NO: 100):

AACAACTCACTGCGGACCTTCACGCCGCAGCCCCCGGGCCTGGAGCGCCTGTGGCTGGAG GGTAACCCCTGGGACTGTGGC

TGCCCTCTCAAGGCGCTGC

Y

GGACTTCGCCCTGCAGAACCCCAGTGCTGTGCCCCGCTTCGTCCAGGCCATCTGTGA GGGGGACGATTGCCAGCCGCCCGC GTACACCTACAACAACATC

Celera SNP ID: hCV25995019

Public SNP ID: rs9282731

SNP Chromosome Position: 1780778

SNP in Transcript Sequence SEQ ID NO: 13 SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasian (T,0|C,34) Tfrican Tmerican (T,1|C,9) total (T,1|C,43)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 52, at position 548,(R,CGG) (W,TGG) SNP Source: dbSNP; Applera

Popul ati on (Al 1 el e , Count) Caucasian (C,218|T,2)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 52, at position 548,(R,CGG) (W,TGG)

Gene Number: 13

Gene Symbol IGFBP3 - 3486

Gene Name: insulin-like growth factor binding protein 3 Public Transcript Accessi on : NM_000598

Public Protein Accession: NP_000589

Chromosome : 7

OMIM NUMBER: 146732

OMIM Information:

Transcript Sequence (SEQ ID NO: 14):

Protein Sequence (SEQ ID NO: 53):

SNP Information

Context (SEQ ID NO: 101):

CCTACCTGCTGCCAGCGCCGCCAGCTCCAGGAAATGCTAGTGAGTCGGAGGAAGACCGCA GCGCCGGCAGTGTGGAGAGCC

CGTCCGTCTCCAGCACGCA

M

CGGGTGTCTGATCCCAAGTTCCACCCCCTCCATTCAAAGATAATCATCATCAAGAAA GGGCATGCTAAAGACAGCCAGCGC TACAAAGTTGACTACGAGT

Celera SNP ID: hCV29670713

Public SNP ID: rs9282734

SNP Chromosome Position: 45923494

SNP in Transcript Sequence SEQ ID NO: 14

SNP Position Transcript: 606

SNP Source: dbSNP

Popul ati on (Allele, Count) : Caucasian (A,113|C,1)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 53, at position 158,(H,CAC) (P,CCC)

Gene Number: 13

Gene Symbol IGFBP3 - 3486

Gene Name: i nsu1 i n-1 i ke g factor binding protein 3

Public Transcript Accession: NM_001013398

Public Protein Accession: NP_001013416

Chromosome : 7

OMIM NUMBER: 146732

OMIM Information:

Transcript Sequence (SEQ ID NO: 15):

Protein Sequence (SEQ ID NO: 54):

SNP Information

Context (SEQ ID NO: 102):

CGCCAGCTCCAGGTGAGCCGCCCGCGCCAGGAAATGCTAGTGAGTCGGAGGAAGACCGCA GCGCCGGCAGTGTGGAGAGCC

CGTCCGTCTCCAGCACGCA

M

CGGGTGTCTGATCCCAAGTTCCACCCCCTCCATTCAAAGATAATCATCATCAAGAAA GGGCATGCTAAAGACAGCCAGCGC TACAAAGTTGACTACGAGT

Celera SNP ID: hCV29670713

Public SNP ID: rs9282734

SNP Chromosome Position: 45923494

SNP in Transcript Sequence SEQ ID NO: 15

SNP Position Transcript: 624

SNP Source: dbSNP SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 54, at position 164, (H , CAC) (P,CCC)

Gene Number: 14

Gene Symbol KRAS - 3845

Gene Name: v-Ki-ras2 Ki rsten rat sarcoma viral oncogene homolog

Public Transcript Accession: NM_004985

Public Protein Accession: NP_004976

Chromosome : 12

OMIM NUMBER:

OMIM Information:

Transcript Sequence (SEQ ID NO: 16):

Protein Sequence (SEQ ID NO: 55):

SNP Information

Context (SEQ ID NO: 103):

GAATAGTCATAACTAGATTAAGATCTGTGTTTTAGTTTAATAGTTTGAAGTGCCTGTTTG GGATAATGATAGGTAATTTAG

ATGAATTTAGGGGAAAAAA

M

AGTTATCTGCAGATATGTTGAGGGCCCATCTCTCCCCCCACACCCCCACAGAGCTAA CTGGGTTACAGTGTTTTATCCGAA AGTTTCCAATTCCACTGTC

Celera SNP ID: hDV75942727

Public SNP ID: rs34719539

SNP Chromosome Position: 25249931

SNP in Transcript Sequence SEQ ID NO: 16

SNP Position Transcript: 4813

SNP Source: CDX;dbSNP

Population (Allele, Count) : no_pop (C,-|A,-)

SNP Type: UTR3

Gene Number: 14

Gene Symbol KRAS - 3845

Gene Name: v-Ki-ras2 Ki rsten rat sarcoma viral oncogene homolog

Public Transcript Accession: NM_033360

Public Protein Accession: NP_203524

Chromosome : 12

OMIM NUMBER:

OMIM Information:

Transcript Sequence (SEQ ID NO: 17):

Protein Sequence (SEQ ID NO: 56):

SNP Information

Context (SEQ ID NO: 104):

GAATAGTCATAACTAGATTAAGATCTGTGTTTTAGTTTAATAGTTTGAAGTGCCTGTTTG GGATAATGATAGGTAATTTAG

ATGAATTTAGGGGAAAAAA

M

AGTTATCTGCAGATATGTTGAGGGCCCATCTCTCCCCCCACACCCCCACAGAGCTAA CTGGGTTACAGTGTTTTATCCGAA AGTTTCCAATTCCACTGTC

Celera SNP ID: hDV75942727

Public SNP ID: rs34719539

SNP Chromosome Position: 25249931

SNP in Transcript Sequence SEQ ID NO: 17

SNP Position Transcript: 4937

SNP Source: CDX;dbSNP

Population (Allele, Count) : no_pop (C,-|A,- SNP Type: UTR3

Gene Number: 15

Gene Symbol LEPR - 3953

Gene Name: leptin receptor Public Protein Accession: NP_001003679

Chromosome : 1

OMIM NUMBER: 601007

OMIM Information: Obesity, morbid, with hypogonadism (3)

Transcript Sequence (SEQ ID NO: 18):

Protein Sequence (SEQ ID NO: 57):

SNP Information

Context (SEQ ID NO: 105):

TAATTGGAGCAATCCAGCCTACACAGTTGTCATGGATATAAAAGTTCCTATGAGAGGACC TGAATTTTGGAGAATAATTAA

TGGAGATACTATGAAAAAG

S

AGAAAAATGTCACTTTACTTTGGAAGCCCCTGATGAAAAATGACTCATTGTGCAGTG TTCAGAGATATGTGATAAACCATC ATACTTCCTGCAATGGAAC

Celera SNP ID: hCV8722378

Public SNP ID: rs8179183

SNP Chromosome Position: 65848540

SNP in Transcript Sequence SEQ ID NO: 18

SNP Position Transcript: 2171

SNP Source: Appl era

Population (Allele, Count) : Caucasian (C,5|G,31) African American (C,9|G,23) total (C,14|G,54)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 57, at position 656,(K,AAG) (N , AAC) SNP Source: dbSNP; HapMap; HGBASE

Population (Allele, Count) : Caucasian (G, 108 |C, 12)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 57, at position 656,(K,AAG) (N , AAC)

Context (SEQ ID NO: 106):

TATTAGAAGATTTTTACATTTTGAAGAAGGGGAGCAAATCTAAAAAAAATTCAGTTGAAC TTCTGAGAGTTAACATATGGT

GGATTATGTTGATTTAGAA

M

TTAAAATAGATGTGTAAATTTGGGTTCAAAATGTAGATTTGAGTCCAGTTTGGATGT GTGATTAATTTTCAAATCATCTAA AGTTTAAAAGTAGTATTCA

Celera SNP ID: hDV70950526

Public SNP ID: rsl7415296

SNP Chromosome Position: 65871601

SNP in Transcript Sequence SEQ ID NO: 18

SNP Position Transcript: 3054

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (C,198|A, 28)

SNP Type: UTR3

Gene Number: 15

Gene Symbol LEPR - 3953

Gene Name: leptin receptor

Public Transcript Accession: NM_001003680

Public Protein Accession: NP_001003680

Chromosome : 1

OMIM NUMBER: 601007

OMIM Information: Obesity, morbid, with hypogonadism (3)

Transcript Sequence (SEQ ID NO: 19)

Protein Sequence (SEQ ID NO: 58)

SNP Information

Context (SEQ ID NO: 107):

TAATTGGAGCAATCCAGCCTACACAGTTGTCATGGATATAAAAGTTCCTATGAGAGGACC TGAATTTTGGAGAATAATTAA

TGGAGATACTATGAAAAAG

S

AGAAAAATGTCACTTTACTTTGGAAGCCCCTGATGAAAAATGACTCATTGTGCAGTG TTCAGAGATATGTGATAAACCATC Celera SNP ID: hCV8722378

Public SNP ID: rs8179183

SNP Chromosome Position: 65848540

SNP in Transcript Sequence SEQ ID NO: 19

SNP Position Transcript: 2171

SNP Source: Appl era

Population (Allele, Count) : Caucasian (C,5|G,31) African American (C,9|G,23) total (C,14|G,54)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 58, at position 656,(K,AAG) (N , AAC) SNP Source: dbSNP; HapMap; HGBASE

Population (Allele, Count) : Caucasian (G, 108 |C, 12)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 58, at position 656,(K,AAG) (N , AAC)

Gene Number: 15

Gene Symbol LEPR - 3953

Gene Name: leptin receptor

Public Transcript Accession: NM_002303

Public Protein Accession: NP_002294

Chromosome : 1

OMIM NUMBER: 601007

OMIM Information: Obesity, morbid, with hypogonadism (3)

Transcript Sequence (SEQ ID NO: 20):

Protein Sequence (SEQ ID NO: 59):

SNP Information

Context (SEQ ID NO: 108):

TAATTGGAGCAATCCAGCCTACACAGTTGTCATGGATATAAAAGTTCCTATGAGAGGACC TGAATTTTGGAGAATAATTAA

TGGAGATACTATGAAAAAG

S

AGAAAAATGTCACTTTACTTTGGAAGCCCCTGATGAAAAATGACTCATTGTGCAGTG TTCAGAGATATGTGATAAACCATC ATACTTCCTGCAATGGAAC

Celera SNP ID: hCV8722378

Public SNP ID: rs8179183

SNP Chromosome Position: 65848540

SNP in Transcript Sequence SEQ ID NO: 20

SNP Position Transcript: 2171

SNP Source: Appl era

Population (Allele, Count) : Caucasian (C,5|G,31) African American (C,9|G,23) total (C,14|G,54)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 59, at position 656,(K,AAG) (N , AAC) SNP Source: dbSNP; HapMap; HGBASE

Population (Allele, Count) : Caucasian (G, 108 |C, 12)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 59, at position 656,(K,AAG) (N , AAC)

Gene Number: 16

Gene Symbol LOC283951 - 283951

Gene Name: hypothetical protein LOC283951

Public Transcript Accession: NM_001010878

Public Protein Accession: NP_001010878

Chromosome : 16

OMIM NUMBER:

OMIM Information:

Transcript Sequence (SEQ ID NO: 21):

Protein Sequence (SEQ ID NO: 60):

SNP Information

Context (SEQ ID NO: 109):

CTTCTCCTTACTGCTCCTTCACAGGCAGAAGCCGAGCCGACGCCCCGGCGCGGGCGGCAG GAAATGGCCAGCCCAGGCTTC R

TCGGCCTCGTCGGTGCTGGTCACTGTCCTGGACGCCAAGGCTCTGCCCCTGACTCTGCTG TCCTGGGGCAGCTTGTGCGCA ACTGCCCAAAACCACAACA

Celera SNP ID: hCV32105505

Public SNP ID: rsll645222

SNP Chromosome Position: 1418455

SNP in Transcript Sequence SEQ ID NO: 21

SNP Position Transcript: 198

Related interrogated SNP: hCV25995019

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Gaucasian (G,221|A,1)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 60, at position 66,(S,AGC) (N , AAC)

Gene Number: 17

Gene Symbol LOC390667 - 390667

Gene Name: similar to Neuronal pentraxin II precursor (NP- (N P2 )

Public Transcript Accession: NM_001013658

Public Protein Accession: NP_001013680

Chromosome : 16

OMIM NUMBER:

OMIM Information:

Transcript Sequence (SEQ ID NO: 22):

Protein Sequence (SEQ ID NO: 61):

SNP Information

Context (SEQ ID NO: 110):

GTCTTCCTCAGCCCTGGTTTCGTCACTGCCCTGCGAGCCCTGTCCTTCTGCAGCTGGGTC CGCACGGCCTCCGGCCGCCTG

GGCACCCTCCTGTCCTACG

K

CACCGAGGACAATGACAACAAGCTGGTGCTGCACGGCCGAGACTCCCTGCTGCCCGG ATCCATCCACTTCGTGATCGGGGA CCCGGCCTTCAGGGAGCTG

Celera SNP ID: hCV32105457

Public SNP ID: rsl3332460

SNP Chromosome Position: 1476429

SNP in Transcript Sequence SEQ ID NO: 22

SNP Position Transcript: 935

Related interrogated SNP: hCV25995019

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Gaucasian (G,222|T,4)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 61, at position 312,(A,GCC) (S,TCC)

Gene Number: 18

Gene Symbol LRP5 - 4041

Gene Name: low density lipoprotein receptor-related protein 5

Public Transcript Accession NM_002335

Public Protein Accession: NP_002326

Chromosome : 11

OMIM NUMBER: 603506

OMIM Information: Osteoporosi s-pseudogl ioma syndrome, 259770 (3); [Bone mineral density/

variability 1], 601884 (3); Osteopetrosis, autosomal dominant, type I, 607634 (3); Hyperostosis, end

osteal , 144750 (3) ; van Buchem disease, type 2, 607636/(3); {Osteoporosis}, 166710 (3); Exudative vi

treoreti nopathy , dominant, 133780 (3); Exudative vitreoretinopathy, recessive, 601813 (3)

Transcript Sequence (SEQ ID NO: 23):

Protein Sequence (SEQ ID NO: 62): Context (SEQ ID NO: 111):

CTGAGTGACATGAAGACCTGCATCGTGCCTGAGGCCTTCTTGGTCTTCACCAGCAGAGCC GCCATCCACAGGATCTCCCTC

GAGACCAATAACAACGACG

R

GGCCATCCCGCTCACGGGCGTCAAGGAGGCCTCAGCCCTGGACTTTGATGTGTCCAA CAACCACATCTACTGGACAGACGT CAGCCTGAAGACCATCAGC

Celera SNP ID: hCV25604912

Public SNP ID: rs4988321

SNP Chromosome Position: 67930765

SNP in Transcript Sequence SEQ ID NO: 23

SNP Position Transcript: 2075

SNP Source: Appl era

Population (Allele, Count) : Caucasi an (A,2|G,38) African American (A,1|G,35) total (A, 3 IG, 73)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 62, at position 667,(V,GTG) (M , ATG) SNP Source: HGMD ; dbSNP; Applera

Population (Allele, Count) : Caucasian (G,111|A,3)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 62, at position 667,(V,GTG) (M , ATG)

Gene Number: 19

Gene Symbol MAPKl - 5594

Gene Name: mi togen-acti protein kinase 1

Public Transcript Accessi on : NM_002745

Public Protein Accession: NP_002736

Chromosome : 22

OMIM NUMBER: 176948

OMIM Information:

Transcript Sequence (SEQ ID NO: 24):

Protein Sequence (SEQ ID NO: 63):

SNP Information

Context (SEQ ID NO: 112):

CCCGGAGATGGTCCGCGGGCAGGTGTTCGACGTGGGGCCGCGCTACACCAACCTCTCGTA CATCGGCGAGGGCGCCTACGG

CATGGTGTGCTCTGCTTAT

Y

ATAATGTCAACAAAGTTCGAGTAGCTATCAAGAAAATCAGCCCCTTTGAGCACCAGA CCTACTGCCAGAGAACCCTGAGGG AGATAAAAATCTTACTGCG

Celera SNP ID: hCV25922338

Public SNP ID: rs3729910

SNP Chromosome Position: 20492126

SNP in Transcript Sequence SEQ ID NO: 24

SNP Position Transcript: 370

SNP Source: Appl era

Population (Allele, Count) : Caucasi an (T,33|C,1) Tfrican Tmerican (T,34|C,0) total (T,67|C,1)

SNP Type: ESS

Protein Coding: SEQ ID NO: 63, at position None

SNP Source: dbSNP; HapMap; HGBASE

Population (Allele, Count) : Caucasian (T,112|C,4)

SNP Type: ESS

Protein Coding: SEQ ID NO: 63, at position None

Context (SEQ ID NO: 113):

TGAGCTACTTCAAATGTGGGTGTTTCAGTAACCACGTTCCATGCCTGAGGATTTAGCAGA GAGGAACACTGCGTCTTTAAA

TGAGAAAGTATACAATTCT

K

TTTCCTTCTACAGCATGTCAGCATCTCAAGTTCATTTTTCAACCTACAGTATAACAA TTTGTAATAAAGCCTCCAGGAGCT CATGACGTGAAGCACTGTT

Celera SNP ID: hCV7626903

Public SNP ID: rsl3058

SNP Chromosome Position: 20447502

SNP in Transcript Sequence SEQ ID NO: 24 SNP Source: dbSNP; HapMap

Population (Allele, Count) : Gaucasian (T,113|G,5)

SNP Type: UTR3

Gene Number: 19

Gene Symbol MAPKl - 5594

Gene Name: mi togen-acti vated protein kinase 1

Public Transcript Accession: NM_138957

Public Protein Accession: NP_620407

Chromosome : 22

OMIM NUMBER: 176948

OMIM Information:

Transcript Sequence (SEQ ID NO: 25):

Protein Sequence (SEQ ID NO: 64):

SNP Information

Context (SEQ ID NO: 114):

CCCGGAGATGGTCCGCGGGCAGGTGTTCGACGTGGGGCCGCGCTACACCAACCTCTCGTA CATCGGCGAGGGCGCCTACGG

CATGGTGTGCTCTGCTTAT

Y

ATAATGTCAACAAAGTTCGAGTAGCTATCAAGAAAATCAGCCCCTTTGAGCACCAGA CCTACTGCCAGAGAACCCTGAGGG AGATAAAAATCTTACTGCG

Celera SNP ID: hCV25922338

Public SNP ID: rs3729910

SNP Chromosome Position: 20492126

SNP in Transcript Sequence SEQ ID NO: 25

SNP Position Transcript: 370

SNP Source: Appl era

Population (Allele, Count) : Caucasi an (T,33|C,1) Tfrican Tmerican (T,34|C,0) total (T,67|C,1)

SNP Type: ESS

Protein Coding: SEQ ID NO: 64, at position None

SNP Source: dbSNP; HapMap; HGBASE

Population (Allele, Count) : Caucasian (T,112|C,4)

SNP Type: ESS

Protein Coding: SEQ ID NO: 64, at position None

Gene Number: 20

Gene Symbol NBN - 4683

Gene Name: ni bri n

Public Transcript Accession: NM_001024688

Public Protein Accession: NP_001019859

Chromosome: 8

OMIM NUMBER:

OMIM Information:

Transcript Sequence (SEQ ID NO: 26):

Protein Sequence (SEQ ID NO: 65):

SNP Information

Context (SEQ ID NO: 115):

AACAGCATAAGAAATTGAGTTCCGCAGTTGTCTTTGGAGGTGGGGAAGCTAGGTTGATAA CAGAAGAGAATGAAGAAGAAC

ATAATTTCTTTTTGGCTCC

Y

GGAACGTGTGTTGTTGATACAGGAATAACAAACTCACAGACCTTAATTCCTGACTGT CAGAAGAAATGGATTCAGTCAATA ATGGATATGCTCCAAAGGC

Celera SNP ID: hCV7566051

Public SNP ID: rs769420

SNP Chromosome Position: 91051867

SNP in Transcript Sequence SEQ ID NO: 26

SNP Position Transcript: 958

SNP Source: dbSNP; ABI_Val HGBASE

Population (Allele, Count) : Caucasian (C,120|T,-) Protein Coding: SEQ ID NO: 65, at position 184,(P,CCG) (L , CTG)

Gene Number: 20

Gene Symbol NBN - 4683

Gene Name: nibrin

Public Transcript Accession: NM_002485

Public Protein Accession: NP_002476

Chromosome: 8

OMIM NUMBER :

OMIM Information:

Transcript Sequence (SEQ ID NO: 27):

Protein Sequence (SEQ ID NO: 66):

SNP Information

Context (SEQ ID NO: 116):

AACAGCATAAGAAATTGAGTTCCGCAGTTGTCTTTGGAGGTGGGGAAGCTAGGTTGATAA CAGAAGAGAATGAAGAAGAAC

ATAATTTCTTTTTGGCTCC

Y

GGAACGTGTGTTGTTGATACAGGAATAACAAACTCACAGACCTTAATTCCTGACTGT CAGAAGAAATGGATTCAGTCAATA ATGGATATGCTCCAAAGGC

Celera SNP ID: hCV7566051

Public SNP ID: rs769420

SNP Chromosome Position: 91051867

SNP in Transcript Sequence SEQ ID NO: 27

SNP Position Transcript: 908

SNP Source: dbSNP; ABI_Val ; HGBASE

Population (Allele, Count) : Caucasian (C,120|T,-)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 66, at position 266,(P,CCG) (L , CTG)

Gene Number: 21

Gene Symbol NHEJl - 79840

Gene Name: nonhomologous end-joining factor 1

Public Transcript Accession: NM_024782

Public Protein Accession: NP_079058

Chromosome : 2

OMIM NUMBER:

OMIM Information:

Transcript Sequence (SEQ ID NO: 28):

Protein Sequence (SEQ ID NO: 67):

SNP Information

Context (SEQ ID NO: 117):

CGAGCGGGCAGGAAAGCGTGCGTGCGGCTAAGAGAGTGGGCGCTCTCGCGGCCGCTGACG ATGGAAGAACTGGAGCAAGGC

CTGTTGATGCAGCCATGGG

R

GTGGCTACAGCTTGCAGAGAACTCCCTCTTGGCCAAGGTTTTTATCACCAAGCAGGG CTATGCCTTGTTGGTTTCAGATCT TCAACAGGTGTGGCATGAA

Celera SNP ID: hCV25636054

Public SNP ID: rs34689457

SNP Chromosome Position: 219731289

SNP in Transcript Sequence SEQ ID NO:

SNP Position Transcript: 123

SNP Source: Appl era

Population (Allele, Count) : Gaucasi an (G,40|A,0) African American (G,32|A,6) total (G,72|A,6)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 67, at position 14,(A,GCG) (T , ACG) SNP Source: dbSNP

Population (Allele, Count) : no_pop (G,-|A,-)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 67, at position 14,(A,GCG) (T , ACG) Gene Number: 22

Gene Symbol NTHLl - 4913

Gene Name: nth endonucle ill-like 1 (E. coli)

Public Transcript Accession: NM_002528

Public Protein Accession: NP_002519

Chromosome : 16

OMIM NUMBER: 602656

OMIM Information:

Transcript Sequence (SEQ ID NO: 29):

Protein Sequence (SEQ ID NO: 68):

SNP Information

Context (SEQ ID NO: 118):

GCCTCTGTGGCCGAGCTGGTGGCGCTGCCGGGTGTTGGGCCCAAGATGGCACACCTGGCT ATGGCTGTGGCCTGGGGCACT

GTGTCAGGCATTGCAGTGG

K

CACGCATGTGCACAGAATCGCCAACAGGCTGAGGTGGACCAAGAAGGCAACCAAGTC CCCAGAGGAGACCCGCGCCGCCCT GGAGGAGTGGCTGCCTAGG

Celera SNP ID: hCVl5793839

Public SNP ID: rs3087468

SNP Chromosome Position: 2030235

SNP in Transcript Sequence SEQ ID NO: 29

SNP Position Transcript: 735

Related interrogated SNP: hCV25995019

SNP Source: dbSNP; HGBASE

Population (Allele, Count) : Gaucasian (G,220|T,2)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 68, at position 239,(D,GAC) (Y , TAC)

Context (SEQ ID NO: 119):

GTGGGGACATCCCAGCCTCTGTGGCCGAGCTGGTGGCGCTGCCGGGTGTTGGGCCCAAGA TGGCACACCTGGCTATGGCTG

TGGCCTGGGGCACTGTGTC

Y

GGCATTGCAGTGGACACGCATGTGCACAGAATCGCCAACAGGCTGAGGTGGACCAAG AAGGCAACCAAGTCCCCAGAGGAG ACCCGCGCCGCCCTGGAGG

Celera SNP ID: hCV32396801

Public SNP ID: rs3211977

SNP Chromosome Position: 2033577

SNP in Transcript Sequence SEQ ID NO: 29

SNP Position Transcript: 721

Related interrogated SNP: hCV25995019

SNP Source: dbSNP; Celera; HapMap; HGBASE

Population (Allele, Count) : Caucasian (C,220|T,4)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 68, at position 234,(S,TCA) (L , TTA)

Gene Number: 23

Gene Symbol PCNT - 5116

Gene Name: peri centri n (kendri n)

Public Transcript Accession: NM_006031

Public Protein Accession: NP_006022

Chromosome : 21

OMIM NUMBER: 170285

OMIM Information:

Transcript Sequence (SEQ ID NO: 30):

Protein Sequence (SEQ ID NO: 69):

SNP Information

Context (SEQ ID NO: 120):

CGGGAGCGGGAGAACCGGGAAGGCGCAAACCTCCTCTCCATGCTCAAGGCCGACGTCAAC CTGTCCCACAGCGAAAGAGGG

GCCCTCCAGGACGCCCTGC

Y CCTGGATGACGCGGGCGCA

Celera SNP ID: hCV2446917

Public SNP ID: rs7279204

SNP Chromosome Position: 46633107

SNP in Transcript Sequence SEQ ID NO: 30

SNP Position Transcript: 3576

SNP Source: Appl era

Population (Allele, Count) : Caucasian (C,34|T,4) African American (C,34|T,4) total (C,68|T,8)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 69, at position 1163,(R,CGC) (C,TGC) SNP Source: Celera;dbSNP

Population (Allele, Count) : no_pop (C,-|T,-)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 69, at position 1163,(R,CGC) (C,TGC)

Context (SEQ ID NO: 121):

CAAACAGCGTGCAGAAGCTCCTGGCGGCGGAGCAGACTGTAGTGCGAGATTTGAAGTCCG ACCTCTGTGAGAGCAGGCAGA

AGAGCGAACAGCTGTCCCG

R

TCCCTCTGCGAGGTGCAGCAGGAGGTCCTCCAGCTGAGATCCATGCTGAGCAGTAAG GAGAACGAGCTGAAGGCCGCGCTT CAGGAGCTGGAGAGTGAGC

Celera SNP ID: hCV25474258

Public SNP ID: rs8131693

SNP Chromosome Position: 46674535

SNP in Transcript Sequence SEQ ID NO: 30

SNP Position Transcript: 7963

SNP Source: Appl era

Population (Allele, Count) : Caucasi an (A,0|G,40) African American (A,7|G,31) total (A, 7IG, 71)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 69, at position 2625,(R,CGG) (Q, CAG) SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (G,120|A,-)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 69, at position 2625,(R,CGG) (Q, CAG)

Gene Number: 24

Gene Symbol PRKCH - 5583

Gene Name: protein kinase C, eta

Public Transcript Accession: NM_006255

Public Protein Accession: NP_006246

Chromosome : 14

OMIM NUMBER: 605437

OMIM Information:

Transcript Sequence (SEQ ID NO: 31):

Protein Sequence (SEQ ID NO: 70):

SNP Information

Context (SEQ ID NO: 122):

CCTCCAGGAAATGCTGTACGGGCCTGCAGTAGACTGGTGGGCAATGGGCGTGTTGCTCTA TGAGATGCTCTGTGGTCACGC

GCCTTTTGAGGCAGAGAAC

Y

AAGATGACCTCTTTGAGGCCATACTGAATGATGAGGTGGTCTACCCTACCTGGCTCC ATGAAGATGCCACAGGGATCCTAA AATCTTTCATGACCAAGAA

Celera SNP ID: hCV7600033

Public SNP ID: rsl088680

SNP Chromosome Position: 61066979

SNP in Transcript Sequence SEQ ID NO: 31

SNP Position Transcript: 1980

Related interrogated SNP: hCV7600023

SNP Source: Appl era

Population (Allele, Count) : Caucasian (C,4|T,32) African American (C,17|T,11) total (C,21|T,43)

SNP Type: Silent Mutation SNP Source: dbSNP; HapMap; ABI_Val ; HGBASE

Population (Allele, Count) : Caucasian (C,31|T,193)

SNP Type: Silent Mutation

Protein Coding: SEQ ID NO: 70, at position 558,(N,AAC) (Ν,ΑΑΤ)

Gene Number: 25

Gene Symbol PTPNl - 5770

Gene Name: protein tyrosine phosphatase, non-receptor type 1

Public Transcript Accession: NM_002827

Public Protein Accession: NP_002818

Chromosome : 20

OMIM NUMBER: 176885

OMIM Information: {insulin resistance, susceptibility to} (3)

Transcript Sequence (SEQ ID NO: 32):

Protein Sequence (SEQ ID NO: 71):

SNP Information

Context (SEQ ID NO: 123):

GCCTCATTCTTGAACTTTCTTTTCAAAGTCCGAGAGTCAGGGTCACTCAGCCCGGAGCAC GGGCCCGTTGTGGTGCACTGC

AGTGCAGGCATCGGCAGGT

K

TGGAACCTTCTGTCTGGCTGATACCTGCCTCTTGCTGATGGACAAGAGGAAAGACCC TTCTTCCGTTGATATCAAGAAAGT GCTGTTAGAAATGAGGAAG

Celera SNP ID: hDV88320149

Public SNP ID:

SNP Chromosome Position: 48628535

SNP in Transcript Sequence SEQ ID NO: 32

SNP Position Transcript: 839

SNP Source: CDX

Population (Allele, Count) : no_pop (G,-|T,-)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 71, at position 222,(S,TCT) (A, GCT)

Gene Number: 26

Gene Symbol PEX2 - 5828

Gene Name: peroxisomal membrane protein 3, 35kDa (Zellweger syndrome)

Public Transcript Accession NM_000318

Public Protein Accession: NP_000309

Chromosome : 8

OMIM NUMBER: 170993

OMIM Information: Zellweger syndrome-3 (3); Refsum disease, infantile form, 266510 (3)

Transcript Sequence (SEQ ID NO: 33)

Protein Sequence (SEQ ID NO: 72)

SNP Information

Context (SEQ ID NO: 124):

AAAGCCAAGCTGTCTTCATGGTGTATTCCTCTTACTGGTGCACCTAATAGTGACAATACA TTAGCCACCAGTGGCAAAGAA

TGCGCTCTATGTGGAGAGT

Y

GCCCACCATGCCTCACACCATAGGATGTGAGCATATTTTCTGTTATTTCTGTGCTAA GAGTAGTTTCTTATTTGACGTGTA CTTTACTTGTCCTAAGTGT

Celera SNP ID: hDV88202422

Public SNP ID:

SNP Chromosome Position: 78058222

SNP in Transcript Sequence SEQ ID NO: 33

SNP Position Transcript: 1207

SNP Source: CDX

Population (Allele, Count) : no_pop (T,-|C,-)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 72, at position 250,(W,TGG) (R, CGG) Context (SEQ ID NO: 125):

AATGTCCAGAAGTTGAAAGCCAAGCTGTCTTCATGGTGTATTCCTCTTACTGGTGCACCT AATAGTGACAATACATTAGCC

ACCAGTGGCAAAGAATGCG

R

TCTATGTGGAGAGTGGCCCACCATGCCTCACACCATAGGATGTGAGCATATTTTCTG TTATTTCTGTGCTAAGAGTAGTTT CTTATTTGACGTGTACTTT

Celera SNP ID: hDV88214691

Public SNP ID:

SNP Chromosome Position: 78058237

SNP in Transcript Sequence SEQ ID NO: 33

SNP Position Transcript: 1192

SNP Source: CDX

Population (Allele, Count) : no_pop (G,-|A,-)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 72, at position 245,(A,GCT) (T , ACT)

Gene Number: 27

Gene Symbol SOS2 - 6655

Gene Name: son of sevenless homolog 2 (Drosophila)

Public Transcript Accession: NM_006939

Public Protein Accession: NP_008870

Chromosome : 14

OMIM NUMBER: 601247

OMIM Information:

Transcript Sequence (SEQ ID NO: 34)

Protein Sequence (SEQ ID NO: 73)

SNP Information

Context (SEQ ID NO: 126):

GAATCGGTGCCAAACATGAACGGCATATTTTTCTGTTTGATGGCTTAATGATCAGTTGTA AACCTAATCATGGCCAGACTC

GGCTTCCAGGTTACAGTAG

R

GCAGAATACAGGTTAAAAGAAAAATTTGTCATGAGGAAAATACAAATTTGTGATAAA GAAGATACTTGTGAGCACAAGCAT GCATTTGAATTAGTATCCA

Celera SNP ID: hCV25598905

Public SNP ID: rsl7122201

SNP Chromosome Position: 49696303

SNP in Transcript Sequence SEQ ID NO: 34

SNP Position Transcript: 1547

SNP Source: Appl era

Population (Allele, Count) : Gaucasian (G,26|A,0) African American (G,25|A,1) total (G,51|A,1)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 73, at position 483,(S,AGT) (Ν,ΑΑΤ) SNP Source: Appl era

Population (Allele, Count) : Gaucasian (G,40|A,0) African American (G,31|A,3) total (G,71|A,3)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 73, at position 483,(S,AGT) (Ν,ΑΑΤ) SNP Source: dbSNP; HapMap

Population (Allele, Count) : Gaucasian (G,120|A,-)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 73, at position 483,(S,AGT) (Ν,ΑΑΤ)

Gene Number:

Gene Symbol SPAG17 - 200162

Gene Name: sperm associated antigen 17

Public Transcript Accession: NM_206996

Public Protein Accession: NP_996879

Chromosome : 1

OMIM NUMBER:

OMIM Information:

Transcript Sequence (SEQ ID NO: 35): SNP Information

Context (SEQ ID NO: 127):

CTCCGGTCAAGGTCATGGGAAACATTTCCCTCAGTTGAGAAAAAAACTCCAGGACCTCCG TTTGGTACTCAGATTTGGAAA

GGCCTTTGCATTGAGTCCA

R

ACAGCTAGTGAGTGCCCCGGGTGCCATACTCAAGAGCCCCAGTGTGCTACAGATGCG CCAATTCATTCAGCATGAGGTCAT AAAGAATGAGGTGAAACTG

Celera SNP ID: hCV25750081

Public SNP ID: rs35290515

SNP Chromosome Position: 118336734

SNP in Transcript Sequence SEQ ID NO: 35

SNP Position Transcript: 5294

SNP Source: Appl era

Population (Allele, Count) : Gaucasi an (G,1|A,35) African American (G,0|A,38) total (G,1|A,73)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 74, at position 1747, (K, AAA) (E , GAA) SNP Source: dbSNP

Population (Allele, Count) : no_pop (G,-|A,-)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 74, at position 1747, (K, AAA) (E , GAA)

Gene Number: 29

Gene Symbol TSC2 - 7249

Gene Name: tuberous sclerosis

Public Transcript Accession NM_000548

Public Protein Accession: NP_000539

Chromosome : 16

OMIM NUMBER: 191092

OMIM Information: Tuberous sclerosis- 2, 191100 (3)

Lymphangi ol ei omyomatosi s , /somati c 6

06690 (3)

Transcript Sequence (SEQ ID NO: 36)

Protein Sequence (SEQ ID NO: 75)

SNP Information

Context (SEQ ID NO: 128):

GGCCTCTTTCTCCTCCCTGTACCAGTCCAGCTGCCAAGGACAGCTGCACAGGAGCGTTTC CTGGGCAGACTCCGCCGTGGT

CATGGAGGAGGGAAGTCCG

R

GCGAGGTTCCTGTGCTGGTGGAGCCCCCAGGGTTGGAGGACGTTGAGGCAGCGCTAG GCATGGACAGGCGCACGGATGCCT ACAGCAGGTCGTCCTCAGT

Celera SNP ID: hDV75028111

Public SNP ID: rsll551373

SNP Chromosome Position: 2073728

SNP in Transcript Sequence SEQ ID NO: 36

SNP Position Transcript: 4022

Related interrogated SNP: hCV25995019

SNP Source: CDX; dbSNP

Population (Allele, Count) : Caucasian (G,216|A,2)

SNP Type: Silent Rare Codon

Protein Coding: SEQ ID NO: 75, at position 1305,(P,CCG) (P,CCA)

Gene Number: 29

Gene Symbol TSC2 - 7249

Gene Name: tuberous sclerosis 2

Public Transcript Accession: NM_001077183

Public Protein Accession: NP_001070651

Chromosome : 16

OMIM NUMBER: 191092

OMIM Information: Tuberous sclerosis-2, 191100 (3);

Lymphangi ol ei omyomatosi s , /somati c , 6 Transcript Sequence (SEQ ID NO: 37):

Protein Sequence (SEQ ID NO: 76):

SNP Information

Context (SEQ ID NO: 129):

GTACAAGTCACTGTCGGTGCCGGCAGCCAGCACGGCCAAACCCCCTCCTCTGCCTCGCTC CAACACAGACTCCGCCGTGGT

CATGGAGGAGGGAAGTCCG

R

GCGAGGTTCCTGTGCTGGTGGAGCCCCCAGGGTTGGAGGACGTTGAGGCAGCGCTAG GCATGGACAGGCGCACGGATGCCT ACAGCAGGTCGTCCTCAGT

Celera SNP ID: hDV75028111

Public SNP ID: rsll551373

SNP Chromosome Position: 2073728

SNP in Transcript Sequence SEQ ID NO: 37

SNP Position Transcript: 3821

Related interrogated SNP: hCV25995019

SNP Source: CDX; dbSNP

Population (Allele, Count) : Caucasian (G,216|A,2)

SNP Type: Silent Rare Codon

Protein Coding: SEQ ID NO: 76, at position 1238,(P,CCG) (P,CCA)

Gene Number: 30

Gene Symbol ZBTB38 - 253461

Gene Name: zinc finger and BTB domain containing 38

Public Transcript Accession: NM_001080412

Public Protein Accession: NP_001073881

Chromosome : 3

OMIM NUMBER:

OMIM Information:

Transcript Sequence (SEQ ID NO: 38):

Protein Sequence (SEQ ID NO: 77):

SNP Information

Context (SEQ ID NO: 130):

CAGCGCCTCCGAGTTGTCTTGAAGTGAGGCTCTGCTGTAGTCCTGTTCTTCTGGCTCTAA GATCTGAATGTTGTGACCACT

AATTTGCTCTTTCCTGGAG

R

GTAACCCCAGTTTGGTCCACAAGGCTTGCTGCCCAATCTTTGCCAACAGTTGAACCA AGACTCTGAGGCTGATATGCAATG TCACTTACAACATTAATCA

Celera SNP ID: hCV29279566

Public SNP ID: rs6764769

SNP Chromosome Position: 142582970

SNP in Transcript Sequence SEQ ID NO: 38

SNP Position Transcript: 517

SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (A, 130 |G, 96)

SNP Type: UTR5

Context (SEQ ID NO: 131):

TGGAATAGATTCCACCTCAAGAAACCAGTTTCTTTGCTCATCCATAAGAAGCAACTCCTC ATCTGATCAAGTTTTATAATA

AGATTGCAGAAATTCAGTC

Y

CATCTTTAGGCTCCACTTCTAGTTCTTATGCTATTTCCACCACATCTGCAGTTACTT CCTCCACTGAAGTCTTGAATCTCT CAAAGTCATCCATGAGGGT

Celera SNP ID: hCV2923649

Public SNP ID: rsl582874

SNP Chromosome Position: 142597909

SNP in Transcript Sequence SEQ ID NO: 38

SNP Position Transcript: 751

Related Interrogated SNP: hCV2416397

Related Interrogated SNP: hCV29279566 Population (Allele, Count) : Caucasi an (T,62|C,58)

SNP Type: UTR5

Gene Number: 31

Gene Symbol ZNF276 - 92822

Gene Name: zinc finger protein 276

Public Transcript Accession: NM_152287

Public Protein Accession: NP_689500

Chromosome : 16

OMIM NUMBER:

OMIM Information:

Transcript Sequence (SEQ ID NO: 39):

Protein Sequence (SEQ ID NO: 78):

SNP Information

Context (SEQ ID NO: 132):

CACCCTTCGTGTGCACCCGCATGGGAGGGTCGGAGGGTGCTGCCCGCCCTTGGTGCTGGA GGCGGGCTTGGTGTCCGGCTC

AAGTAGCCTTCCTCTGCTC

Y

GGGACCAGTGGTTTATTTTCCCGCAAACGCTGAGTGACTCGGGGCCGGACAGTTCAT AAATAATTGATTCCTTTCCCCACT AAAGCAGTCGAGGAGATTT

Celera SNP ID: hCV3020887

Public SNP ID: rsl230

SNP Chromosome Position: 88332356

SNP in Transcript Sequence SEQ ID NO: 39

SNP Position Transcript: 2093

SNP Source: Appl era

Population (Allele, Count) : Caucasi an (C,23| T,17) African American (C,8| T,28) total (C,31|T,45)

SNP Type: UTR3

SNP Source: dbSNP; HapMap; HGBASE

Population (Allele, Count) : Caucasian (C,133|T,93)

SNP Type: UTR3

Context (SEQ ID NO: 133):

TCAGAGGACACTGTCCTCCGAGTACTGCGGCGTCATCCAGGTCGTGTGGGGCTGCGACCA GGGCCACGACTACACCATGGA

TACCAGCTCCAGCTGCAAG

Y

CCTTCTTGCTGGACAGTGCGCTGGCAGTCAAGTGGCCATGGGACAAAGAGACGGCGC CACGGCTGCCCCAGCACCGAGGGT GGAACCCTGGGGATGCCCC

Celera SNP ID: hCV25923374

Public SNP ID: rs6500437

SNP Chromosome Position: 88317399

SNP in Transcript Sequence SEQ ID NO: 39

SNP Position Transcript: 835

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: Appl era

Population (Allele, Count) : Caucasian (C,13| T,19) African American (C,19| T,9) total (C,32|T,28)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 78, at position 188,(W,TGG) (R , CGG) SNP Source: Appl era

Population (Allele, Count) : Caucasian (C,16|T,24) African American (C,18|T,12) total (C,34|T,36)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 78, at position 188,(W,TGG) (R , CGG) SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (T,142|C,84)

SNP Type: Missense Mutation

Protein Coding: SEQ ID NO: 78, at position 188,(W,TGG) (R , CGG)

Context (SEQ ID NO: 134):

GGTCTGGGAAACACTGCCCAGCCCTGACCAGCCCTGTGGGTGGAGGTACCTGTAAAAAGC GAAAGGCAGCAGCCTGGTGTG GGAGGAGCCGCCCCAGCCTGAGGTCTGCAACACCAAGAAGTGGCTCAGGCAACTCTGGAC ATCTCTGCCTATTATCAGTGC TGGGGACACCCCTGGGGGT

Celera SNP ID : hCV7518972

Public SNP ID : rsl061646

SNP Chromosome Position: 88333478

SNP in Transcript Sequence SEQ ID NO : 39

SNP Position Transcript: 3215

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: Appl era

Population (Allele, Count) : Caucasian (A 12 IG, 20) African American (A,24|G,14) total (A, 361G, 34)

SNP Type: UTR3

SNP Source: dbSNP; HapMap ABI_Val HGBASE

Population (Allele, Count) : Caucasian (G,142 A, 84)

SNP Type: UTR3

Gene Symbol : ACAN 176

Gene Name: aggrecan

Chromosome : 15

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 135):

SNP Information

Context (SEQ ID NO: 180):

CCTTGACTTCAGTGGGCAGCTGTCAGGGGACAGGGCAAGTGGACTGCCCTCTGGAGACCT GGACTCCAGTGGTCTTACTTC

CACAGTGGGCTCAGGCCTG

M

CTGTGGAAAGTGGACTACCCTCAGGGGATGAAGAGAGAATTGAGTGGCCCAGCACTC CTACGGTTGGTGAACTGCCCTCTG GAGCTGAGATCCTAGAGGG

Celera SNP ID: hCV25473397

Public SNP ID: rs35430524

SNP Chromosome Position: 87199557

SNP in Genomic Sequence: SEQ ID NO: 135

SNP Position Genomic: 61563

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasian (A,3|C,35) African American (A,0|C,36) total (A, 3 IC, 71)

SNP Type: MISSENSE MUTATION

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasian (A,7|C,33) African American (A,0|C,32) total (A, 7IC, 65)

SNP Type: MISSENSE MUTATION

SNP Source: Appl era; dbSNP

Popul ati on (Al 1 el e , Count) no_pop (A,-|C,-)

SNP Type: MISSENSE MUTATION

Gene Number: 2

Gene Symbol : ATAD5 - 79915

Gene Name: ATPase fami ly, AAA domain containing 5

Chromosome : 17

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 136)

SNP Information

Context (SEQ ID NO: 181) :

TTAAAATTTATATTTTGTATTATATTGCTTGAAATAAGTGCCTT TTTCTCTTTTAAATTGCCAGCCATGCAAAAAGCGAAA

GAAAGATGATGACACATCT W

CCTGCAAAACAATTACAAAATATTTATCACCACTAGGGAAGACTAGAGACAGGGTTT TTGCTCCACCAAAACCTAGTAATA TTCTGGATTATTTTAGAAA

Celera SNP ID: hCV27849348

Public SNP ID: rs9910051

SNP Chromosome Position: 26185328

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 12182

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasian (A,21|T,3) African American (A,1|T,5) total (A,22|T,8)

SNP Type: MISSENSE MUTATION; ESE; ESE SYNONYMOUS

SNP Source: dbSNP; HapMap; HGBASE

Popul ati on (Al 1 el e , Count) Caucasian (A, 106 |T, 14)

SNP Type: MISSENSE MUTATION; ESE; ESE SYNONYMOUS

Context (SEQ ID NO: 182):

GATTTGTGATTGTATTTTTTTCTATTATTAAATATAAAATATTTTCTTGTGATGTAAATT AATGTTTCAATTTTTTGTTTA

GGCAAGCAATACTTCAAAA

M

ACATATCAAAAGCAAAACAATTGATTGAAAAAGCAAAAGCTTTACACATCAGTAGGT CAAAGGTGACTGAAGAAATAGCGA Celera SNP ID: hCVl955740

Public SNP ID: rs3764421

SNP Chromosome Position: 26191779

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 18633

Related interrogated SNP: hCV27849348

SNP Source: Appl era

Population (Allele, Count) : Caucasian (A,35|C, 3) African American (A,35|C,3) total (A, 701C, 6)

SNP Type: MISSENSE MUTATION; ESS; ESE

SNP Source: dbSNP; Celera; HapMap; ABI HGBASE

Population (Allele, Count) : Caucasian (A, 202 |C, 24)

SNP Type: MISSENSE MUTATION; ESS; ESE

Context (SEQ ID NO: 183):

TTGCACAGGTTCACCCTATTCCGCCCAAAAAGACAGGGAAAATACCCCGAATTTTCTTGA AACAAAAGCAATTTGAAATGG

AAAATAGTTTATCTGATCC

Y

GAGAATGAACAGACAGTTCAGAAAAGAAAATCTAATGTTGTTATACAGGAGGAAGAA TTAGAATTGGCTGTTTTGGAAGCT GGAAGTTCTGAAGCTGTGA

Celera SNP ID: hCVl955744

Public SNP ID: rsll655623

SNP Chromosome Position: 26186299

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 13153

Related interrogated SNP: hCV27849348

SNP Source: Appl era

Population (Allele, Count) : Caucasian (C,3|T,37) African American (C,7|T,31) total (C,10|T,68)

SNP Type: SILENT MUTATION

SNP Source: dbSNP; Celera; HapMap

Population (Allele, Count) : Caucasian (T,200|C,24)

SNP Type: SILENT MUTATION

Context (SEQ ID NO: 184):

CTAGCCTAGGGCGTTAAAAGTCTAAATTTTAATTCTGTCAACAACTGACTAGGTGACTTA GTGAAATCACGTCCTCAACGG

TGAAACTGATAGGACAGAA

R

TTCAAATTTCCAAACTCCCGGGTTGGCTTTCAATTCCACGGTGCAATGGTTCCGCCT CCCGCGGGTTCGCCGAGGGAGTCA TTTTGGCCCTCTCGGCTCA

Celera SNP ID: hCVl955747

Public SNP ID: rs999798

SNP Chromosome Position: 26182966

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 9820

Related interrogated SNP: hCV27849348

SNP Source: Appl era

Population (Allele, Count) : Caucasian (A,36|G,4) African American (A,11|G,13) total (A,47|G,17)

SNP Type: INTRON

SNP Source: dbSNP; Celera; HGBASE

Population (Allele, Count) : Caucasian (A, 200 |G, 26)

SNP Type: INTRON

Context (SEQ ID NO: 185):

TTACTGGTTTTTGTTGATTAGTAAGCACATGCACTTCTTTAATTCCCAAAGCAGAACTGG AGGCTGATGTCAGCCATAAAG

AAACCAAAAGGAAACTCGT

R

GAAGCAGAAAATTCTAAGTCAAAAAGAAAGAAACCAAATGAGTATTCAAAAAATCTG GAGAAGACCAATAGGAAGTCAGAA GAACTTAGCAAAAGAAACA

Celera SNP ID: hCV25642628

Public SNP ID: rs9896095

SNP Chromosome Position: 26211623

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 38477

Related interrogated SNP: hCV27849348

SNP Source: Appl era

Population (Allele, Count) : Caucasian (A,37|G,3) African American (A,30|G,6) SNP Type: ESE SYNONYMOUS; SILENT RARE CODON; SILENT

MUTATION; CODING REGION

SNP Source: dbSNP; HapMap; ABI_Val

Popul ati on (Al 1 el e , Count) Caucasian (A, 202 |G, 24)

SNP Type: ESE SYNONYMOUS; SILENT RARE CODON; SILENT

MUTATION; CODING REGION

Context (SEQ ID NO: 186):

GCAAATTAAACTGTCCACTCTAGAATAATTTTTCAGGAAGATGATTAATGTAATTCACGG CTGCTAATTATTGTTAAATGA

TTGTATAAATTATTCTGAT

Y

CATATCTGTCTAGTTATAGGTGGCTGCGTTTGTTTTTAACATTTGATAGTTGATAAT TTTAAAATTCATTATAGTGTATGA CATAAACTTTCAACATGAG

Celera SNP ID: hCVl48865

Public SNP ID: rs4131618

SNP Chromosome Position: 26228927

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 55781

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; Celera; HapMap; ABI_Val ; HGBASE

Popul ati on (Allele, Count) : Caucasian (C,194|T,24)

SNP Type: TRANSCRIPTION FACTOR BINDING SITE : INTRON : PSEUDOGENE

Context (SEQ ID NO: 187):

CAGTGTTATAGTATTCATATTTATAATTTTGTTGTAAGATATTCTATCAAGCTATACTGT TACTTAATCCTAAGGGGTTTT

ATCAAGGTTTATAAAACTG

Y

CTTCAGTGTTCAGGTTGGAGAATCTCCTATAAAAGTTTCCTTGCTGTCTTGCACAAT ATACAGTTAATAAAAGAAATACAT GTAAATGCTTTTAATTTAA

Celera SNP ID: hCV516198

Public SNP ID: rsll650271

SNP Chromosome Position: 26238069

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 64923

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; Celera; HapMap; ABI_Val

Popul ati on (Allele, Count) : Caucasian (C,107|T,13)

SNP Type: INTRON

Context (SEQ ID NO: 188):

CCAGGCAGGCCGGGCTGGACCGCGTGAGGTCCTAGGAGACGGGATTCCGGGAAGCGGGGA GTATGGTGGGGGTCCTGGCCA

TGGCGGCTGCAGCTGCTCC

S

CCTCCCGTGAAGGACTGCGAGATTGAGGTGAGGTTGAGTCGAGGATCTGTTGAGTTC CTTCCTCTATCTTTTGGGGGATTG GAAGGTGGGTCTTGGCGGA

Celera SNP ID: hCV7472194

Public SNP ID: rs999796

SNP Chromosome Position: 26183530

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 10384

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; Celera; HGBASE

Popul ati on (Allele, Count) : Caucasian (G,103|C,11)

SNP Type: SILENT RARE CODON; SILENT MUTATION : CODING

REGION; INTRON

Context (SEQ ID NO: 189):

CAACAGTTGGTGTTACGTTAGAGCTAATAATTATACTTTAGCACGTTAACCTCAGAATTC TAAGGCTGAGAGTCAAACACT

GCTAATTCATAGAAGGCAA

Y

AGCTTGTAATAATGAATCATAAAGCTCTTCTACTCTTTGTAGTTCAGTAGATAAAAA CATCTGTCTGTAGTGAACTATTTT ATCTGATGGGAAGAACACC

Celera SNP ID: hCVll413173

Public SNP ID: rs2433

SNP Chromosome Position: 26250354

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 77208

Related Interrogated SNP: hCV27849348 Popul ati on (Al 1 el e , Count) Caucasian (T,202|C,24)

SNP Type: MISSENSE MUTATION :ESE:UTR3

Context (SEQ ID NO: 190):

GAAACAACAAACGTAACTGTACATTATAAGAAATGCCACCATAAAACTATTGTAGAGAGA AGTGGTCAGGGAAGGTTTACT

GGAGGACTAGGAGAATGAG

R

CAGTAAATGGGAAGTTATTTCACCCAGATGTCTGGAAAGATAGGCTGTTTGACATCT CACACTCTGGCAGTAGAATAAAGA CTGAATAGGAAAAGGGCAG

Celera SNP ID: hCVll616069

Public SNP ID: rsll658435

SNP Chromosome Position: 26252687

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 79541

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; Celera

Popul ati on (Allele, Count) : Caucasian (A, 202 |G, 24)

SNP Type: INTRON

Context (SEQ ID NO: 191):

AGAGTACACCACTGCACTCCAGCCTGGGCGACAGAGAGAGACTCCATTTCAAAAAAAAAA AAAGAATAAAAATAAAAAAGA

AAGCCCATGGTCATAATAA

R

CGTACCCTGATATCATATAAACTTGTTTGATGTAAGCATGGACTCCTGCTATTCTAT TGTGTGTTTTCTGTTTCAATGAGA TAATATCTGATGGGAGGTG

Celera SNP ID: hCVll616097

Public SNP ID: rsll651858

SNP Chromosome Position: 26194844

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 21698

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; Celera; HapMap

Popul ati on (Allele, Count) : Caucasian (A, 202 |G, 24)

SNP Type: INTRON

Context (SEQ ID NO: 192):

GCATCATGACAAAAGTCTTGAAAAGTGTTATTTCATATATTATGTCCAGTTTTCTTGTTC TTATTTATGATGGGAGGATAA

ATCCAGTGCCAGTTCTATA

Y

CTTGACTAGAAGCAGAATCCCATCTTATTTTCTTTTGGTGCTCATATTTTTCCATCT TTGACTAGCAAGGAACTATTTTAA TTGGTTTGTGTCCTTTTGA

Celera SNP ID: hCVll627478

Public SNP ID: rs9899349

SNP Chromosome Position: 26224248

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 51102

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; Celera; HapMap; ABI_Val

Popul ati on (Allele, Count) : Caucasian (C,202|T,24)

SNP Type: INTRON

Context (SEQ ID NO: 193):

AACTTAGATTTGCCTGACTCCAGAGCCTATGTATGTTGCCTTTGATACAATTGCAGCTTT ATAAATAATAACTGAATGGCG

TTTTTCTAATACATGTATG

R

TTTCTTTTTGTTTTTTGAGACAAGGTCTTGCTCTGTCACCCAGGCTGGAGTGCAGTG GCACAATCTTGGCTCACTGCAACC TCCGCCTCCCAGGTTCAAG

Celera SNP ID: hCV26024164

Public SNP ID: rsll656462

SNP Chromosome Position: 26184826

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 11680

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; Celera; HapMap

Popul ati on (Allele, Count) : Caucasian (G, 107 | A, 13)

SNP Type: INTRON

Context (SEQ ID NO: 194) : CTTTTGGTTTTCTTTAGCT

M

AGTGACTCTCAAGCTTTACTGTGCACAAGCATTACTGAACCAGACTACACACAATAC TTCGTCGGCAATCGATTTTTTCTT AAAGGATTTTACTGCATGA

Celera SNP ID: hCV26030672

Public SNP ID: rsll650305

SNP Chromosome Position: 26253487

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 80341

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; Celera

Population (Allele, Count) : Caucasian (A, 202 |C, 24)

SNP Type: INTRON

Context (SEQ ID NO: 195):

GCCCAAAATACAGACTTCCTTTTGGTTTTCTTTAGCTAAGTGACTCTCAAGCTTTACTGT GCACAAGCATTACTGAACCAG

ACTACACACAATACTTCGT

S

GGCAATCGATTTTTTCTTAAAGGATTTTACTGCATGACTTATATCTCCATAAAAACT GACTTAAAATCCAGCCCCCTAAAT AAGATGCAACTCCACTCTA

Celera SNP ID: hCV26030673

Public SNP ID: rsll654914

SNP Chromosome Position: 26253550

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 80404

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; Celera; HapMap

Population (Allele, Count) : Caucasian (C,94|G,12)

SNP Type: INTRON

Context (SEQ ID NO: 196):

TTTTGCTCCACCAAAACCTAGTAATATTCTGGATTATTTTAGAAAGACTTCACCCACAAA TGAGAAGACACAATTAGGGAA

AGAGTGCAAGATAAAGTCA

Y

CTGAATCAGTACCTGTTGACAGCAACAAAGACTGTACGACACCTTTGGAAATGTTCT CAAATGTAGAGTTTAAGAAGAAAA GAAAGAGGGTTAATTTATC

Celera SNP ID: hCV27493873

Public SNP ID: rs3816780

SNP Chromosome Position: 26185484

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 12338

Related interrogated SNP: hCV27849348

SNP Source: Appl era

Population (Allele, Count) : Caucasian (C,33|T,3) African American (C,23|T,7) total (C,56|T,10)

SNP Type: MISSENSE MUTATION

SNP Source: Appl era

Population (Allele, Count) : Caucasian (C,37|T,3) African American (C,17|T,5) total (C,54|T,8)

SNP Type: MISSENSE MUTATION

SNP Source: dbSNP; HapMap; ABI_Val HGBASE

Population (Allele, Count) : Caucasian (C,200|T,24)

SNP Type: MISSENSE MUTATION

Context (SEQ ID NO: 197):

TGACACATTGTGTGCAACAGTTGCCAGAGTGTGTCGTTTAGAGTCGTGTCAAGTCCTGAT AAACATTTGGATTCTGAGATA

TTTGCGGGGTCACAGTAAA

Y

TGGGGACTTAAGATAACACGGCCAGTTCCCAGATCCCGAAATGTTGGTGGAACGTGA TGTTTTGGACTTCCGACATGTCAC AGAGGATCCCAGGGTCAAG

Celera SNP ID: hCV30679094

Public SNP ID: rsll651802

SNP Chromosome Position: 26183786

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 10640

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (T,201|C,23) Context (SEQ ID NO: 198):

AACTTTGAGAGGACAATGCAGGAGAAGAGCTTGAGCCCAGGAGTTCGAGACCAGCCTGGG CAACACAGCAAGATCCTGTCT

CTAAACTAGCTAACTAACT

W

AATTAATTAATTAATTAAAATTTGCTGGGCATGACGGTGTATGCCTGTAGTCCCAGC TACTCGGGAGGCTGAGGTGGGAGG ATCACTTGAGCCTAGGAGG

Celera SNP ID: hCV30662630

Public SNP ID: rsll652409

SNP Chromosome Position: 26206833

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 33687

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (T, 107 | A, 13)

SNP Type: INTRON

Context (SEQ ID NO: 199):

GTTAACTGCAAATACTTGTGATATCAGAAAAAGTATCCTTTACTTACAATTCTGGATTAG AAGTGGAGGTGGAGTTTTAGA

AGAACGACCATTAACCCTT

Y

ATCGTAAGTTGATTTGTTATTAAAGAAATTTCTATTATGGGACCCTATTTAAAAATC TGTGCTATGGCTGGGTGCAGTGGC TCATGCCTGTAATCCCAGC

Celera SNP ID: hCV30686611

Public SNP ID: rsll657270

SNP Chromosome Position: 26238513

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 65367

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (T,202|C,24)

SNP Type: MISSENSE MUTATION; ESS

Context (SEQ ID NO: 200):

TTCACATTCTGGATTTGTCTGCTGATTATATCCTCATGGTGTCAGTTAGTATAGTCCTCT TCCCTATATTTCTTGTAAACT

GGCAGTTAGATCTATGGGC

Y

TTATTAGATTCAGGTTCTGTTCTGGGTCTGGCATACATATACAGGTGGCCTGTGTAC TTCCTATGACATCATAGCAGATTA TCCCTTGTAGATTACAAAA

Celera SNP ID: hCV30664356

Public SNP ID: rsl2103588

SNP Chromosome Position: 26221586

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 48440

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (C,202|T,24)

SNP Type: INTRON

Context (SEQ ID NO: 201):

AACATTACACGTGTTGAAGAAAACATGGACAAGACTGTTCATTGCCTCAGCATTTGAATA ACAGAAAATTGGAGACAATTT

AAATATTCATCAGTAAGGA

W

ATGGATACAGGTGGCTCACCTGTAGTCCCAGCACTTTGGAAGGCCAAGGAGGGAGGA TTGCTTGAGCCCAGGAAGTTCCAG ACCAGCCTGGGCAACATGG

Celera SNP ID: hCV30327630

Public SNP ID: rs9898858

SNP Chromosome Position: 26180337

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 7191

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (A, 107 |T, 13)

SNP Type: INTERGENIC ; UNKNOWN

Context (SEQ ID NO: 202):

CTGTTCCCCCTTTCCTCTTCAAAAGTTTTTCTTTTCTTTCTTTTTTTTTTTTTTTTGAGG TAGGGTCTCGCTATATTGCCC AGGCTGGAGTATAGTGACT TTCATGGGCAGGATCATAATGCACAGCCCTGAACTCCTGGGCTCAAGCGATACTCCTGTC CTAGCCTCCTGAGAAGGCCAC TGTGTTCAGCTTCCTCCCC

Celera SNP ID: hCV29859378

Public SNP ID: rs9914242

SNP Chromosome Position: 26240371

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 67225

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (C, 198 | A, 24)

SNP Type: INTRON

Context (SEQ ID NO: 203):

CAAACCCATGAAAACAATGCAAATGATGCATGAGATCAGAAACCAGCAAACTACTGGTAG GTACCCTGCGAGGACTGAACG

CAGGCCAACCAGATGAAGC

R

ATGACTCGGCTGTTCGAGAGGATGGAATCCACAGAAAGAAATGCCTTCTTAGTCGAA TAGGTACTTCGACTTTTATAGGTA TAAAAGTCGAATTTCGGAT

Celera SNP ID: hCV30507741

Public SNP ID: rs9915139

SNP Chromosome Position: 26182641

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 9495

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (A, 202 |G, 24)

SNP Type: INTRON

Context (SEQ ID NO: 204):

ATTACAGGCATGAGCCACCGTGCCCAGCCCCATTCAGTATATATAGCTTTTCCAAAGTAT GCTATTGATTTATTCATTTAT

ATAGCTTTATACAGGATGA

R

TATCCCTAATCCAAAAATCTGAAATTTGAAATGCTCCAAAATCCAAAACATTTTGAG TGCTGACATGGTGCCCTAAGTGGA AAATTCCATACCTGGGGCC

Celera SNP ID: hCV30075535

Public SNP ID: rs7342938

SNP Chromosome Position: 26213956

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 40810

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (A, 200 |G, 26)

SNP Type: INTRON

Context (SEQ ID NO: 205):

TCATTTATATAGCTTTATACAGGATGAATATCCCTAATCCAAAAATCTGAAATTTGAAAT GCTCCAAAATCCAAAACATTT

TGAGTGCTGACATGGTGCC

M

TAAGTGGAAAATTCCATACCTGGGGCCAGGCACCATGGCTCATCCCTATAATCCCAG CACTTTGAGAGGCCGAGGTGGGAG CATTGCTTGAGCCTAGGAG

Celera SNP ID: hCV30615799

Public SNP ID: rs6505215

SNP Chromosome Position: 26214029

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 40883

Related interrogated SNP: hCV27849348

SNP Source: dbSNP

Population (Allele, Count) : Caucasian (C,200|A,26)

SNP Type: INTRON

Context (SEQ ID NO: 206):

AAGTAGCTGGCAGGCATGCACCAATGATATTTAATACTTTGACATCAAAGAGACTTAGGT TCATAAAGAAGATATATTGAG

GACCTCAACTAATGTAGAC

R

GTGGTAAAATGGACATCAAACGATGGTCTGTCAAGTTAAAATATTGCAAAGTTAAAA AATGAGCCTGCTGGGCACGGTGGC TCATGCCTGTAATCCCAAC

Celera SNP ID: hCV30686614

Public SNP ID: rsll080138 SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 75522

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (A,202|G, 24)

SNP Type: INTRON

Context (SEQ ID NO: 207):

TTATTCAGTAAATATTTAAATACCTACTAGTATGTACCAGGTACTGTTTTTGGTATCAGA GATATTATGGGGATAAGACAG

GACACATTCCCTGTCCTCC

Y

GTGGCTTAAGTGGAGATGGAAGATGGTCTATGATTAAACATTCATTGGGTCAACAAA TGAAAAATTGCAGTTGTGCTAAGG AGAGGTATAATTCATATTG

Celera SNP ID: hDV76805555

Public SNP ID: rs36056619

SNP Chromosome Position: 26196410

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 23264

Related interrogated SNP: hCV27849348

SNP Source: CDX; dbSNP

Population (Allele, Count) : Caucasian (T,202|C,24)

SNP Type: INTRON

Context (SEQ ID NO: 208):

GTTTTGTGTGCTCTTTCCTATTATCCCCACCACCACCATCACCACAAGATTACCAAAATA TTCGATTTCTATTTCCATCAA

TTAGTTTGATTTCTATTAC

M

ATAGATTAATTGTGTCTATTCTAGAACATCACATAAACTTCATATATATATTATTTT GTGTCTGGCTGCTTTTGCATAGTA TACACGCCCACAAACAAAT

Celera SNP ID: hDV77311325

Public SNP ID: rs9909497

SNP Chromosome Position: 26197354

SNP in Genomic Sequence: SEQ ID NO: 136

SNP Position Genomic: 24208

Related interrogated SNP: hCV27849348

SNP Source: CDX; dbSNP

Population (Allele, Count) : Caucasian (C,200|A,24)

SNP Type: INTRON

Gene Number: 3

Gene Symbol : BCAS3 - 54828

Gene Name: breast carcinoma amplified sequence 3

Chromosome : 17

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 137)

SNP Information

Context (SEQ ID NO: 209):

TACATCAAGAAATCTGGAATTTCATGAAATACATAGTACTGGGAATGAACCGCCTTTGTT GATTATGATTGGCTACAGTGA

TGGAATGCAGGTCTGGAGC

R

TCCCTGTAAGTACACATGTGGTTGAATACCTAAAACATACTTCCCAGCATGTTAGCT TATGTGAAATCTGTAGATACTTTT TTTTTTTGAGACAGAGTCT

Celera SNP ID: hCV25962833

Public SNP ID: rs34712615

SNP Chromosome Position: 56141463

SNP in Genomic Sequence: SEQ ID NO: 137

SNP Position Genomic: 41448

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasi an (A,40|G,0) African American (A,27|G,9) total (A, 67IG, 9)

SNP Type: MISSENSE MUTATION

SNP Source: Applera;dbSNP

Popul ati on (Al 1 el e , Count) no_pop (A,-|G,-) Gene Number: 4

Gene Symbol : BUBlB - 701

Gene Name: BUBl budding uninhibited by benzimidazoles 1 homolog beta (yeast)

Chromosome : 15

OMIM NUMBER: 602860

OMIM Information: Colorectal cancer, 114500 (3)

Genomic Sequence (SEQ ID NO: 138):

SNP Information

Context (SEQ ID NO: 210):

GAACCCTTGAGCGAGGATGCCATTATCACAGGCTTCAGAAATGTAACAATTTGTCCTAAC CCAGAAGACACTTGTGACTTT

GCCAGAGCAGCTCGTTTTG

Y

ATCCACTCCTTTTCATGAGATAATGTCCTTGAAGGATCTCCCTTCTGATCCTGAGAG ACTGTTACCGGAAGAAGATCTAGA TGTAAAGACCTCTGAGGAC

Celera SNP ID: hCV8868138

Public SNP ID: rsl801528

SNP Chromosome Position: 38285795

SNP in Genomic Sequence: SEQ ID NO: 138

SNP Position Genomic: 55265

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasi an (C,0|T,36) African American (C,10|T,26) total (C,10|T,62)

SNP Type: MISSENSE MUTATION

SNP Source: Appl era ; HGBASE ; HapMap ; dbSNP

Popul ati on (Al 1 el e , Count) no_pop (C,-|T,-)

SNP Type: MISSENSE MUTATION

Context (SEQ ID NO: 211):

TGTTTCCTTCTTCACAGTGAAGCCATGTCCCTGGAGGGAGATGAATGGGAACTGAGTAAA GAAAATGTACAACCTTTAAGG

CAAGGGCGGATCATGTCCA

Y

GCTTCAGGGAGCACTGGCACAAGAATCTGCCTGTAACAATACTCTTCAGCAGCAGAA ACGGTGTGTAGAATGGCTGAGTCT CAACCTGTCGTCATTCATC

Celera SNP ID: hDV81584461

Public SNP ID:

SNP Chromosome Position: 38244629

SNP in Genomic Sequence: SEQ ID NO: 138

SNP Position Genomic: 14099

SNP Source: dbSNP

Popul ati on (Allele, Count) : no_pop (C,-|T,-)

SNP Type: MMIISSSSEENNSSEE MMUUTTAATTIIOONN;; INTRON

Gene Number:

Gene Symbol : Cl7orf42 - 79736

Gene Name: chromosome 17 open reading frame 42

Chromosome : 17

OMIM NUMBER:

OMIM Informati

Genomic Sequence (SEQ ID NO: 139)

SNP Information

Context (SEQ ID NO: 212):

CAACAGTTGGTGTTACGTTAGAGCTAATAATTATACTTTAGCACGTTAACCTCAGAATTC TAAGGCTGAGAGTCAAACACT

GCTAATTCATAGAAGGCAA

Y

AGCTTGTAATAATGAATCATAAAGCTCTTCTACTCTTTGTAGTTCAGTAGATAAAAA CATCTGTCTGTAGTGAACTATTTT ATCTGATGGGAAGAACACC

Celera SNP ID: hCVll413173

Public SNP ID: rs2433 SNP in Genomic Sequence: SEQ ID NO : 139

SNP Position Genomic: 9774

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap; ABI_Val ; HGBASE

Population (Allele, Count) : Caucasian (T,202|C,24)

SNP Type: MISSENSE MUTATION : ESE : UTR3

Context (SEQ ID NO : 213):

TATGTATAAAATTGCCAGTATTTGCCAGTTGTCTATTTGCAAAAATGGCAATTTCACATG GTTAAACCTGATTACAAGAAT

GCTCATAGCAGCACTATTT

K

TATTAGCCAAAACCTCAATGGCAGATTATTGTGTATATATTGAATAAACGTTTCACC CAGTAACATGGGTAAATCCCACAA ATATGATGTTGAATGAAAG

Celera SNP ID: hCVll612362

Public SNP ID: rs9911989

SNP Chromosome Position: 26261828

SNP in Genomic Sequence: SEQ ID NO: 139

SNP Position Genomic: 21248

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; Celera

Population (Allele, Count) : Caucasian (G,202|T,24)

SNP Type: TRANSCRIPTION FACTOR BINDING SITE : INTRON

Context (SEQ ID NO: 214):

GAAACAACAAACGTAACTGTACATTATAAGAAATGCCACCATAAAACTATTGTAGAGAGA AGTGGTCAGGGAAGGTTTACT

GGAGGACTAGGAGAATGAG

R

CAGTAAATGGGAAGTTATTTCACCCAGATGTCTGGAAAGATAGGCTGTTTGACATCT CACACTCTGGCAGTAGAATAAAGA CTGAATAGGAAAAGGGCAG

Celera SNP ID: hCVll616069

Public SNP ID: rsll658435

SNP Chromosome Position: 26252687

SNP in Genomic Sequence: SEQ ID NO: 139

SNP Position Genomic: 12107

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; Celera

Population (Allele, Count) : Caucasian (A , 202 |G, 24)

SNP Type: INTRON

Context (SEQ ID NO: 215):

GTAGGGGCAGCGTAGACAAGGTCCTCAAATAACCTTTTCACCAGGTAGACTGGAATAACG GGGAGAGATGCGAAGTGTTTG

AGGAGCTCAGCGGGGAAAC

R

GGGCAGGCAAGGGATTAGGTAAAGGCGAGGGAGGAGGAGATTGCGTTGGCGCTGGAG CGGTATTCCTCTTAGAAGGGATAA AGGGAGATGAATGTAGCGC

Celera SNP ID: hCVl5877773

Public SNP ID: rs2269916

SNP Chromosome Position: 26257889

SNP in Genomic Sequence: SEQ ID NO: 139

SNP Position Genomic: 17309

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap; ABI_Val ; HGBASE

Population (Allele, Count) : Caucasian (A, 202 |G, 24)

SNP Type: UTR5: INTRON

Context (SEQ ID NO: 216):

ATACCCATCTCCCTTTCATTGCTAAGGACTGGATAAATATCTTAAAGACAAAATAGTATA GATGCCCAAAATACAGACTTC

CTTTTGGTTTTCTTTAGCT

M

AGTGACTCTCAAGCTTTACTGTGCACAAGCATTACTGAACCAGACTACACACAATAC TTCGTCGGCAATCGATTTTTTCTT AAAGGATTTTACTGCATGA

Celera SNP ID: hCV26030672

Public SNP ID: rsll650305

SNP Chromosome Position: 26253487

SNP in Genomic Sequence: SEQ ID NO: 139

SNP Position Genomic: 12907

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; Celera SN P Type: INTRON

Context (SEQ ID NO: 217):

GCCCAAAATACAGACTTCCTTTTGGTTTTCTTTAGCTAAGTGACTCTCAAGCTTTACTGT GCACAAGCATTACTGAACCAG

ACTACACACAATACTTCGT

S

GGCAATCGATTTTTTCTTAAAGGATTTTACTGCATGACTTATATCTCCATAAAAACT GACTTAAAATCCAGCCCCCTAAAT AAGATGCAACTCCACTCTA

Celera SNP ID: hCV26030673

Public SNP ID: rsll654914

SNP Chromosome Position: 26253550

SNP in Genomic Sequence: SEQ ID NO: 139

SNP Position Genomic: 12970

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; Celera; HapMap

Population (Allele, Count) : Caucasian (C,94|G,12)

SNP Type: INTRON

Context (SEQ ID NO: 218):

ATGTAAGGAGAGTGGAAAGAAAAGAATTATTTCTGGAAGATGGGGAGCCAGTTTTGTGAA AAACGGGGAATTCAGGAGGGA

GGGAAAGGTGATGAGTTTG

Y

GTTTTTATGAGGCAGCAATGGGTTGATTGTTTGTGTCTGGAAGGCAGTGGGGATGTA GGGGAATCATAAGTATTAATAAAA TGTGCTGGTCGGGAGCAGT

Celera SNP ID: hCV30384549

Public SNP ID: rs9889755

SNP Chromosome Position: 26258631

SNP in Genomic Sequence: SEQ ID NO: 139

SNP Position Genomic: 18051

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (C,202|T,24)

SNP Type: INTRON

Context (SEQ ID NO: 219):

CACCTGGTCAAAAGTAAGACTTGAATTTAGGCATGGAGGCAGGAGTTTGCTCCACCAACC AATGGAGGCTGGGCTGGATGA

TGTTGTAGAGGAGAGAGCT

R

GGGTAGGAGAAGGGGCAGCATGAGCGAGATACAATGGCATGGAGTTGGATAGCTCTG TGTTCAAAGGATGTGGACAGATCA CACACCAAGCACATCCCAG

Celera SNP ID: hCV29590899

Public SNP ID: rs9895684

SNP Chromosome Position: 26266726

SNP in Genomic Sequence: SEQ ID NO: 139

SNP Position Genomic: 26146

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (G,202|A,24)

SNP Type: INTRON

Context (SEQ ID NO: 220):

CGAAACTCCGTCTCAAAAAAAAAAAAAAAAGGGTTTTGTCTTCACTTCCATTTTCACATT TTAGTATCTCATCTGGTGGAA

CTAAATAAAATTAAATTTT

R

TACGTTTATAAGAAATGTTTCAGCTAAGTGATAGATTTAAGGGCAGTTTTACTTTCT TCCGTACACTTTTCAAGACTTCTA CATGACGTTTTTGCAAGTA

Celera SNP ID: hCV29663173

Public SNP ID: rs9914271

SNP Chromosome Position: 26256751

SNP in Genomic Sequence: SEQ ID NO: 139

SNP Position Genomic: 16171

Related interrogated SNP: hCV27849348

SNP Source: dbSNP

Population (Allele, Count) : Caucasian (G,202|A,24)

SNP Type: INTRON

Context (SEQ ID NO: 221):

TGGAGGCAGAGGTTGCAGTGAGCCGAGATTGCACCACTGCATTCCAGCCTGGGCGATAAG AGAGAGACTCCGTCTCAAAGA R

CCACATTGCAATACCACTACACACCCATGAGAATACCTACTGGAAATCTCATACATTGCT GATGGAAGTGTGGGTTGGTTG AATCACTTTGAAAAGCTGG

Celera SNP ID: hCV29626991

Public SNP ID: rs9913782

SNP Chromosome Position: 26261510

SNP in Genomic Sequence: SEQ ID NO: 139

SNP Position Genomic: 20930

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (A, 202 |G, 24)

SNP Type: INTRON

Context (SEQ ID NO: 222):

AAGTAGCTGGCAGGCATGCACCAATGATATTTAATACTTTGACATCAAAGAGACTTAGGT TCATAAAGAAGATATATTGAG

GACCTCAACTAATGTAGAC

R

GTGGTAAAATGGACATCAAACGATGGTCTGTCAAGTTAAAATATTGCAAAGTTAAAA AATGAGCCTGCTGGGCACGGTGGC TCATGCCTGTAATCCCAAC

Celera SNP ID: hCV30686614

Public SNP ID: rsll080138

SNP Chromosome Position: 26248668

SNP in Genomic Sequence: SEQ ID NO: 139

SNP Position Genomic: 8088

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (A, 202 |G, 24)

SNP Type: INTRON

Gene Number: 6

Gene Symbol : CENPW - 387103

Gene Name: chromosome 6 open reading frame 173

Chromosome :

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 140)

SNP Information

Context (SEQ ID NO: 223):

GAGCTTAAAAATCCACTTGGATTTTCTGTTTTAAAGGTCCATCTGAACTGTTTACTGTTT GTTCATCGATTAGCAGAAGAG

TCCAGGACAAACGCTTGTG

Y

GAGTAAATGTAGAGTCATTAACAAGGAGCATGTACTGGCCGCAGCAAAGGTAAAATC CAAATTTCTTTTCTCGAGCAAGAA TTAAACTTCAAAAATAACA

Celera SNP ID: hDV88213803

Public SNP ID:

SNP Chromosome Position: 126709108

SNP in Genomic Sequence: SEQ ID NO: 140

SNP Position Genomic: 16145

SNP Source: CDX

Population (Allele, Count) : no_pop (C, I T , -)

SNP Type: NONSENSE MUTATION ;MISSENSE MUTATION

Gene Number: 7

Gene Symbol : CEP290 - 80184

Gene Name: centrosomal protein 290kDa

Chromosome : 12

OMIM NUMBER:

OMIM Informati

Genomic Sequence (SEQ ID NO: 141)

SNP Information TAGAGACTGAATTGTTTGGCGCAGATGTTTTGCTCTGTTTCTTCCCTCCAAACGAGCATA ATAGAGAGCCTGTTCTTTTTC

ATCAAGTTTCTGCTCTAAG

Y

GCAAGTTGTAGGCCTCCATCTTCTGCAGTTTAGATGTAATTGACTCCAACTTACCAA GAGCAGTAGCCTCACTCAGTTGAA GAGAGACATTATGTTGGTG

Celera SNP ID: hCV29120804

Public SNP ID: rs7307793

SNP Chromosome Position: 87007259

SNP in Genomic Sequence: SEQ ID NO: 141

SNP Position Genomic: 50334

SNP Source: dbSNP; HapMap

Popul ati on (Al 1 el e , Count) Caucasian (C,120|T,-)

SNP Type: MISSENSE MUTATION

Context (SEQ ID NO: 225):

ACTAATGTTAAAAATGTT ITACTTACATTATATTCTTTTACTTTTATAGCATCTTGTTGGACTTGATCCTCAAGTTTT CTC TTTTCCTCTTTTATTGTTT Y

AGATTCTGTTTTCCAGGTCTCCTTTTCACTAAAAACAAAACAAAACAAAAAGACAAT ACTGTAAACCTAATAAAATGTTTA TAAGAAAAGATAACTTCAG

Celera SNP ID: hCV31193798

Public SNP ID: rslll04738

SNP Chromosome Position: 87024978

SNP in Genomic Sequence: SEQ ID NO: 141

SNP Position Genomic: 68053

SNP Source: dbSNP; HapMap

Popul ati on (Al 1 el e , Count) Caucasian (T,215|C,9)

SNP Type: MISSENSE MUTATION ;ESE;UTR3

Gene Number:

Gene Symbol : FANCA - 2175

Gene Name: Fanconi anemia, complementation group A

Chromosome : 16

OMIM NUMBER: 607139

OMIM Informati Fanconi anemia, complementation group A, 227650 (3)

Genomic Sequence (SEQ ID NO: 142)

SNP Information

Context (SEQ ID NO: 226):

TTACCAATAAAACACAATAGTGGTCTAACAAATTTCTCTACAGAAGATCCACAATTCTTC GCATTGTCAGAAGAAACCTGG

AAGTAGTCATCCCCTTCTA

R

CCGTTGCTGCATACCTCTTCAGAGACTCTATAAACGCCACACGGGAGTCAGGGACTT TGGGGAGCTGTGGGAAGAGAAGAG ACCTGTGAGAGACTGACAA

Celera SNP ID: hCVll951343

Public SNP ID: rsl800337

SNP Chromosome Position: 88372695

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 51235

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasi an (A,7|G,9) African American (A,8|G,18) total (A, 15 IG, 27)

SNP Type: INTRON

SNP Source: dbSNP; HapMap

Popul ati on (Al 1 el e , Count) Caucasian (A,134|G, 92)

SNP Type: INTRON

Context (SEQ ID NO: 227):

AAAGCAATAGTTCCTCCAGGTCTAGTCTAGTATAAATATGCAATGCAATCTAGTCTAGTA CAAATTATATGTCAAAGCCAG

AAATCAAACCCGTCTGATT

Y

TGGGCTTTGAAATATAATTTATACTAGACTAGACTGCAAAAACAGTAACACTGAATC ATCATTAGCACGCTACCTTTCCAG CAGCTCTTGCAGGCTCACA

Celera SNP ID: hCVll951344

Public SNP ID: rsl800285 SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 80669

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasian (C,4|T,16) African American (C,3|T,13) total (C,7|T,29)

SNP Type: INTRON

SNP Source: Appl era ; HGBASE ; dbSNP

Popul ati on (Al 1 el e , Count) no_pop (C,-|T,-)

SNP Type: INTRON

Context (SEQ ID NO: 228):

TTTAAACAAGTTTGTGCTTAATCTGTCCCAACTAAAATGGAGCTTATAAACTTACTTAGC AAGGAACCTCAAGGAGGGCTC

GTTCTTAACCATTTGCAAG

W

TGCCTCTGAAAAGAGCGGCCCTCCGCATTTGTGCCTCAGCAGCGTGTTTCTTACCAC TCTCTGTCAACTGAAAGAGTGCCA GCCAGGATATCTTCCTCTT

Celera SNP ID: hCVl2112567

Public SNP ID: rs7195906

SNP Chromosome Position: 88333848

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 12388

SNP Source: Applera

Popul ati on (Allele, Count) : Caucasian (A,25|T,15) African American (A,13|T,23) total (A,38|T,38)

SNP Type: MISSENSE MUTATION; TRANSCRIPTION FACTOR BINDING

SITE ;UTR3; INTRON

SNP Source: dbSNP; Celera; HapMap; ABI_Val

Popul ati on (Al 1 el e , Count) Caucasian (A,67|T,53)

SNP Type: MISSENSE MUTATION; TRANSCRIPTION FACTOR BINDING

SITE ;UTR3; I NTRON

Context (SEQ ID NO: 229):

GTGAACCTCCTGCGTTTCCAGAACTTCTTGCAAATGGCCAACCAACTCCTCTGCACTCAG CATCACAAAGAGCTGAAATAA

AAGCATCCGCTCCCTTCAA

Y

ATCCAAGCAAACCAATGTGCGACAGATGACCCCTCACCTTCCTCCCAGCCGGTGGCC ACCGCAGCCCCCTCACTTCCCACT GCAAAGGTAACACATGGAG

Celera SNP ID: hCVl2112711

Public SNP ID: rs6500452

SNP Chromosome Position: 88386006

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 64546

SNP Source: Applera

Popul ati on (Allele, Count) : Caucasian (C,14| T,24) African American (C,22| T,16) total (C,36|T,40)

SNP Type: INTRON

SNP Source: dbSNP; Celera; HapMap

Popul ati on (Al 1 el e , Count) Caucasian (T,146|C,80)

SNP Type: INTRON

Context (SEQ ID NO: 230):

GAACTTCTTGCAAATGGCCAACCAACTCCTCTGCACTCAGCATCACAAAGAGCTGAAATA AAAGCATCCGCTCCCTTCAAT

ATCCAAGCAAACCAATGTG

S

GACAGATGACCCCTCACCTTCCTCCCAGCCGGTGGCCACCGCAGCCCCCTCACTTCC CACTGCAAAGGTAACACATGGAGC TGTGACAGCTCACACCGTG

Celera SNP ID: hCVl2112715

Public SNP ID: rsl800287

SNP Chromosome Position: 88386026

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 64566

SNP Source: Applera

Popul ati on (Allele, Count) : Caucasian (C,22|G,14) African American (C,10|G,26) total (C,32|G,40) SNP Type: INTRON

SNP Source: dbSNP; Celera; HapMap; HGBASE

Popul ati on (Al 1 el e , Count) Caucasian (C, 56|G, 50)

SNP Type: INTRON

Context (SEQ ID NO: 231):

CCATCAAACGCGCCACCCAGTCTAGTTAAGAACCATGACATAGTCACAGCAAGGCAAGGG CAGCCAGCAGGAACATGACGT

GAGTTATGCTGGGTGATCA

R

GTATTCCAGAAGGAGACTGTGCACACCCAAACACCAAGTTTTAAAAGACTACACAGC AATTACAGCATGTCAAGTGCAAAC CACTAGAGACCTGAATGAA

Celera SNP ID: hCV2590883

Public SNP ID: rs6500450

SNP Chromosome Position: 88385525

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 64065

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasian (A,32|G,8) African American (A,10|G,22) total (A,42|G, 30)

SNP Type: UTR3; INTRON

SNP Source: dbSNP; Celera; Applera

Popul ati on (Al 1 el e , Count) Caucasian (A, 130 |G, 92)

SNP Type: UTR3; INTRON

Context (SEQ ID NO: 232):

TGCCCGCCCTTGGTGCTGGAGGCGGGCTTGGTGTCCGGCTCAAGTAGCCTTCCTCTGCTC TGGGACCAGTGGTTTATTTTC

CCGCAAACGCTGAGTGACT

Y

GGGGCCGGACAGTTCATAAATAATTGATTCCTTTCCCCACTAAAGCAGTCGAGGAGA TTTGTAATCCACTTTTTAGTGCAA CAAGAGCTCCATGTTATGC

Celera SNP ID: hCV3020887

Public SNP ID: rsl230

SNP Chromosome Position: 88332356

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 10896

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasian (C,23|T,17) African American (C,8|T,28) total (C,31|T,45)

SNP Type: MICRORNA;UTR3

SNP Source: dbSNP; HapMap; HGBASE

Popul ati on (Al 1 el e , Count) Caucasian (C,133|T,93)

SNP Type: MICRORNA;UTR3

Context (SEQ ID NO: 233):

CCGGAAGGTGCTAAGTGATTCTTCAGGACCCCCAGGTAAGAGTCTGTGCCACAGCTGGCA CTGGGCGTCAGCATGGTGGGC

GGACCCTGTACCCAAAGCA

S

CGGCTTGAGCTGGCACAGCCACCCCCGAGCTCACTCGGGTGGTGTAGCACAACAGAC ACTCAAGGTTAGGAAAATGGAAAA GCACAAGTCCCAGAGTGGA

Celera SNP ID: hCV3275471

Public SNP ID: rs3785275

SNP Chromosome Position: 88369530

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 48070

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasian (C,8|G,0) African American (C,5|G,17) total (C,13|G,17)

SNP Type: INTRON

SNP Source: dbSNP; Celera; HapMap; ABI_Val ; HGBASE

Popul ati on (Al 1 el e , Count) Caucasian (C, 73|G, 47)

SNP Type: INTRON

Context (SEQ ID NO: 234):

GGAAAAACATGAGATAAAAATGAGAATTTGATGATCCAAGCAGCTCACAATAAAACTGGT GGCAACACCTGAACCCAGAGT

TATACATTGGTATTTGTTA

Y

GTTTCCCATGACACAAAAGGAGCAAGATAAAGAAATATATTCTGACCAAGAACTTTA TCATCTTTTTACAAAGGAGCACAA Celera SNP ID: hCV2590841

Public SNP ID: rsll859183

SNP Chromosome Position: 88405221

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 83761

SNP Source: Celera;dbSNP

Popul ati on (Al 1 el e , Count) no_pop (C , - | T , -)

SNP Type: INTRON

Context (SEQ ID NO: 235):

GAACATGCAGAGGAAGATCCGCTGAGGCCCCGACAGGGAGAACCCAGGCTCCTCGGCACA CGCAGAGGAAGATCTGCCAAG

GCCACTCGGCAAAGCTGAC

R

GCAAGGTTGCTCACTCACATGACAGAGAATCAGGTGGGGACAGCATGGTCCCCACTC CCAGGCCTTCTGGGAAGATCAGGT ATTAGGTAGCCGATTGGCA

Celera SNP ID: hCV2590886

Public SNP ID: rs8049660

SNP Chromosome Position: 88385201

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 63741

SNP Source: dbSNP; Celera; HapMap; ABI_Val

Popul ati on (Al 1 el e , Count) Caucasian (A, 142 |G, 82)

SNP Type: UTR3; INTRON

Context (SEQ ID NO: 236):

TCCACAGGAAAGAAACCTTAGTTTTATCAAGAATGATTTCTTACAGGATTTCCCTAGCAC AAAGATGTTAGTACTGTAATC

CTTCTTTCTAAGTATAAAA

S

GGCTATTTTAGTCTGGGCAACATAGTAAGACCTCATCTCATTTAAAAATTACCTGGG CACGGTGGCTCATGCCTGTAATCC CAGCACTTTGGGAGGCTGA

Celera SNP ID: hCV26871795

Public SNP ID: rs6500441

SNP Chromosome Position: 88356170

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 34710

SNP Source: dbSNP; Celera; HapMap

Popul ati on (Al 1 el e , Count) Caucasian (C,130|G,92)

SNP Type: INTRON

Context (SEQ ID NO: 237):

GAAAACTGATACAATTGCTAATAAGCAAACTAAGTCATTTACAGTCTGGGCTGCAGTGCA ATTAACTTACAAATCAGCATT

CTCTGCAGTACATCAACCG

Y

GACCTGTCAAAATAGAATGTGAGTTACCATCTTGGTAATCTTCTGTAATTTGTGTGA TACCTGCATCACACAAGAGAATTA TTACTTGTTACTCTAAAGT

Celera SNP ID: hCV30590701

Public SNP ID: rs7190823

SNP Chromosome Position: 88393544

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 72084

SNP Source: dbSNP; HapMap; ABI_Val

Popul ati on (Al 1 el e , Count) Caucasian (T,132|C,94)

SNP Type: MISSENSE MUTATION ;ESE

Context (SEQ ID NO: 238):

CTGGGTGACAGAGTGAGACTCCAACTAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAGTAA CCAACCAATTTTGGAGCCAAT

ATTTTACCAATAAAACACA

W

TAGTGGTCTAACAAATTTCTCTACAGAAGATCCACAATTCTTCGCATTGTCAGAAGA AACCTGGAAGTAGTCATCCCCTTC TAACCGTTGCTGCATACCT

Celera SNP ID: hCV31692807

Public SNP ID: rs7187436

SNP Chromosome Position: 88372611

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 51151

SNP Source: dbSNP; HapMap

Popul ati on (Al 1 el e , Count) Caucasian (A,65|T,45)

SNP Type: INTRON Context (SEQ ID NO: 239):

GGCGCACAACCAGGAACGCAGTGACCATGCTGTCCAGCTGGCAGCTCTCGAATGCCTGGG CCATCAAACGCGCCACCCAGT CTAGTTAAGAACCATGACA

AGTCACAGCAAGGCAAGGGCAGCCAGCAGGAACATGACGTGAGTTATGCTGGGTGAT CAAGTATTCCAGAAGGAGACTGTG CACACCCAAACACCAAGTT

Celera SNP ID: hCV2590884

Public SNP ID: rsl800330

SNP Chromosome Position 88385465

SNP in Genomic Sequence SEQ ID NO: 142

SNP Position Genomic: 64005

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV2590886

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasian (C,15|T,21) African American (C,24|T,14) total (C,39|T,35)

SNP Type: INTRON

SNP Source: dbSNP; Celera; HapMap; ABI_Val : HGBASE

Popul ati on (Al 1 el e , Count) Caucasian (T,142|C,82)

SNP Type: INTRON

Context (SEQ ID NO: 240):

CCAGTGCACAACCCAAGACCGTGAACAAACAAGCCCTGCACCCCTGTGGACATGAAGGTG CCCGTGGGGTCTGAGTGGGGT

CCACAGGGGAGAAGTCCTG

M

GGGTGCCATGGTGACGGCGGTGGGGGCAGGGACGGTTCTGGGAACTCAGGATGTGCG GCCCTCATCTGCTATGAGCTGGCA TCTTTAACTGTGGCTTCCA

Celera SNP ID: hCV25922424

Public SNP ID: rsl2102297

SNP Chromosome Position: 88340263

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 18803

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source: Appl era

Popul ati on (Allele, Count) : Caucasian (A,17|C,21) African American (A,24|C,6) total (A,41|C,27)

SNP Type: INTRON

SNP Source: dbSNP; HapMap

Popul ati on (Allele, Count) : Caucasian (C,55|A,49)

SNP Type: INTRON

Context (SEQ ID NO: 241):

TGGAGGTACCTGTAAAAAGCGAAAGGCAGCAGCCTGGTGTGCTGATCCGGGGCCACACGG AGGAGGAGCCGCCCCAGCCTG

AGGTCTGCAACACCAAGAA

R

TGGCTCAGGCAACTCTGGACATCTCTGCCTATTATCAGTGCTGGGGACACCCCTGGG GGTCGGGACGTGTACCCTGGGAGG CCTGGCTGTGGGGATAGTG

Celera SNP ID: hCV7518972

Public SNP ID: rsl061646

SNP Chromosome Position: 88333478

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 12018

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: Appl era

Popul ati on (Allele, Count) : Caucasian (A,12|G,20) African American (A,24|G,14) total (A, 361G, 34) SNP Type: TRANSCRIPTION FACTOR BINDING

SITE ; MICRORNA; UTR3 ; INTRON

SNP Source: dbSNP; HapMap; ABI_Val ; HGBASE

Population (Allele, Count) : Caucasian (G, 142 | A, 84)

SNP Type: TRANSCRIPTION FACTOR BINDING

SITE ; MICRORNA; UTR3 ; INTRON

Context (SEQ ID NO: 242):

CGTGAAACCATCAGTACTAGCCATTCAGTCCTGCACATCCCTCCAACAGCTAATCCAACC ACCAGCGGCCGAAGAAAGAGC

CAAGCTGTTCCCCAAAACA

R

TGGTCTTTCTGGAAGACAACCCATCTTCTGCAGTGCTTCCCAACTTCTGCTGCGTCC TATTTGATGAAACTCAGCATCGCC GCATGCTCCTGCGGAGACG

Celera SNP ID: hCV7518999

Public SNP ID: rs886952

SNP Chromosome Position: 88364282

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 42822

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

Related interrogated SNP: hCV31692807

SNP Source: Appl era

Population (Allele, Count) : Caucasian (A,16|G. 22) African American (A,24|G,12) total (A,40|G,34)

SNP Type: UTR5 ; INTRON

SNP Source: dbSNP; HapMap; ABI_Val HGBASE

Popul ati on (Al 1 el e , Count) Caucasian (G,69|A,51)

SNP Type: UTR5 ; INTRON

Context (SEQ ID NO: 243):

CCCAAAACAGTGGTCTTTCTGGAAGACAACCCATCTTCTGCAGTGCTTCCCAACTTCTGC TGCGTCCTATTTGATGAAACT

CAGCATCGCCGCATGCTCC

Y

GCGGAGACGAGCTCATGAGTCCCTGGTCTGCAGACTTGGCCCAGCAAGAGGTGGCAC CCAGAGGAGCCCCACCACTCAGGG AGCTGCCCGCGCCTTCACC

Celera SNP ID: hCV7519008

Public SNP ID: rs886950

SNP Chromosome Position: 88364373

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 42913

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source: Appl era

Popul ati on (Allele, Count) : Caucasian (C,17| T,23) African American (C,25| T,13) total (C,42| T,36)

SNP Type: UTR5 ; INTRON

SNP Source: dbSNP; HGBASE

Popul ati on (Allele, Count) : Caucasian (T,133|C,93)

SNP Type: UTR5 ; INTRON

Context (SEQ ID NO: 244):

TTGACTCACATTGATGGTTGTGATAAAATTAGGCAGGGATTTCCCAACATTCTGCCATGC ACCTGGTGGGCAGGTGCAGTC ACAGCTGTGCTCAGTCCGC GGCCACCAAGTGGAACCTCACTAACAGCCTGCAGGCAGCCACCATTCTCCTGAGCAACCA GCCACTGGTCTGCATTCAATA AAGTGAGAAACGGTGGGCA

Celera SNP ID: hCV2590840

Public SNP ID: rsll076631

SNP chromosome Position: 88405476

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 84016

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source: dbSNP; Celera; HapMap

Popul ati on (Al 1 el e , Count) : Caucasian (A,66|G,54)

SNP Type: INTRON

Context (SEQ ID NO: 245):

GACAAAGGTCAGGCTTCAGTGTGCCCTGTGCATGTCCCTTGTCTTTCTCACTCAACCCTC TCCCATTTGATAAAACAGGAT

CTGCTTTAGCCACTCACTG

Y

GAACACTGTGCCTGTCACACTGCCCTGATCTCCCTGCAGCCTCCCCTTCTCATCCCC CTAACTCACACTCTATTTTTTTTT TTTTGAGACAGAGTCGCGC

Celera SNP ID: hCV2590844

Public SNP ID: rsll076628

SNP chromosome Position: 88402747

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 81287

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source: dbSNP; Celera

Popul ati on (Allele, Count) : Caucasian (T,128|C,98)

SNP Type: INTRON

Context (SEQ ID NO: 246):

CCAGGGATCCCTGAGGTCTCAGGAGCTCAGACTCAGTAGTCTCAAATGGGCCCTGGATCT TTATTTCCAAAGCCCCCTCCA

GGCGAGTCTAATGCCCACT

Y

AGGTTCAGGAACAGCTGCATAAACTTCTGTCAGAGAGCACACTGTGTGTGTTCCAAA GAAAAAGGAAGAATATGTGATACG GCTGAAGAAATGAAGTACT

Celera SNP ID: hCV2590894

Pub c SNP ID: rs6500449

SNP Chromosome Position: 88383894

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 62434

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

Related interrogated SNP: hCV31692807

SNP Source: dbSNP; Celera; HapMap

Popul ati on (Allele, Count) : Caucasian (T,67|C,51)

SNP Type: TFBS SYNONYMOUS; INTRON; PSEUDOGENE

Context (SEQ ID NO: 247):

ATGGGCATGGCCCTGAACGCATCATAGTGAACCTGCAGACAGAATGTGGGCCTCTGTGAA CACTGAACCGCTTACCTGCAA

AACCAGACGAGCTCCTGCC

R

CCCTAGCCCCACTTGAGACCACAGGACATCCTGGTGAAACCTCAGCAAGTTACCATC TATCAGGAAACCTGAACTCCAACG TGAACTGAAGGCTCACCTT

Celera SNP ID: hCV2590902

Public SNP ID: rs8046243

SNP Chromosome Position: 88379634

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 58174

Related Interrogated SNP: hCVll951343 Related Interrogated SNP: hCVl2112715

Related Interrogated SNP: hCV2590883

Related Interrogated SNP: hCV26871795

Related Interrogated SNP: hCV3020887

Related Interrogated SNP: hCV30590701

Related Interrogated SNP: hCV31692807

SNP Source : dbSNP; Celera; HapMap; ABI_Val

Popul ati on(Allele, Count) : Caucasian (A,69|G,49)

SNP Type INTRON

Context (SEQ ID NO: 248):

GCGCAGCACCGTTAGTCTGGGAACTGCCTGGGACTCCAGGGAGGCCACAATTCACTTCCA ACATCCACAGTGCTGAGTAGA

GAAACACAGCCCTTTACAG

W

CAGACTTATGAGTATGCAAAGCAAACCATTAGTAAAATTAAAACACAAGCCGGGCGC AGCGGCTTACACCTGTAATCCCAG CACTTTGGGAGGCTGAGGC

Celera SNP ID: hCV2590905

Public SNP ID: rsl2448860

SNP Chromosome Position: 88377130

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 55670

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

Related interrogated SNP: hCV31692807

SNP Source: dbSNP; Celera; HapMap

Popul ati on (Allele, Count) : Caucasian (T,69|A,51)

SNP Type: INTRON

Context (SEQ ID NO: 249):

TGAGCTGTCTCACTGCAAGCTTATCTGGGGCTGTCCCTCAGCACATGAATCAAGGCTACT GCAGCATGAACACAGAAGGCA

CCACTTGAAGGCTGACAGC

M

TTTACGCTGGGCTGTGATGAGGATAAAAATAAGCTGAAGAAACGCACTTCAAGCCTG GGCAACACAGTGAGACCCCCATCT CTTTTAATTTTTACTTTAA

Celera SNP ID: hCV3020893

Public SNP ID: rs6500439

SNP Chromosome Position: 88335776

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 14316

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source: dbSNP; Celera; HapMap

Popul ati on (Allele, Count) : Caucasian (A,64|C,52)

SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON

Context (SEQ ID NO: 250):

CTCTCAAGTTCTGCAGCATGAGGCTTTCCCAGAGCTCTTTCATTTTCCTTCAGTTCTCCT CTCTGCACAATCATTATGTAC

TGAAACATTTTCTTTCACT

S

AAGAATGATGCAGCCGGGTGCGGTAGCTCACGCCTATAATCCCAGCACTTTGGGAGG CCGAGGTGGGCAGATCGCTTGAGC CCAGGAGTTCAAGACCAGC

Celera SNP ID: hCV26871781

Public SNP ID: rs2016571

SNP Chromosome Position: 88371777

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 50317

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV2590886 Related interrogated SNP: hCV3275471

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (G,73|C. 47)

SNP Type: INTRON

Context (SEQ ID NO: 251):

GTGATCCAAGGATACCTTATTATTCTAAACAATAACTTCCAGGTCTACTCTCAAGTTCTG CAGCATGAGGCTTTCCCAGAG

CTCTTTCATTTTCCTTCAG

Y

TCTCCTCTCTGCACAATCATTATGTACTGAAACATTTTCTTTCACTGAAGAATGATG CAGCCGGGTGCGGTAGCTCACGCC TATAATCCCAGCACTTTGG

Celera SNP ID: hCV3275469

Public SNP ID: rsl006547

SNP Chromosome Position: 88371730

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 50270

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV2590886

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: dbSNP

Population (Allele, Count) : Caucasian (T 144IC 80)

SNP Type: INTRON

Context (SEQ ID NO: 252):

CCTGTGGTCTCAGCTACTGGGAGGCTGAGGTGGGAAGATCACTTCAGCCTGGGGGACACA GTGAGACCTGTGTCATTTACT

CAACATACATACCTACAGC

M

ATACCCATGTGAAAAATTCTCACTTGTAACCAAGGAAGCTCAGAATGAGATTCCATG AGGCAATGGAGATGTCAAAGCACT GTCATGGTGTTCTTACAGT

Celera SNP ID: hCV3275489

Public SNP ID: rsll860203

SNP Chromosome Position: 88362162

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 40702

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV2590886

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: dbSNP; Celera; HapMap

Population (Allele, Count) : Caucasian (A,65|C,41)

SNP Type: INTRON

Context (SEQ ID NO: 253):

AATCACCGGAAGGCTGCACTCAGGAACTGGCGCACTTGGTCTGAGTGAAGACCGCCAAGG CGCTGCAGCCCCAGCTAGCGC

TAACCAAGCTGTGTTAACA

Y

TGCCTCCATGCGGAGCTTGCAGTGAGCTGAGATCACGCCACTGCACTCCAGCCTGGG TGACAGAGCAAGACTCCGTCTCAA AAAAATATATATATATCAC

Celera SNP ID: hCV7519014

Public SNP ID: rsl007931

SNP Chromosome Position: 88366335

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 44875

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV2590886

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: dbSNP; HGBASE

Population (Allele, Count) : Caucasian (T,144|C,82)

SNP Type: INTRON

Context (SEQ ID NO: 254):

AGGAGGCTCCGTCAACTAAGTGAGACAGAAACCAGGGGAAGGAGCTGAGGCCCCGACAGG GAGAACCCAGGCTCCTCGGAA

CATGCAGAGGAAGATCCGC

Y

GAGGCCCCGACAGGGAGAACCCAGGCTCCTCGGCACACGCAGAGGAAGATCTGCCAA GGCCACTCGGCAAAGCTGACAGCA AGGTTGCTCACTCACATGA Public SNP ID: rsl057042

SNP Chromosome Position: 88385123

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 63663

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV2590886

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: dbSNP; ABI_Val ; HGBASE

Population (Allele, Count) : Caucasian (T,73|C,47)

SNP Type: TRANSCRIPTION FACTOR BINDING

SITE ; MICRORNA; UTR3 ; INTRON

Context (SEQ ID NO: 255):

TGCCCCATGTGGCTCTGGGCAGAAATGGGACACACTCCAAAGAGCCCCAGACGCTGGCAG GCATCAGAGCGGAGTCTGCAC

ACCCTGCAGGCATCAGAGC

R

GAGTCTGCACATACTGCAGGCATCAGAGCGCGGTCTGCACACACTGCAGCTGCTAGA GGCCTTTTCGGCAGCCCAGCCTAC CTGGCCTCCATGACGGTGA

Celera SNP ID: hCVll951325

Public SNP ID: rsl800335

SNP Chromosome Position: 88373696

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 52236

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

Related interrogated SNP: hCV31692807

SNP Source: dbSNP; HGBASE

Population (Allele, Count) : Caucasian (A,67|G,49)

SNP Type: INTRON

Context (SEQ ID NO: 256):

GTGGCCACCGCAGCCCCCTCACTTCCCACTGCAAAGGTAACACATGGAGCTGTGACAGCT CACACCGTGGCGTCTCTCCCC

TCACAGTGGCCAGCACCTG

S

TTGGAGAGAATTCTCCCTATCTCAAGGAGGAGGGGCTCGGCCCAAGGGACAAGTTCA GTCTCCTGACCTGAGTGGTGGCCT TGATGAGGACAGCCACATC

Celera SNP ID: hCVl2112716

Public SNP ID: rs6500453

SNP Chromosome Position: 88386158

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 64698

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

Related interrogated SNP: hCV31692807

SNP Source: dbSNP; Celera; HapMap

Population (Allele, Count) : Caucasian (C,58|G,50)

SNP Type: TFBS SYNONYMOUS; INTRON

Context (SEQ ID NO: 257):

CAGTGAAACAGCCCATCTCTAGGCCTCTGCCAGGAATGGCGTTCCCACCAAAAATGCACA CCAACTGGACAAGCCAGACAC

ACTATTGGTGCTGCGTGAC

Y

GTGTCCATCTCTGCCCCCGAGGAGATGAGAGCCTCCCATGTTTATAACCAGCCTGCT CCAAGGACTGTCGTCCCTGCTCAG CATGCTGGGTGGGAACCAC

Celera SNP ID: hCVl5835113

Public SNP ID: rs2159113

SNP Chromosome Position: 88359584 SNP Position Genomic: 38124

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV2590886

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: dbSNP; HapMap; ABI_Val HGBASE

Population (Allele, Count) : Caucasian (C,74|T,46)

SNP Type: INTRON

Context (SEQ ID NO: 258):

ACCTGACCATGTGTAGATTCTTTTGAATGTTATCATCATGCAGACAGACCCAAAAAGCCA TTAGATAAAAAGCGGAAAATG

CTGATAACGCTTGTCAAAT

S

TCTCTGAGAGGGACAGAGTCACGGAAAAACAAAGCTCAGAGACATGAACTGTCTGTG CCAAATACCAGGAAAGCAGCTCAA TACTTGTCAGTTAAAAATT

Celera SNP ID: hCVl6172654

Public SNP ID: rs2238529

SNP Chromosome Position: 88380618

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 59158

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV2590886

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: dbSNP; HapMap; HGBASE

Population (Allele, Count) : Caucasian (G,65|C,37)

SNP Type: INTRON

Context (SEQ ID NO: 259):

GAACCAGGGGTGGGTGGAGAATGTGCACCTGAGGATAGATAGCAGAGCGCAGCACCGTTA GTCTGGGAACTGCCTGGGACT

CCAGGGAGGCCACAATTCA

Y

TTCCAACATCCACAGTGCTGAGTAGAGAAACACAGCCCTTTACAGTCAGACTTATGA GTATGCAAAGCAAACCATTAGTAA AATTAAAACACAAGCCGGG

Celera SNP ID: hCVl6174688

Public SNP ID: rs2239360

SNP Chromosome Position: 88377084

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 55624

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV2590886

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: dbSNP; HapMap; HGBASE

Population (Allele, Count) : Caucasian (C,143|T,81)

SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON

Context (SEQ ID NO: 260):

CTCAAACAGTCACAACAGGGACTGAGGCCAGCTCTGTCCATGAAGATGAGGAAGGAATGG AAGGGACTAAGGTTTCCTGGG

CCATCTGTGTGAGAGAACA

S

GATGTTCTGGGGGTGAATGGGGTCACAGAGCCAGGTGGCAAGAGCACTTGAGGTCTG TTAGCCTGCCACATCCCAGCAGGC CTATACAGACCACCAAACC

Celera SNP ID: hCV26871766

Public SNP ID: rsl2709096

SNP Chromosome Position: 88390462

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 69002

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV2590886

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: dbSNP; Celera; HapMap

Population (Allele, Count) : Caucasian (C,72|G,46)

SNP Type: INTRON

Context (SEQ ID NO: 261):

GGGAGGGGCATCACCTGCTTTTACAGAGGAAAAAATGTTTCACAGCAAATGCACAGCTCT TGACCTCACCCCGTATCCCTT ACAGCCCTGACTCCTGTCTCTCTCTGAATAGACAGTGGCCAACCTGCCCCATGTGGCTCT GGGCAGAAATGGGACACACTC CAAAGAGCCCCAGACGCTG

Celera SNP ID: hCV27475628

Public SNP ID: rs3743859

SNP Chromosome Position: 88373551

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 52091

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

Related interrogated SNP: hCV31692807

SNP Source: dbSNP; HapMap; ABI_Val ; HGBASE

Population (Allele, Count) : Caucasian (C, 134 |T, 92)

SNP Type: INTRON

Context (SEQ ID NO: 262):

TGAGGTCTGTTAGCCTGCCACATCCCAGCAGGCCTATACAGACCACCAAACCAAACCCAG ACCCTCTCGTGAGGCTTACAA

CCTGCAACCAGCAAGCGGC

R

CTTTATGCCGATTCCCCAGGTAAGAAAATCAAGGGTCCAGCCGGGCACGGTGGCTCA TGCCTGTAATCCCAGCACTCTGGG AGGCTGAGGCGGGCAGATC

Celera SNP ID: hCV27897053

Public SNP ID: rs4785722

SNP Chromosome Position: 88390611

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 69151

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV2590886

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: dbSNP; HapMap; HGBASE

Population (Allele, Count) : Caucasian (A, 146 |G, 80)

SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON

Context (SEQ ID NO: 263):

CCCGAGGCCCATGTCTGAGGTGTGGGATCCGCACAGCTGCCATCTGACTCCCTCTCCTTG CTCCACGTACATTTCTTGCGC

CTCTTCTAAGTTCTCTGTT

R

TTCAGACCCTGTCATAATGTCAGATCTCCCCTTTCCCGCACAGGGTCTCCGGCACCG CAACAGGGCTCTGTCCCGACCTGG GCTACCTCTGCCCAAGAGA

Celera SNP ID: hCV27897055

Public SNP ID: rs4785595

SNP Chromosome Position: 88363022

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 41562

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

Related interrogated SNP: hCV31692807

SNP Source: dbSNP; HapMap; HGBASE

Population (Allele, Count) : Caucasian (A, 133 |G, 91)

SNP Type: INTRON

Context (SEQ ID NO: 264):

GATCTGTGGAGGCCAGGCAGCGGGAGTCTGTAGAGGCACAGCTACAGTGTGTTCTAGAAA TGTGGGGGGCTGAGAGGCAGG

GCCAGCTCTAGAGCCTGAA

Y

CACACCCAGGGAAGGAGGAGCAAGGGGAGACTCCACACAGGAGGAGGTCACAGTGAG TGGGACAAACATTGGTGCAGGACT TCCAGAGGCGGAACAGGAT Public SNP ID: rsl0852623

SNP Chromosome Posi ti on : 88392743

SNP in Genomic Sequence : SEQ ID NO: 142

SNP Positi on Genomi c : 71283

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source dbSNP; HapMap

Population (Allele, Count) Caucasian (T, 132 |C,94)

SNP Type: TRANSCRIPTION FACTOR BINDING SITE ; UTR3 ; INTRON

Context (SEQ ID NO: 265):

CCCCGATGTCCACCTTCCACCCAGCCCCCACTCCTCAGCTTCCGCCTCCCGACCTGTAAG GGTCTCCGCACATCTCCACAG

AGCCATGGAGAGAAAAAGC

W

AATAGGGCCAAGCTTTGCCTACTGGTGAATCTGAGCAGGATCTGTGGAGGCCAGGCA GCGGGAGTCTGTAGAGGCACAGCT ACAGTGTGTTCTAGAAATG

Celera SNP ID: hCV31692778

Public SNP ID: rsll076626

SNP chromosome Position: 88392604

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 71144

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

Related interrogated SNP: hCV31692807

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (T,69|A,51)

SNP Type: MICRORNA; UTR3 : INTRON

Context (SEQ ID NO: 266):

CAAGGGAGCGCTATTACTGAAGGTTATTTTAACAGAAACAAGTCATCACATAAGGACGTG AAGGATCAGAAAATAACTTAC

TGTTGTTGACCCAGAACTT

W

CCCTATCTCCCACTCTCAAACTGGGGGGAGAAGGAGGTACCTAGAAAATTGTTCTCC CGTCTGCTCTCCTGGGCACACCAC AGCCTGTCTCACTACTTCC

Celera SNP ID: hCV31692756

Public SNP ID: rsll076632

SNP chromosome Position: 88408038

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 86578

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source: dbSNP; HapMap

Popul ati on (Al 1 el e , Count) : Caucasian (A,66|T,54)

SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON

Context (SEQ ID NO: 267):

TGGGCTGCTAGGGGAGCCTGCTGAGCTCTGGCGGGAGCTGAGGTGAAGTCTCTGCTCCGA AGTCCCAAGAAAGCATAGTCA

GGCGCAAGTGGGCCACAGT

Y

ATGCTCTCGTGACGGGGCACAGGCAGCCACCGTACAGCCTCCAGCCAGTGCACAACC CAAGACCGTGAACAAACAAGCCCT GCACCCCTGTGGACATGAA

Celera SNP ID: hCV31692619

Public SNP ID: rsl2102290

SNP Chromosome Position: 88340118

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 18658

Related Interrogated SNP: hCVll951343 Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (C,68|T,52)

SNP Type: INTRON

Context (SEQ ID NO: 268):

GCCTCAGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGTGGCTGGCCCAAAATG TTTTCTGATCCATCAAAATGA

ATCAAAATCCTAAAGAGCT

R

AACTAAAAATAAATGATCTGGACTTTATAAAAATTTAAAACCTTTGTGCATTAAACG ATACTATCAAGAGAGTGAAAAAAG AATTAACAGAATGGGAAAA

Celera SNP ID: hCV31692842

Public SNP ID: rs7195752

SNP Chromosome Position: 88349461

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 28001

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV2590886

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (A,72|G,48)

SNP Type: INTRON

Context (SEQ ID NO: 269):

ATACTATCAAGAGAGTGAAAAAAGAATTAACAGAATGGGAAAAAATATTTACAAATCATA TATTTGATAAGAACTTTATCT

AAAATATATAAAGAACTCA

Y

ACAACTCAGTAAGACAAATACAGTCATGAACTGCTCAATGACAAGGATCCATTCTGA GAAACACATCTTTAGGTGGTTTCA TCACGTGAACATCCAAGAG

Celera SNP ID: hCV31692841

Public SNP ID: rs7201028

SNP Chromosome Position: 88349619

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 28159

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV2590886

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (T,72|C,48)

SNP Type: INTRON

Context (SEQ ID NO: 270):

TGAGACTCTGACTCAAACAAACAAACAAAAAAGATATTTCTATTTTAATGACAATTATTT TGTCCACTCATAATTCTGAAT

TTTCTTATAAAAATCTGTT

S

CTTTCAGGTAAAAGGATATTTAGTAACAATCTCAGGCATCTGAGGACCCAGTCTCTG GTTCAAGACAGACGTAAAAGAGGT CCTAGAATTCCTGGCATCT

Celera SNP ID: hCV31692786

Public SNP ID: rs8051231

SNP Chromosome Position: 88389633

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 68173

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV2590886

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (G,74|C,44)

SNP Type: INTRON

Context (SEQ ID NO: 271):

GACAGAGTGAGACTCTGTCTCAAAAAAAAAAAAGAAAAAAGAAACTGCATGTTCTCAATC CACAGATGAACATTTCTTACT R

TCACATGGAAGCAGGATCACAGGGCAGAGACCCTGTGTGTCTGATGTGACATCGACTCCG GCAGGCAGGATGAGCGGGAAA ACAGGCATCCTAGTCACGC

Celera SNP ID: hCV31692816

Public SNP ID: rsl2599180

SNP Chromosome Position: 88366807

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 45347

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

Related interrogated SNP: hCV31692807

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (A, 133 |G, 91)

SNP Type: INTRON

Context (SEQ ID NO: 272):

GTGAAGGGACCACACTCCTCTGAGCTGGGAACGAAACAGTGAAGAGACCACACTGCCCTG AGCTGGGAATGCCTGGTCCTT

GGATGCCCTCAGCTGAGAG

R

TGGCGTTCTAAACACCGAAGAGTTCATTTCTCACGAATTCCACCAACTGAGCTACAA CTCGGTGCAAATGCAGCCTGCTTG GGGAGCTCCCTGGGGAACA

Celera SNP ID: hCV31692620

Public SNP ID: rsl2922302

SNP Chromosome Position: 88339784

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 18324

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source: dbSNP

Population (Allele, Count) : Caucasian (G,67|A,51)

SNP Type: INTRON

Context (SEQ ID NO: 273):

GTCTCTACTAAAAATACAAAAAAATTAGCTAGGTGCGGTGGCGGGTGTCTATAGTCCCAG CTACTCGGGAGACTGAGGCAG

GAGAATAGCTTGAACCCGG

K

AGGCGGAGCTTGCAGTGAACCAAGATGGCACCACTGCACTCCAGCCTGGGAGACAGA GCAAGACTCCATCTCAAAAAAAAA AAAAAGAAAAAAGAAAAAA

Celera SNP ID: hCV31692774

Public SNP ID: rsl2599799

SNP Chromosome Position: 88394869

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 73409

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

Related interrogated SNP: hCV31692807

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (T,69|G,51)

SNP Type: INTRON

Context (SEQ ID NO: 274):

GTTTTGCCATGTTGGCCAGGCTGGTCTCAAACTCCTGACCTCAAGTGATCCACCTGCCTC GGCCTTCCAAAGTGCTGGGAT TACAGGCATGAACTATCAC CCTGACCATGTGTAGATTCTTTTGAATGTTATCATCATGCAGACAGACCCAAAAAGCCAT TAGATAAAAAGCGGAAAATGC TGATAACGCTTGTCAAATG

Celera SNP ID: hCV31692794

Public SNP ID: rsl2709094

SNP Chromosome Position: 88380518

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 59058

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (A,133|G,93)

SNP Type: INTRON

Context (SEQ ID NO: 275):

GTAATCCATACAAAATAAGGGATGAAGGAAAAAGTTACTTTGAATTTCATAAAACTGAAT TTAGTGCATTCCGAACTGGAT

GGCCTGAGCATTGGTCCTT

S

GTTTTTTGGTTCGTTTGTTGTGAGACAGTCTTGCTCTGCCGCCCAGGCTGGAGTGCA GTGGCACCACCTGGGCTCACTGCA ATCTCTGCCTCCCGGGTTC

Celera SNP ID: hCV31692827

Public SNP ID: rs7203907

SNP Chromosome Position: 88361275

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 39815

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (C,56|G,48)

SNP Type: INTRON

Context (SEQ ID NO: 276):

TTTTTTTTTGGTGGAGATGAGGTTTCACTATGGTGTCCAGGCTTGATTTCGCTAATTTTC TTATAAAAGACAGCAGGAGGC

TCCGTCAACTAAGTGAGAC

R

GAAACCAGGGGAAGGAGCTGAGGCCCCGACAGGGAGAACCCAGGCTCCTCGGAACAT GCAGAGGAAGATCCGCTGAGGCCC CGACAGGGAGAACCCAGGC

Celera SNP ID: hDV77251247

Public SNP ID: rs8045232

SNP Chromosome Position: 88385049

SNP in Genomic Sequence: SEQ ID NO: 142

SNP Position Genomic: 63589

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

Related interrogated SNP: hCV31692807

SNP Source: CDX; dbSNP

Population (Allele, Count) : Caucasian (A,68|G,48)

SNP Type: UTR3; INTRON

Gene Number: 9

Gene Symbol : FANCL - 55120

Gene Name: Fanconi anemia, complementation group L

Chromosome : 2

OMIM NUMBER: 608111 Genomic Sequence (SEQ ID NO: 143)

SNP Information

Context (SEQ ID NO: 277):

TACTGCCTGTCCCACCAAAATGCAAAAATGCACGTTTATAACTAAACACCATATCACCTT GCATTCTTCAGTTGTAAATCT

TCAGGCAACACTATCCTAA

R

GTGGAAGTCTCTTCCCTGTGGAAAATATTGAAAAGGATCACTCAAATTTTTATCTTT CACTTAATGCTGAGAAGTTAAACA GAATCACAAAGAAAAGACA

Celera SNP ID: hDV81424415

Public SNP ID:

SNP Chromosome Position: 58312736

SNP in Genomic Sequence: SEQ ID NO: 143

SNP Position Genomic: 82854

SNP Source: dbSNP

Population (Allele, Count) : no_pop (A, -)

SNP Type: MISSENSE MUTATION; TRANSCRIPTION FACTOR BINDING

SITE; ESS SYNONYMOUS; INT

RON

Gene Number: 10

Gene Symbol : FGFR3 - 2261

Gene Name: fibroblast growth factor receptor 3

(achondropl asi a, thanatophoric dwa

rfi sm)

Chromosome : 4

OMIM NUMBER: 134934

OMIM Information: Achondroplasia, 100800 (3); Hypochondropl asi a, 146000 (3) ;/Thanatophor

ic dysplasia, types I and II 187600 (3); Crouzon syndrome with acanthosis nigricans (3); Muenke syn

drome, 602849 (3); Bladder cancer , /109800 (3) Colorectal cancer, somatic, 109800 (3); Cervical cane

er, somatic, 603956 (3)

Genomic Sequence (SEQ ID NO: 144)

SNP Information

Context (SEQ ID NO: 278):

AGGCCTCAACGCCCATGTCTTTGCAGCCGAGGAGGAGCTGGTGGAGGCTGACGAGGCGGG CAGTGTGTATGCAGGCATCCT

CAGCTACGGGGTGGGCTTC

Y

TCCTGTTCATCCTGGTGGTGGCGGCTGTGACGCTCTGCCGCCTGCGCAGCCCCCCCA AGAAAGGCCTGGGCTCCCCCACCG TGCACAAGATCTCCCGCTT

Celera SNP ID: hDV71078050

Public SNP ID: rsl7881656

SNP Chromosome Position: 1775929

SNP in Genomic Sequence: SEQ ID NO: 144

SNP Position Genomic: 20508

SNP Source: ABI_Val ;Celera;HGBASE;dbSNP

Popul ati on (Al 1 el e , Count) no_pop (C,-|T,-)

SNP Type: MISSENSE MUTATION; TRANSCRIPTION FACTOR BINDING SITE;UTR5;INTRON

Gene Number: 11

Gene Symbol : IGFl - 3479

Gene Name: insulin-like growth factor 1 (somatomedin C) Chromosome : 12

OMIM NUMBER: 147440

OMIM Informati Growth retardation with deafness and mental ficiency, 608747 (3)

Genomic Sequence (SEQ ID NO: 145):

SNP Information

Context (SEQ ID NO: 279):

TCTATGTGGGTTTAACTTATTATTCCTCATTCTGATATAAAAAAAGAAGAAAAGAACCAA GTCATTTTGAACATTAAGAAA

TTCATAAAGACTGTATAAA

G

TAAAAAAAAAAAAAAAACAAAAACAAGAAACAAAAAATCTTCACAGATTGTTAGCCA TCTCTTTCAACAATTTCTCATAAA TTCTTTCTTTATCAGTAGA

Celera SNP ID: hDV89345868

Public SNP ID:

SNP Chromosome Position: 101315993

SNP in Genomic Sequence: SEQ ID NO: 145

SNP Position Genomic: 12187

SNP Source: CDX

Population (Allele, Count) : no_pop (G,-|,-)

SNP Type: UTR3 INDEL

Gene Number: 12

Gene Symbol : IGFALS - 3483

Gene Name: insulin-like growth factor binding protein, acid labile subunit

Chromosome : 16

OMIM NUMBER: 601489

OMIM Information: Acid-labile subunit, deficiency of (3)

Genomic Sequence (SEQ ID NO: 146):

SNP Information

Context (SEQ ID NO: 280):

ATGTTGTTGTAGGTGTACGCGGGCGGCTGGCAATCGTCCCCCTCACAGATGGCCTGGACG AAGCGGGGCACAGCACTGGGG

TTCTGCAGGGCGAAGTCCC

R

CAGCGCCTTGAGAGGGCAGCCACAGTCCCAGGGGTTACCCTCCAGCCACAGGCGCTC CAGGCCCGGGGGCTGCGGCGTGAA GGTCCGCAGTGAGTTGTTC

Celera SNP ID: hCV25995019

Public SNP ID: rs9282731

SNP Chromosome Position: 1780778

SNP in Genomic Sequence: SEQ ID NO: 146

SNP Position Genomic: 10358

SNP Source: Applera

Population (Allele, Count) : Caucasian (A,0|G,34) African American (A,1|G,9) total (A,1|G,43)

SNP Type: MISSENSE MUTATION; INTRON

SNP Source: dbSNP; Applera

Population (Allele, Count) : Caucasian (G,218|A,2)

SNP Type: MISSENSE MUTATION; INTRON

Gene Number: 13

Gene Symbol : IGFBP3 - 3486

Gene Name: insulin- like growth factor binding protein 3 Chromosome: 7

OMIM NUMBER: 146732

OMIM Information:

Genomic Sequence (SEQ ID NO: 147)

SNP Information

Context (SEQ ID NO: 281) : CTTGGGATCAGACACCCGG

K

GCGTGCTGGAGACGGACGGGCTCTCCACACTGCCGGCGCTGCGGTCTTCCTCCGACT CACTAGCATTTCCTTAAAACGCCC AAGAGAGACAAACACATGA

Celera SNP ID: hCV29670713

Public SNP ID: rs9282734

SNP Chromosome Position: 45923494

SNP in Genomic Sequence: SEQ ID NO: 147

SNP Position Genomic: 15125

SNP Source: dbSNP

Popul ati on (Al 1 el e , Count) Caucasian (T,113|G,1)

SNP Type: MISSENSE MUTATION ; UTR5

Context (SEQ ID NO: 282):

AGTCATCCTGTAGTATTTCCTAGAAATTACAATAAGCCTTCTTAATTTATAAAATTCAAA TATTAATTGATAATTGTACTC

TAGTCCTGTGAAGCAAAAG

Y

ACACTCAGACATTTCAGTTCTATTTGTCCCTTTCCTGATTTCTATGCTCTCGTTGTC ATATATTTTAATTTCACCTGTATA ATCTACATCCTAAAAATGT

Celera SNP ID: hCVll329931

Public SNP ID: rsl464931

SNP Chromosome Position: 45951148

SNP in Genomic Sequence: SEQ ID NO: 147

SNP Position Genomic: 42779

Related interrogated SNP: hCV29670713

SNP Source: dbSNP; HapMap; HGBASE

Popul ati on (Allele, Count) : Caucasian (C,119|T,1)

SNP Type: INTERGENIC ; UNKNOWN

Context (SEQ ID NO: 283):

TTTCCTAGAAATTACAATAAGCCTTCTTAATTTATAAAATTCAAATATTAATTGATAATT GTACTCTAGTCCTGTGAAGCA

AAAGCACACTCAGACATTT

Y

AGTTCTATTTGTCCCTTTCCTGATTTCTATGCTCTCGTTGTCATATATTTTAATTTC ACCTGTATAATCTACATCCTAAAA ATGTTAGTGTTCTTGTTTT

Celera SNP ID: hCVll329934

Public SNP ID: rsl534152

SNP Chromosome Position: 45951163

SNP in Genomic Sequence: SEQ ID NO: 147

SNP Position Genomic: 42794

Related interrogated SNP: hCV29670713

SNP Source: dbSNP; HapMap; HGBASE

Popul ati on (Allele, Count) : Caucasian (C,117|T,1)

SNP Type: INTERGENIC ; UNKNOWN

Context (SEQ ID NO: 284):

AATAGTTGTTTGAAATGTCACTCCCTGACGCAGCATTAACAAATGTGTTAACATGTCCAC TTGCAGTTTATAAAGGGTGCC

ACTGGGCAGCATCTTGTCC

R

CCCTGTGGGTGAACCATTGAAAGGACAGGAGTGGGAAGCGGGTGGTGGAAAGGCACT AGGGTTGAGGATTATGGCCAATAT AGCAGCACTCAGAGCAACA

Celera SNP ID: hCV29250463

Public SNP ID: rs6953668

SNP Chromosome Position: 45922400

SNP in Genomic Sequence: SEQ ID NO: 147

SNP Position Genomic: 14031

Related interrogated SNP: hCV29670713

SNP Source: dbSNP; HapMap

Popul ati on (Allele, Count) : Caucasian (G,224|A,2)

SNP Type: INTRON

Gene Number: 14

Gene Symbol : KRAS - 3845

Gene Name: v-Ki-ras2 Ki rsten rat sarcoma viral oncogene homolog

Chromosome : 12

OMIM NUMBER:

OMIM Information: Genomic Sequence (SEQ ID NO: 148):

SNP Information

Context (SEQ ID NO: 285):

GACAGTGGAATTGGAAACTTTCGGATAAAACACTGTAACCCAGTTAGCTCTGTGGGGGTG TGGGGGGAGAGATGGGCCCTC

AACATATCTGCAGATAACT

K

TTTTTTCCCCTAAATTCATCTAAATTACCTATCATTATCCCAAACAGGCACTTCAAA CTATTAAACTAAAACACAGATCTT AATCTAGTTATGACTATTC

Celera SNP ID: hDV75942727

Public SNP ID: rs34719539

SNP Chromosome Position: 25249931

SNP in Genomic Sequence: SEQ ID NO: 148

SNP Position Genomic: 10484

SNP Source: CDX;dbSNP

Popul ati on (Al 1 el e , Count) no_pop (G, T -)

SNP Type: MICR0RNA;UTR3 UTR3

Gene Number: 15

Gene Symbol : LEPR - 3953

Gene Name: leptin receptor

Chromosome : 1

OMIM NUMBER: 601007

OMIM Informati Obesity, morbid, with hypogonadism (3)

Genomic Sequence (SEQ ID NO: 149)

SNP Information

Context (SEQ ID NO: 286):

AAAAGTATTTCTTCAAAAACATATACACAACTTGTCATTTTGCAGTTCCTATGAGAGGAC CTGAATTTTGGAGAATAATTA

ATGGAGATACTATGAAAAA

S

GAGAAAAATGTCACTTTACTTTGGAAGGTATTCCCAATTTTAATATTAATCTTAAAT TGTATTTTTATACTCTTAAAAATT TACTTCATGGTCCATAATC

Celera SNP ID: hCV8722378

Public SNP ID: rs8179183

SNP Chromosome Position: 65848540

SNP in Genomic Sequence: SEQ ID NO: 149

SNP Position Genomic: 199634

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasian (C,5|G,31) African American (C,9|G,23) total (C,14|G,54)

SNP Type: MISSENSE MUTATION ;ESE SYNONYMOUS ; INTRON

SNP Source: dbSNP; HapMap; HGBASE

Popul ati on (Al 1 el e , Count) Caucasian (G,108|C,12)

SNP Type: MISSENSE MUTATION :ESE SYNONYMOUS : INTRON

Context (SEQ ID NO: 287):

ACTTCAATATCAAGTGAAATATTCAGAGAATTCTACAACAGTTATCAGAGAAGTAAGTAT ATTTTAGTAAGTAAAAGGAAA

AGTTGAGAAGTAAATAAAG

R

CCCTCTTAAGTCCCATAGCAATTACCCTCTGCATACTAAATATATACATTTCTTCTA AAGCAGAATGAATTATAATTCAAC ATTTCATATTATATATCAT

Celera SNP ID: hCV25597196

Public SNP ID: rs3828034

SNP Chromosome Position: 65834913

SNP in Genomic Sequence: SEQ ID NO: 149

SNP Position Genomic: 186007

Related interrogated SNP: hCV8722378

SNP Source: Appl era

Popul ati on (Allele, Count) : Caucasian (A,23|G,5) African American (A,13|G,3) total (A, 361G, 8)

SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON

SNP Source: dbSNP; HapMap; ABI_Val ; HGBASE SNP Type: TRANSCRIPTION FACTOR BINDING SITE ; INTRON

Context (SEQ ID NO: 288):

CAAATTGGCTATCACTGGAACATGCCTTTGAAAAATTGCAATCTTCTGTCTCTGGCTAAG ATTTTTAGAAAAATATTTGGA

AAACTATTGTCATGACTAG

R

TAATTAGAAGTGCTTAAGTTTGTTTTGAAACTCCCTTGATAATTTAATCCACAAATA ATAAGTAATTTCTATGTTTGGAAA TATATGATAGTCACTTTAA

Celera SNP ID: hCV25597209

Public SNP ID: rs3790437

SNP Chromosome Position: 65858021

SNP in Genomic Sequence: SEQ ID NO: 149

SNP Position Genomic: 209115

Related interrogated SNP: hCV8722378

SNP Source: Appl era

Population (Allele, Count) : Caucasian (A,28|G,6) African American (A,24|G,8) total (A, 52 IG, 14)

SNP Type: UTR3; INTRON

SNP Source: dbSNP; HapMap; ABI_Val ; HGBASE

Population (Allele, Count) : Caucasian (A, 199 |G, 27)

SNP Type: UTR3: INTRON

Context (SEQ ID NO: 289):

ACCACGCGTGGCTAATTTTTTGTATTTTTTAGTAGAGACGGGGTTTCACCGTGTTAGCCA GGATCGGCATGTTATCTTTTG

CTTGCAGAGCCAATGGTTC

R

ATTTCTAATCAGGTACTACTACTAGCTTTCAGAGTAACATGAATAATGTATTGACTT TTTTCAGTCAAGTCTATATTTGCG AAAAAGAGATAAATCCCTC

Celera SNP ID: hCVl5785939

Public SNP ID: rs2376018

SNP Chromosome Position: 65846754

SNP in Genomic Sequence: SEQ ID NO: 149

SNP Position Genomic: 197848

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; Celera; ABI_Val HGBASE

Population (Allele, Count) : Caucasian (A, 199 |G, 27)

SNP Type: INTRON

Context (SEQ ID NO: 290):

TTCTAGTCTTAGTGCAGATAATCAAGACATGACTATGTAAATGTAGTGTGTATCATAAAG TTGATGCTTGGAGTCATAACA

GAGTTAGGGCTTCAGAGAC

R

CACTGTTATGCTTGGGCTTTCAGGCTTTTAGTTTAAAATATGCCACATTTCCATATT GCCTGTTATTGTCAGGAAGATTGG CCCTCAAAGTTAAAAATTA

Celera SNP ID: hCV26465953

Public SNP ID: rs4606347

SNP Chromosome Position: 65845949

SNP in Genomic Sequence: SEQ ID NO: 149

SNP Position Genomic: 197043

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; Celera; HapMap;

Population (Allele, Count) : Caucasian (G, 104 | A, 12)

SNP Type: INTRON

Context (SEQ ID NO: 291):

TGAAATATTTAATAAGAGTTACTGTCAGTTTCTGTGGAAAGATATAGAATTGGGAAAAAT TAAAAAATGCCTTTCTAATAA

GAATGTCTTTTTTTAGATG

K

AGTGAAATTGTCTGTATTTTATTTATTTTAATTTAATTTAATTTAATTTTATTTTGT TTTTGAGACAGTCTCCCTCTGTCG CCCAGGCTGCAGTGCAGTG

Celera SNP ID: hCV31223419

Public SNP ID: rsl2077336

SNP Chromosome Position: 65842574

SNP in Genomic Sequence: SEQ ID NO: 149

SNP Position Genomic: 193668

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (G,108|T,12) Context (SEQ ID NO: 292):

TATAAGGAATAGTAATTTACCAGTTTGTGATCATCTCTTTCATCATCATTGTTCTCTACA TATGATATTATTAGCTCTTAT

TTTCAGATAGTCTCAAGCA

K

ATTCTCAGTATACAGCAGATAAGTTTTTAATAGTCAACACAATTATTTTACTTTCAT ACCATATCTTATTTCACAACATAG TTATTTTAACTGTTTTTAG

Celera SNP ID: hDV70888487

Public SNP ID: rsl7127838

SNP Chromosome Position: 65873863

SNP in Genomic Sequence: SEQ ID NO: 149

SNP Position Genomic: 224957

Related interrogated SNP: hCV8722378

SNP Source: dbSNP

Population (Allele, Count) : Caucasian (G,194|T,32)

SNP Type: INTRON

Context (SEQ ID NO: 293):

TTGCTCTAGGCCCTTCTTTCCTCAAGCCTTCCTTTAACCAGTGTAATTCAAAAGAATTTC TACCCCCTTTAAGTTCCTAGA

TCATTGTACTGTTTTTTTA

R

TTGTGGATAGTGCTCTGAATTCAAAGACTGTATTTTATCCATCACAAATATTTGTAG TACTCCTCCTGCTGTTCTTTATGT GCAAAGCACTGAGATACAT

Celera SNP ID: hDV70949464

Public SNP ID: rsl7406429

SNP Chromosome Position: 65862296

SNP in Genomic Sequence: SEQ ID NO: 149

SNP Position Genomic: 213390

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (A, 108 |G, 12)

SNP Type: INTRON

Context (SEQ ID NO: 294):

TATTAGAAGATTTTTACATTTTGAAGAAGGGGAGCAAATCTAAAAAAAATTCAGTTGAAC TTCTGAGAGTTAACATATGGT

GGATTATGTTGATTTAGAA

M

TTAAAATAGATGTGTAAATTTGGGTTCAAAATGTAGATTTGAGTCCAGTTTGGATGT GTGATTAATTTTCAAATCATCTAA AGTTTAAAAGTAGTATTCA

Celera SNP ID: hDV70950526

Public SNP ID: rsl7415296

SNP Chromosome Position: 65871601

SNP in Genomic Sequence: SEQ ID NO: 149

SNP Position Genomic: 222695

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (C,198|A,28)

SNP Type: MICRORNA; UTR3 ; INTRON ; PSEUDOGENE

Context (SEQ ID NO: 295):

GAACTCTATCGTCAGTTCTCTCTTAATTTTTCTTACACAGAGTGTCTACATTTGGCCTTA GTTATGGTTTGGGTTATTTAG

GTTTCTTTTTGTTGGTGGT

S

GTTTGTTGGTTGGATGGTTTCATACATTAGCCCTTCAGCTTCCCTTTTTGCTACTGC AGTTGTTTCCTGCATATTCCAGCC AAGGGCCATCTCTCACTTT

Celera SNP ID: hDV71040566

Public SNP ID: rs6661050

SNP Chromosome Position: 65845484

SNP in Genomic Sequence: SEQ ID NO: 149

SNP Position Genomic: 196578

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (G,108|C,12)

SNP Type: INTRON

Context (SEQ ID NO: 296):

CCAACTTTTCGATTTCAAGTGTACTAGTACTGTGCTTCTACTTTGTTCTTATTTTCTACC CCCAGATGACCCCTCACTCCT CATTTTCATTTTTGCCCAC CACCACCATTTATTCACACACACACACACACACACATTCATGATTGTAATTTTGAGAAGA CAAGAAAAAGAAGTGGTATAG AAAATAGAAAATGACAGAA

Celera SNP ID: hDV71040668

Public SNP ID: rs6665672

SNP Chromosome Position: 65841608

SNP in Genomic Sequence: SEQ ID NO: 149

SNP Position Genomic: 192702

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (G,198|A,28)

SNP Type: INTRON

Context (SEQ ID NO: 297):

GTGGACTAGGATAGCTTTGAATGCAGCCCAACACAAATTTATAAACTGTCTGAAAACATT AGGAGATTTTTTTTGCAACTG

GTTTTTTTTTTTTTTTTTG

R

TTCATCAGCTATCGTTAGTATATTTTATGTGTGGCCCAAGACAGTTCTTCTTCCAGT GTGGCCTAGGGAAGCCAAAAGATT GGACACCCCTGCTTTATGG

Celera SNP ID: hCV30009175

Public SNP ID: rs7545475

SNP Chromosome Position: 65841988

SNP in Genomic Sequence: SEQ ID NO: 149

SNP Position Genomic: 193082

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; HapMap

Population (Allele, Count) : CCaauuccaassiiaann ((AA,, 110088 |G, 12)

SNP Type: INTRON

Context (SEQ ID NO: 298):

ATCAAGACATACTGCAACCACAAAGTTCCATCTCACTTAGATGTGGATGAAAAAAGATCT CTTGCTAAATTATTTTCTGTG

ACCTTAAAAGAAATTTGTT

M

CACTTTTCATCTTTCAAGGGTCATCTTGATAGTTACCTTAACAAACCTTTCTCAGCT ATTTATTATTGAGAAAGCCCATTC TTAAAT TTTTTAAGTCACAAA

Celera SNP ID: hDV81070728

Public SNP ID: rs41459646

SNP Chromosome Position: 65878630

SNP in Genomic Sequence: SEQ ID NO: 149

SNP Position Genomic: 229724

Related interrogated SNP: hCV8722378

SNP Source: dbSNP

Population (Allele, Count) : Caucasian (A, 198 |C, 28)

SNP Type: UTR3;INTRONIC INDEL

Gene Number: 16

Gene Symbol : LOC283951 - 283951

Gene Name: hypothetical protein LOC283951

Chromosome : 16

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 150)

SNP Information

Context (SEQ ID NO: 299):

CTCTGAGGGGCCAGGCCACCAAGTTAATCTCAGTCTCAAACAGAAATGAGACACCTGGGA AGAGTGTGAAATGGGCATCCC

CCGTCCCACTCAGCCCACT

K

TGAGGACTGGAAGACGCCACCCCGGGTTCAGCAGTGCCCCAAATTCACGTCCCCTCA GAACACAAGAACTTGACCTTGTCT GGAAACAGGGTCTTTGCCA

Celera SNP ID: hCVl256109

Public SNP ID: rsll861094

SNP Chromosome Position: 1416535

SNP in Genomic Sequence: SEQ ID NO: 150

SNP Position Genomic: 16590

Related Interrogated SNP: hCV25995019 Popul ati on (Al 1 el e , Count) Caucasian (G,223|T,1)

SNP Type: TRANSCRIPTION FACTOR BINDING SITE : INTRON

Context (SEQ ID NO: 300):

ATGCCCGCCGAGCCCCCGCACACGCCTCCTTCACGAGGGGCTGGGTCTCATTTCCTCACC CTTGGCGTCCAGGACAGTGAC

CAGCACCGACGAGGCCGAG

Y

TGAGGTCCACCTGCGCCCGAAGCCTGGGCTGGCCATTTCCTGCCGCCCGCGCCTTTC AGGACAGAACACAGGGGCCCAGAG GCCCTTCTGGGTCCTCCAC

Celera SNP ID: hCV32105505

Public SNP ID: rsll645222

SNP Chromosome Position: 1418455

SNP in Genomic Sequence: SEQ ID NO: 150

SNP Position Genomic: 18510

Related interrogated SNP: hCV25995019

SNP Source: dbSNP; HapMap

Popul ati on (Allele, Count) : Caucasian (C,221|T,1)

SNP Type: MISSENSE MUTATION

Gene Number: 17

Gene Symbol : LOC390667 - 390667

Gene Name: similar to Neuronal pentraxin II precursor (NP-II) (NP2)

Chromosome : 16

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 151)

SNP Information

Context (SEQ ID NO: 301):

AGCTCCCTGAAGGCCGGGTCCCCGATCACGAAGTGGATGGATCCGGGCAGCAGGGAGTCT CGGCCGTGCAGCACCAGCTTG

TTGTCATTGTCCTCGGTGG

M

GTAGGACAGGAGGGTGCCCAGGCGGCCGGAGGCCGTGCGGACCCAGCTGCAGAAGGA CAGGGCTCGCAGGGCAGTGACGAA ACCAGGGCTGAGGAAGACC

Celera SNP ID: hCV32105457

Public SNP ID: rsl3332460

SNP Chromosome Position: 1476429

SNP in Genomic Sequence: SEQ ID NO: 151

SNP Position Genomic: 10488

Related interrogated SNP: hCV25995019

SNP Source: dbSNP; HapMap

Popul ati on (Allele, Count) : Caucasian (C,222|A,4)

SNP Type: MISSENSE MUTATION

Gene Number: 18

Gene Symbol : LRP5 - 4041

Gene Name: low density lipoprotein receptor-related protein 5 Chromosome : 11

OMIM NUMBER: 603506

OMIM Information: Osteoporosi s-pseudogl ioma syndrome, 259770 (3); [Bone mineral density/

variability 1], 601884 (3); Osteopetrosis, autosomal dominant, type I, 607634 (3); Hyperostosis, end

osteal, 144750 (3); van Buchem disease, type 2, 607636/(3); {Osteoporosis}, 166710 (3); Exudative vi

treoreti nopathy , dominant, 133780 (3); Exudative vitreoretinopathy, recessive 601813 (3)

Genomic Sequence (SEQ ID NO: 152):

SNP Information GCTGAGTGACATGAAGACCTGCATCGTGCCTGAGGCCTTCTTGGTCTTCACCAGCAGAGC CGCCATCCACAGGATCTCCCT

CGAGACCAATAACAACGAC

R

TGGCCATCCCGCTCACGGGCGTCAAGGAGGCCTCAGCCCTGGACTTTGATGTGTCCA ACAACCACATCTACTGGACAGACG TCAGCCTGAAGGTAGCGTG

Celera SNP ID: hCV25604912

Public SNP ID: rs4988321

SNP Chromosome Position: 67930765

SNP in Genomic Sequence: SEQ ID NO: 152

SNP Position Genomic: 104054

SNP Source: Applera

Population (Allele, Count) : Caucasian (A,2|G,38) African American (A,1|G,35) total (A, 3 IG, 73)

SNP Type: MISSENSE MUTATION ; INTERGENIC ; UNKNOWN

SNP Source: HGMD ; dbSNP; Applera

Population (Allele, Count) : Caucasian (G,111|A,3)

SNP Type: MISSENSE MUTATION : INTERGENIC : UNKNOWN

Gene Number: 19

Gene Symbol : MAPKl - 5594

Gene Name: mitogen- activated protein kinase 1

Chromosome: 22

OMIM NUMBER: 176948

OMIM Information:

Genomic Sequence (SEQ ID NO: 153)

SNP Information

Context (SEQ ID NO: 303):

GCAGTAAGATTTTTATCTCCCTCAGGGTTCTCTGGCAGTAGGTCTGGTGCTCAAAGGGGC TGATTTTCTTGATAGCTACTC

GAACTTTGTTGACATTATC

R

TAAGCAGAGCTTAAAAAAGAGAGAGAGAGATGGCATTAAAAACAGCCCTCAGAATAT TTGAAGAAGGCAAGTTGGTAAAGT ATTATATTTTTAACACTGT

Celera SNP ID: hCV25922338

Public SNP ID: rs3729910

SNP Chromosome Position: 20492126

SNP in Genomic Sequence: SEQ ID NO: 153

SNP Position Genomic: 58180

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasi an (A,33|G,1) African American (A,34|G,0) total (A,67|G,1)

SNP Type: ESS; SILENT MUTATION

SNP Source: dbSNP; HapMap; HGBASE

Popul ati on (Al 1 el e , Count) Caucasian (A,112|G,4)

SNP Type: ESS; SILENT MUTATION

Context (SEQ ID NO: 304):

AACAGTGCTTCACGTCATGAGCTCCTGGAGGCTTTATTACAAATTGTTATACTGTAGGTT GAAAAATGAACTTGAGATGCT

GACATGCTGTAGAAGGAAA

M

AGAATTGTATACTTTCTCATTTAAAGACGCAGTGTTCCTCTCTGCTAAATCCTCAGG CATGGAACGTGGTTACTGAAACAC CCACATTTGAAGTAGCTCA

Celera SNP ID: hCV7626903

Public SNP ID: rsl3058

SNP Chromosome Position: 20447502

SNP in Genomic Sequence: SEQ ID NO: 153

SNP Position Genomic: 13556

SNP Source: dbSNP; HapMap

Popul ati on (Al 1 el e , Count) Caucasian (A,113|C,5)

SNP Type: MICRORNA; UTR3 ; INTRON

Context (SEQ ID NO: 305):

TCTGAAGAGGCATCAGACTCATCCAGGGAGCTTTTTAAACAAGTGGACACTTAGTTTCTA TTTTATACCTATTGACTGAAC

AAAACCCCTGGAGAGTGGA

R TTACCCAATAGGGATCTGT

Celera SNP ID: hCVll733314

Public SNP ID: rsl892847

SNP Chromosome Position: 20516538

SNP in Genomic Sequence: SEQ ID NO: 153

SNP Position Genomic: 82592

Related interrogated SNP: hCV25922338

Related interrogated SNP: hCV7626903

SNP Source: dbSNP; Celera; HapMap; HGBASE

Population (Allele, Count) : Caucasian (G,115|A,5)

SNP Type: INTRON

Context (SEQ ID NO: 306):

AAGCTGTTCTCTAAGCCACCCATTTTGGTGAACTTTAATTATCTGAACACGAAACTACAG CACTCTGTTTCACAGATAAAA

ATTATCTTGTCTTCAGATG

Y

TAAGTAAGTTAGACTGAGCCAAACTCATGTTCCAAAAATAAATAGGTAGATAATACT AATGATTGCTTTAAAAGAAAATGT ATTCCTTACTTTAGCTTGG

Celera SNP ID: hCV29249403

Public SNP ID: rs7286558

SNP Chromosome Position: 20510183

SNP in Genomic Sequence: SEQ ID NO: 153

SNP Position Genomic: 76237

Related interrogated SNP: hCV25922338

Related interrogated SNP: hCV7626903

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (C,213|T,13)

SNP Type: INTRON

Context (SEQ ID NO: 307):

GGATAGAGGAACAGATGGACAGATCTATGAGAAAACAAGTAAGATGTTAATGTTAACTGT ATAATCTAGGTGGTGGGAATA

TGGGTGTCTACTTTAAATT

Y

CTTCAACTTTTCAGAATAGTTGAAAACTGTCACTAAAAGAATGTTGGGAAAAAAAAT CATGCTATAAGCACATAGGGAGCA TCTGTGTGTCTTCTGTGTC

Celera SNP ID: hDV71012676

Public SNP ID: rsl7821423

SNP Chromosome Position: 20450153

SNP in Genomic Sequence: SEQ ID NO: 153

SNP Position Genomic: 16207

Related interrogated SNP: hCV25922338

Related interrogated SNP: hCV7626903

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (C,210|T,12)

SNP Type: INTRON

Context (SEQ ID NO: 308):

CAACTTTGTGCTTCAAAGGACACTAGAAAGAAAATGAAAAGACAACTCACAGAATGAGAG AAAAATATTTGCATATCATGT

ATTTGATAAGGAATCTGTA

W

CTAGAATGTATAAAGAACTTTTAAAACTCAATCACAGGAGCTGGGTGTGGTGGCTCA TGCCTGTAATCTCAGCACTTTGTG AGGCTGAAGTGGGAGGATC

Celera SNP ID: hCV31649955

Public SNP ID: rs7285387

SNP Chromosome Position: 20523334

SNP in Genomic Sequence: SEQ ID NO: 153

SNP Position Genomic: 89388

Related interrogated SNP: hCV25922338

Related interrogated SNP: hCV7626903

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (T,115|A,5)

SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON

Gene Number: 20

Gene Symbol : NBN - 4683

Gene Name: ni bri n

Chromosome :

OMIM NUMBER: Genomic Sequence (SEQ ID NO: 154):

SNP Information

Context (SEQ ID NO: 309):

CCTTTGGAGCATATCCATTATTGACTGAATCCATTTCTTCTGACAGTCAGGAATTAAGGT CTGTGAGTTTGTTATTCCTGT

ATCAACAACACACGTTCCC

R

GAGCCAAAAAGAAATTATGTTCTTCTTCATTCTCTTCTGTTATCAACCTAGCTTCCC CACCTCCAAAGACAACTGCGGAAC TCAATTTCTTATGCTAAAA

Celera SNP ID: hCV7566051

Public SNP ID: rs769420

SNP Chromosome Position: 91051867

SNP in Genomic Sequence: SEQ ID NO: 154

SNP Position Genomic: 47127

SNP Source: dbSNP; ABI_ .Val : HGBASE

Popul ati on (Al 1 el e , Count) Caucasian (G,120|A,-)

SNP Type: MISSENSE MUTATION ;ESE

Gene Number: 21

Gene Symbol : NHEJl - 79840

Gene Name: nonhomologous end-joining factor 1

Chromosome :

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 155)

SNP Information

Context (SEQ ID NO: 310):

TCATGCCACACCTGTTGAAGATCTGAAACCAACAAGGCATAGCCCTGCTTGGTGATAAAA ACCTTGGCCAAGAGGGAGTTC

TCTGCAAGCTGTAGCCACG

Y

CCATGGCTGCATCAACAGGCCTTGCTCCAGTTCTTCCATCTGCAAAAAAGTCCTCAT TTAGTAAAGAGCCTCAGGGTCATG CTGGCCTAGGGAGGGCACC

Celera SNP ID: hCV25636054

Public SNP ID: rs34689457

SNP Chromosome Position: 219731289

SNP in Genomic Sequence: SEQ ID NO: 155

SNP Position Genomic: 92997

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasian (C,40|T,0) African American (C,32|T,6) total (C,72|T,6)

SNP Type: MISSENSE MUTATION ; MICRORNA; UTR5 ; UTR3

SNP Source: Applera;dbSNP

Popul ati on (Al 1 el e , Count) no_pop (C,-|T,-)

SNP Type: MISSENSE MUTATION ; MICRORNA; UTR5 ; UTR3

Gene Number: 22

Gene Symbol : NTHLl - 4913

Gene Name: nth endonuclease ill-like 1 (E. col i )

Chromosome : 16

OMIM NUMBER: 602656

OMIM Informati

Genomic Sequence (SEQ ID NO: 156)

SNP Information

Context (SEQ ID NO: 311):

CTAGGCAGCCACTCCTCCAGGGCGGCGCGGGTCTCCTCTGGGGACTTGGTTGCCTTCTTG GTCCACCTCAGCCTGTTGGCG

ATTCTGTGCACATGCGTGT

M GTCTGCCACCACCCCCGTG

Celera SNP ID: hCVl5793839

Public SNP ID: rs3087468

SNP Chromosome Position: 2030235

SNP in Genomic Sequence: SEQ ID NO: 156

SNP Position Genomic: 10418

Related interrogated SNP: hCV25995019

SNP Source: dbSNP; HGBASE

Population (Allele, Count) : Caucasian (C,220| A, 2)

SNP Type: MISSENSE MUTATION : ESS : ESE : MICRORNA: UTR3

Context (SEQ ID NO: 312):

GGTGGGGACATCCCAGCCTCTGTGGCCGAGCTGGTGGCGCTGCCGGGTGTTGGGCCCAAG ATGGCACACCTGGCTATGGCT

GTGGCCTGGGGCACTGTGT

Y

AGGCATTGGTGAGTAGAGGAGGGCGGGGCTGGCTCCAGCCCACTGGCTGCTCTTGGG ATTCCCCACATCCTTGTGACCTGT GACTCCACTTCCAGCATGC

Celera SNP ID: hCV32396801

Public SNP ID: rs3211977

SNP Chromosome Position: 2033577

SNP in Genomic Sequence: SEQ ID NO: 156

SNP Position Genomic: 13760

Related interrogated SNP: hCV25995019

SNP Source: dbSNP; Celera; HapMap; HGBASE

Population (Allele, Count) : Caucasian (C,220|T,4)

SNP Type: MISSENSE MUTATION; ESS

Gene Number: 23

Gene Symbol : PCNT - 5116

Gene Name: peri centri n (kendri n)

Chromosome : 21

OMIM NUMBER: 170285

OMIM Information:

Genomic Sequence (SEQ ID NO: 157)

SNP Information

Context (SEQ ID NO: 313):

CGGCCCCTCAGCAGCATCCAGGGTGGGGGTTCTTATGCCGTGACCAGCTTGCCTGATGAT GGGTGTCTCCTGTCTCAGAGG

GGCCCTCCAGGACGCCCTG

Y

GCAGGCTGCTGGGTTTGTTTGGAGAGACGCTGAGGGCAGCCGTCACCCTGAGGAGCC GGATCGGGGAGCGCGTGGGGCTCT GCCTGGATGACGCGGGCGC

Celera SNP ID: hCV2446917

Public SNP ID: rs7279204

SNP Chromosome Position: 46633107

SNP in Genomic Sequence: SEQ ID NO: 157

SNP Position Genomic: 74624

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasian (C,34|T,4) African American (C,34|T,4) total (C,68|T,8)

SNP Type: MISSENSE MUTATION; MICRORNA; UTR3

SNP Source: Appl era; Cel era; dbSNP

Popul ati on (Al 1 el e , Count) no_pop (C,-|T,-)

SNP Type: MISSENSE MUTATION; MICRORNA; UTR3

Context (SEQ ID NO: 314):

GCAAACAGCGTGCAGAAGCTCCTGGCGGCGGAGCAGACTGTAGTGCGAGATTTGAAGTCC GACCTCTGTGAGAGCAGGCAG

AAGAGCGAACAGCTGTCCC

R

GTCCCTCTGCGAGGTGCAGCAGGAGGTCCTCCAGCTGAGGTGCGCCTGATCCCCCTT CCTGGGACACTGGCGGGAGTCCCC CCGTTGTGCCATGTTTTCT

Celera SNP ID: hCV25474258

Public SNP ID: rs8131693

SNP Chromosome Position: 46674535

SNP in Genomic Sequence: SEQ ID NO: 157 SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasian (A, 0|G, 40) African American (A,7|G,31) total (A, 7IG, 71)

SNP Type: MISSENSE MUTATION ; UTR3

SNP Source: dbSNP; HapMap; ABI_Val

Popul ati on (Al 1 el e , Count) Caucasian (G,120|A,-)

SNP Type: MISSENSE MUTATION ; UTR3

Gene Number: 24

Gene Symbol : PRKCH - 5583

Gene Name: protein kinase C, eta

Chromosome : 14

OMIM NUMBER: 605437

OMIM Information:

Genomic Sequence (SEQ ID NO: 158)

SNP Information

Context (SEQ ID NO: 315):

ATTGTTCTAATCTAAAGAATCAAAGAACCAGAGTTCTGTCAGGCTGTTACCCTCTCTTAT GCAATAGACCCTCTCTTATGC

AGTAGTTATTTTGGGGTCA

R

TTTCAATAGCCCTTGATAACTTTGTTTGCCAAATAGCAAGTATTTCTAGCACTTCGT AACTTTAGTTGAGGGCAGGTGATG TTTCCCCTTCATACAGTCA

Celera SNP ID: hCV7600023

Public SNP ID: rsl092331

SNP Chromosome Position: 61067284

SNP in Genomic Sequence: SEQ ID NO: 158

SNP Position Genomic: 219016

SNP Source: dbSNP; HapMap; HGBASE

Popul ati on (Al 1 el e , Count) Caucasian (A,31|G,195)

SNP Type: INTRON

Context (SEQ ID NO: 316):

TCCTCCAGGAAATGCTGTACGGGCCTGCAGTAGACTGGTGGGCAATGGGCGTGTTGCTCT ATGAGATGCTCTGTGGTCACG

CGCCTTTTGAGGCAGAGAA

Y

GAAGATGACCTCTTTGAGGCCATACTGAATGATGAGGTGGTCTACCCTACCTGGCTC CATGAAGATGCCACAGGGATCCTA AAATCTGTAAGTTTGGCTT

Celera SNP ID: hCV7600033

Public SNP ID: rsl088680

SNP Chromosome Position: 61066979

SNP in Genomic Sequence: SEQ ID NO: 158

SNP Position Genomic: 218711

Related interrogated SNP: hCV7600023

SNP Source: Appl era

Popul ati on (Allele, Count) : Caucasian (C,4|T,32) African American (C,17|T,11) total (C,21|T,43)

SNP Type: ESE ; ESE SYNONYMOUS; SILENT MUTATION

SNP Source: dbSNP; HapMap; ABI_Val ; HGBASE

Popul ati on (Allele, Count) : Caucasian (C,31|T,193)

SNP Type: ESE; ESE SYNONYMOUS; SILENT MUTATION

Context (SEQ ID NO: 317):

GCCACAGGGATCCTAAAATCTGTAAGTTTGGCTTACCCAGCTAGCTTCTGATGTATTGCA AACCAGCTTGTTTCATGTGCT

GCTTGAGTCTTTTCAGTAC

Y

TCCCACCAGTAAACCACTAGCTCTAACTAAAATTTGTATTGTTCTAATCTAAAGAAT CAAAGAACCAGAGTTCTGTCAGGC TGTTACCCTCTCTTATGCA

Celera SNP ID: hCV7600032

Public SNP ID: rsl088679

SNP Chromosome Position: 61067146

SNP in Genomic Sequence: SEQ ID NO: 158

SNP Position Genomic: 218878

Related interrogated SNP: hCV7600023

SNP Source: dbSNP; HapMap; HGBASE SN P Type: MICRORNA; UTR3 : INTRON

Context (SEQ ID NO: 318):

GCTCCTTTCTCATGCCAGCTGCTCCACTGATGGAGGCAGCAGCTGCGATTGTTACATATC ATGCGTCTAGCACTCATTTTC

CTAAATAACACTCGACGCT

S

TCTCTGGGTATCTTCCACATAGGAAGGAGCAGGGGCTCTGGGCTCACAGTGCCGGGC CTGCCTCCCAGTCCTGTTACCTTC TGGCTGAGTGGCCTTGGTG

Celera SNP ID: hCVll659170

Public SNP ID: rsl088677

SNP Chromosome Position: 61069456

SNP in Genomic Sequence: SEQ ID NO: 158

SNP Position Genomic: 221188

Related interrogated SNP: hCV7600023

SNP Source: dbSNP; Celera; HapMap; HGBASE

Population (Allele, Count) : Caucasian (C,31|G,195)

SNP Type: INTRON

Context (SEQ ID NO: 319):

TTGTAAGAACAGTTCATTTGTTATATTAGTAGAAATTTTAGAGGAAACCATAAATATGGC TTTTATAATTTTATGGAAAAA

AAAAGTCACAGAGAAGGGC

Y

TGTCTTCGTGGATTTGTGCCATGAAGTTTCTTAACTTCCTGAAGGGAAATGTACTCA CCTAGGTTGGCTGCAGCCAATTTT GATAACATAAACCATGATA

Celera SNP ID: hCVl5934307

Public SNP ID: rs2184634

SNP Chromosome Position: 61068370

SNP in Genomic Sequence: SEQ ID NO: 158

SNP Position Genomic: 220102

Related interrogated SNP: hCV7600023

SNP Source: dbSNP; HapMap; HGBASE

Population (Allele, Count) : Caucasian (C,29|T,195)

SNP Type: INTRON

Context (SEQ ID NO: 320):

GTAATATGCATAAAACATCCCTCTATCATAGTGCCATCTTAGAATATTTATTGATTCCCT CAGGTGGTTCTTGTTTCAATT

AAAGTCCTTTTGGGAAACA

W

TCTATCCGGGGGATTGGCCGGTGACACTGCTACATAGAAGGGATTGGGCCTGGTGTA GTAAGTCACAAGCCCAGGCCTTGG AGGTGAGCAGAAGTAAATC

Celera SNP ID: hCV32090053

Public SNP ID: rsl2589100

SNP Chromosome Position: 61059870

SNP in Genomic Sequence: SEQ ID NO: 158

SNP Position Genomic: 211602

Related interrogated SNP: hCV7600023

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (A, 106 |T, 14)

SNP Type: INTRON

Context (SEQ ID NO: 321):

ATATCGCTCCAGAGGTGAGTGCAGCTGCTTGATGCAGCTCTGAAATCTGAGCTCTCCAGT AACTCTGACCAGAAATGCCAC

TGGCTGCTTTTATGCACTG

S

AGCTTTGGAGGCAGCATTGAAAGGTGTCTAGAGCCGACACCTCTAGACTCATTTATG GCTCATTGGGTGAATGATGGCTGA AAATGGCCTAAGTCCCTCT

Celera SNP ID: hDV70867209

Public SNP ID: rsl7098729

SNP Chromosome Position: 61065771

SNP in Genomic Sequence: SEQ ID NO: 158

SNP Position Genomic: 217503

Related interrogated SNP: hCV7600023

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (C,106|G,14)

SNP Type: INTRON

Context (SEQ ID NO: 322):

TCCATCTGAAATGCTTCTGTTTATCCCTTTGGTCAGCACCTCCTGCCAGGACCATGCTGG AGCTGCTAAGAAGGAAGACAG GGAATACAGTGCGGGGTATGCTATCATAGAAGTATAAACTGGGCACCCTAGGAGCAGAGT TGATATTGCTATGACTGTCTG GGGACATCAGGACAGACTT

Celera SNP ID: hDV70928489

Public SNP ID: rsl7256254

SNP Chromosome Position: 61061587

SNP in Genomic Sequence: SEQ ID NO: 158

SNP Position Genomic: 213319

Related interrogated SNP: hCV7600023

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (T, 106|C, 14)

SNP Type: TFBS SYNONYMOUS ; INTRON ; PSEUDOGENE

Gene Number: 25

Gene Symbol : PTPNl - 5770

Gene Name: protein tyrosine phosphatase, non-receptor type 1 Chromosome : 20

OMIM NUMBER: 176885

OMIM Information: {insulin resistance, susceptibility to} (3)

Genomic Sequence (SEQ ID NO: 159)

SNP Information

Context (SEQ ID NO: 323):

AGCCTCATTCTTGAACTTTCTTTTCAAAGTCCGAGAGTCAGGGTCACTCAGCCCGGAGCA CGGGCCCGTTGTGGTGCACTG

CAGTGCAGGCATCGGCAGG

K

CTGGAACCTTCTGTCTGGCTGATACCTGCCTCTTGCTGGTAAGGAGGCCCTCGCGGG TGCCCTGGGGAGCTCCTCTACCTG CTCTGCTGTGATGTTTTTT

Celera SNP ID: hDV88320149

Public SNP ID:

SNP Chromosome Position: 48628535

SNP in Genomic Sequence: SEQ ID NO: 159

SNP Position Genomic: 78237

SNP Source: CDX

Population (Allele, Count) : no_pop (G, I T , -)

SNP Type: MISSENSE MUTATION ; UTR5

Gene Number: 26

Gene Symbol : PEX2 - 5828

Gene Name: peroxi somal membrane protein 3 , 35kDa (Zellweger syndrome)

Chromosome :

OMIM NUMBER: 170993

OMIM Information: Zel lweger syndrome- 3 (3) ; Refsum disease, infantile form, 266510 (3)

Genomic Sequence (SEQ ID NO: 160)

SNP Information

Context (SEQ ID NO: 324):

CACTTAGGACAAGTAAAGTACACGTCAAATAAGAAACTACTCTTAGCACAGAAATAACAG AAAATATGCTCACATCCTATG

GTGTGAGGCATGGTGGGCC

R

CTCTCCACATAGAGCGCATTCTTTGCCACTGGTGGCTAATGTATTGTCACTATTAGG TGCACCAGTAAGAGGAATACACCA TGAAGACAGCTTGGCTTTC

Celera SNP ID: hDV88202422

Public SNP ID:

SNP Chromosome Position: 78058222

SNP in Genomic Sequence: SEQ ID NO: 160

SNP Position Genomic: 10509

SNP Source: CDX

Population (Allele, Count) : no_pop (A,-|G,-)

SNP Type: MISSENSE MUTATION Context (SEQ ID NO: 325):

AAGTACACGTCAAATAAGAAACTACTCTTAGCACAGAAATAACAGAAAATATGCTCACAT CCTATGGTGTGAGGCATGGTG

GGCCACTCTCCACATAGAG

Y

GCATTCTTTGCCACTGGTGGCTAATGTATTGTCACTATTAGGTGCACCAGTAAGAGG AATACACCATGAAGACAGCTTGGC TTTCAACTTCTGGACATTG

Celera SNP ID: hDV88214691

Public SNP ID:

SNP Chromosome Position: 78058237

SNP in Genomic Sequence: SEQ ID NO: 160

SNP Position Genomic: 10524

SNP Source: CDX

Population (Allele, Count) : no_pop (C,-|T,-)

SNP Type: MISSENSE MUTATION

Gene Number: 27

Gene Symbol : SOS2 - 6655

Gene Name: son of sevenless homolog 2 (Drosophila)

Chromosome : 14

OMIM NUMBER: 601247

OMIM Informati

Genomic Sequence (SEQ ID NO: 161)

SNP Information

Context (SEQ ID NO: 326):

GGATACTAATTCAAATGCATGCTTGTGCTCACAAGTATCTTCTTTATCACAAATTTGTAT TTTCCTCATGACAAATTTTTC

TTTTAACCTGTATTCTGCA

Y

TACTGTAACCTGGAAGCCGAGTCTGGCCATGATTAGGTTTACAACTGATCATTAAGC CATCAAACAGAAAAATATGCCGTT CATGTTTGGCACCGATTCT

Celera SNP ID: hCV25598905

Public SNP ID: rsl7122201

SNP Chromosome Position: 49696303

SNP in Genomic Sequence: SEQ ID NO: 161

SNP Position Genomic: 51491

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasian (C,26|T,0) African American (C,25| T,1) total (C,51|T,1)

SNP Type: MISSENSE MUTATION

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasian (C,40|T,0) African American (C,31| T,3) total (C,71|T,3)

SNP Type: MISSENSE MUTATION

SNP Source: dbSNP; HapMap

Popul ati on (Al 1 el e , Count) Caucasian (C,120|T,-)

SNP Type: MISSENSE MUTATION

Context (SEQ ID NO: 327):

TCCAGCCTGGGCAACAGAGCAAGACTCTGTCTCAAAAAAAAAAAATTCATGAATATGCAT ATTTTATGAATATTTATTCAA TAATTAATGAAGTTAACAA Y

ATTACATT TTTAGACCTTTAATTCCTTCTCTTATTTATTCCT TTTGTTTTTGCAGTATTTTTATATTTTGGAGGCAATCCA TTTTTTCCCCAAGCCTCAA

Celera SNP ID: hCV30550339

Public SNP ID: rsl0483598

SNP Chromosome Position: 49695725

SNP in Genomic Sequence: SEQ ID NO: 161

SNP Position Genomic: 50913

SNP Source: dbSNP

Popul ati on (Allele, Count) : no_pop (C , - | T , -)

SNP Type: INTRON

Gene Number:

Gene Symbol : SPAG17 - 200162

Gene Name: sperm associated antigen 17 OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 162)

SNP Information

Context (SEQ ID NO: 328):

AGTTTCACCTCATTCTTTATGACCTCATGCTGAATGAATTGGCGCATCTGTAGCACACTG GGGCTCTTGAGTATGGCACCC

GGGGCACTCACTAGCTGTT

Y

GGACTCAATGCAAAGGCCTTTCCAAATCTGAGTACCAAACGGAGGTCCTGGAGTTTT TTTCTGTTAACAAAACAAAGCAAT AACACCACCAAAGAAATCA

Celera SNP ID: hCV25750081

Public SNP ID: rs35290515

SNP Chromosome Position: 118336734

SNP in Genomic Sequence: SEQ ID NO: 162

SNP Position Genomic: 48923

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasi an (C,1| T,35) African American (C,0| T,38) total (C,1|T,73)

SNP Type: MISSENSE MUTATION; ESS;ESE SYNONYMOUS

SNP Source: Appl era; dbSNP

Popul ati on (Al 1 el e , Count) no_pop (C,-|T,-)

SNP Type: MISSENSE MUTATION; ESS;ESE SYNONYMOUS

Gene Number: 29

Gene Symbol : TSC2 - 7249

Gene Name: tuberous sclerosis 2

Chromosome : 16

OMIM NUMBER: 191092

OMIM Information: Tuberous sclerosis-2, 191100 (3)

Lymphangi ol ei omyomatosi s , /somati c 6

06690 (3)

Genomic Sequence (SEQ ID NO: 163)

SNP Information

Context (SEQ ID NO: 329):

CTAGGCAGCCACTCCTCCAGGGCGGCGCGGGTCTCCTCTGGGGACTTGGTTGCCTTCTTG GTCCACCTCAGCCTGTTGGCG

ATTCTGTGCACATGCGTGT

M

CACTGCTGCTGGGAGGCCAAGCGGGGTGAACAGGGGCACACTCCACCAGCCTAGCCC GTGCCCCTCCCCGCCCAGAGGCGA GTCTGCCACCACCCCCGTG

Celera SNP ID: hCVl5793839

Public SNP ID: rs3087468

SNP Chromosome Position: 2030235

SNP in Genomic Sequence: SEQ ID NO: 163

SNP Position Genomic: 1635

Related interrogated SNP: hCV25995019

SNP Source: dbSNP; HGBASE

Popul ati on (Allele, Count) : Caucasian (C,220|A,2)

SNP Type: MISSENSE MUTATION : ESS : ESE : MICRORNA: UTR3

Context (SEQ ID NO: 330):

GGTGGGGACATCCCAGCCTCTGTGGCCGAGCTGGTGGCGCTGCCGGGTGTTGGGCCCAAG ATGGCACACCTGGCTATGGCT

GTGGCCTGGGGCACTGTGT

Y

AGGCATTGGTGAGTAGAGGAGGGCGGGGCTGGCTCCAGCCCACTGGCTGCTCTTGGG ATTCCCCACATCCTTGTGACCTGT GACTCCACTTCCAGCATGC

Celera SNP ID: hCV32396801

Public SNP ID: rs3211977

SNP Chromosome Position: 2033577

SNP in Genomic Sequence: SEQ ID NO: 163 Related interrogated SNP: hCV25995019

SNP Source: dbSNP; Celera; HapMap; HGBASE

Population (Allele, Count) : Caucasian (C,220|T,4)

SNP Type: MISSENSE MUTATION; ESS

Context (SEQ ID NO: 331):

TCGGAGGCCACGTCAGGGCCAGGGCCTGGCCCAGCCCCACATCCAGCAGCCCCGTCTGTG TCCTCCCAGACTCCGCCGTGG

TCATGGAGGAGGGAAGTCC

R

GGCGAGGTTCCTGTGCTGGTGGAGCCCCCAGGGTTGGAGGACGTTGAGGCAGCGCTA GGCATGGACAGGCGCACGGATGCC TACAGCAGGGTGAGTGTGG

Celera SNP ID: hDV75028111

Public SNP ID: rsll551373

SNP Chromosome Position: 2073728

SNP in Genomic Sequence: SEQ ID NO: 163

SNP Position Genomic: 45128

Related interrogated SNP: hCV25995019

SNP Source: CDX; dbSNP

Population (Allele, Count) : Caucasian (G,216|A,2)

SNP Type: ESS ;UTR3; SILENT RARE CODON; SILENT MUTATION

Gene Number: 30

Gene Symbol : ZBTB38 - 253461

Gene Name: zinc finger and BTB domain containing 38

Chromosome :

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 164)

SNP Information

Context (SEQ ID NO: 332):

ATTGAAAGCTTTCTTCAGGAAGAGAATATGAGAGTGTTCTTTCCAGCTTATTTTCTTCCT TAGCAAAAGGATTGTTTGATT

CTCAGAAGCAGAAGGACAC

R

TTCATTGTGGAGCAGCTCTGCTTAAGTGTATGAAATGCCTTCTGTCTGGTTGCAGAA TTTGGAGTTTACTAAACAGTGTTT AGTGATTGGGCTCATCTTG

Celera SNP ID: hCV2416397

Public SNP ID: rs724016

SNP Chromosome Position: 142588260

SNP in Genomic Sequence: SEQ ID NO: 164

SNP Position Genomic: 9849

SNP Source: dbSNP; Celera; HapMap;

Popul ati on (Al 1 el e , Count) Caucasian (A, 130 |G, 94)

SNP Type: INTRON; PSEUDOGENE

Context (SEQ ID NO: 333):

CTACCACAGTCTGCCTTGCAGCCTATGTCATTTGCCACTTTTCCTTTGTTAAAAAACACA TGGTTTACAGTTCCCTTTTCC

TTCCAGCTCTTTCCTGGAG

R

GTAACCCCAGTTTGGTCCACAAGGCTTGCTGCCCAATCTTTGCCAACAGGTATGTAC TCCTTTCTCATGTCCTACACAGAT GCTAATGGATGGACGTGAG

Celera SNP ID: hCV29279566

Public SNP ID: rs6764769

SNP Chromosome Position: 142582970

SNP in Genomic Sequence: SEQ ID NO: 164

SNP Position Genomic: 4559

SNP Source: dbSNP; HapMap; ABI_Val

Popul ati on (Al 1 el e , Count) Caucasian (A, 130 |G, 96)

SNP Type: UTR5; PSEUDOGENE

Context (SEQ ID NO: 334):

GTTCATTTACTTCCTGGTGGTCACTCAGAGATTTAATGGCAAAGGTTGAACTAGACAAAG GGCCCAGAGTCACCCAACCTT

TAGGTAAGAGACAAAAGGC

R

CCAATGAGAAGATTCACTCCTGAGGCAACGCCCTGCCTCAGCCAAGGAGCTCTTACC TGCCCTCAGATAGGCATGCCCGTA Celera SNP ID: hCV2923639

Public SNP ID: rs6440003

SNP Chromosome Position: 142576899

SNP in Genomic Sequence: SEQ ID NO: 164

SNP Position Genomic: 1512

Related interrogated SNP: hCV2416397

Related interrogated SNP: hCV29279566

SNP Source: dbSNP; Celera; HapMap

Population (Allele, Count) : Caucasian (G, 130 | A , 96)

SNP Type: INTRON

Context (SEQ ID NO: 335):

AAACAAAATGGGCAAATATGTGGTTTTCTGTTGGAATGATTTATAATATAAAATACTATA ATATTTATAATACTATAATAC

CAAGATTGCATCTCTTGCC

R

TAATACTAGAGTGGTATTGATCTACCCCATCCATTTCCATGGATCCCCCGGAGATGG ACTGGGAATCAGACTATGACTTAG AGCCTCTTCACTGTTATGT

Celera SNP ID: hCV2923645

Public SNP ID: rs6808936

SNP Chromosome Position: 142592011

SNP in Genomic Sequence: SEQ ID NO: 164

SNP Position Genomic: 13600

Related interrogated SNP: hCV2416397

Related interrogated SNP: hCV29279566

SNP Source: dbSNP; Celera; HapMap

Population (Allele, Count) : Caucasian (A,62|G,58)

SNP Type: INTRON

Context (SEQ ID NO: 336):

TGGAATAGATTCCACCTCAAGAAACCAGTTTCTTTGCTCATCCATAAGAAGCAACTCCTC ATCTGATCAAGTTTTATAATA

AGATTGCAGAAATTCAGTC

Y

CATCTTTAGGCTCCACTTCTAGTTCTTATGCTATTTCCACCACATCTGCAGTTACTT CCTCCACTGAAGTCTTGAATCTCT CAAAGTCATCCATGAGGGT

Celera SNP ID: hCV2923649

Public SNP ID: rsl582874

SNP Chromosome Position: 142597909

SNP in Genomic Sequence: SEQ ID NO: 164

SNP Position Genomic: 19498

Related interrogated SNP: hCV2416397

Related interrogated SNP: hCV29279566

SNP Source: dbSNP; Celera; HapMap; ABI_Val ; HGBASE

Population (Allele, Count) : Caucasian (T,62|C,58)

SNP Type: UTR5 ; INTRON ; PSEUDOGENE

Context (SEQ ID NO: 337):

TAATTATGTCAGTGGGGTCAGTAGCAGAGCATAGTATTTGTGTCCAGGGACATCTGGAAG GCATCAGACAGAGCAGCCCTG

ACTAAGTTGCCCAGTGCTC

R

GTGTACTGATCCCAGGGTGAGACAGGAAGAACATCAGAGGAAGCCCCTCTGTGTCCA GGCATGTCCGTCTTAAGGCAGCCA GATGGAACCAAGCCTGCAG

Celera SNP ID: hCV2923655

Public SNP ID: rsl991431

SNP Chromosome Position: 142616140

SNP in Genomic Sequence: SEQ ID NO: 164

SNP Position Genomic: 37729

Related interrogated SNP: hCV2416397

Related interrogated SNP: hCV29279566

SNP Source: dbSNP; Celera; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (G,62| A,58)

SNP Type: INTRON

Context (SEQ ID NO: 338):

AAGGGCTCTGCCCAAGGAATCCTGTTTTTAAGAGGGACTGCCTGCCCTCAGAGCTAGGAA CTGCCTTGGGGCATTCACTTT

TATGACTCTAGCCTCCTTA

Y

TAAGCCCATGACACCTGAAAGCAGAATGGGCAGGCTCAGCAATGCAGAAAGAGCCCA GCCTTTCCAGGAGTATGCTGCAGT ACTGGGCTACCGTTCACTC Public SNP ID: rs9846396

SNP Chromosome Position: 142623658

SNP in Genomic Sequence: SEQ ID NO: 164

SNP Position Genomic: 45247

Related interrogated SNP: hCV2416397

Related interrogated SNP: hCV29279566

SNP Source: dbSNP; Celera; HapMap

Population (Allele, Count) : Caucasian (C, 130 |T, 96)

SNP Type: INTRON

Context (SEQ ID NO: 339):

TTTTTAATTATTTTTTACTGAACAAAATACAAACTAATGAATCCACTAAACTGAGACTTA AATGAAAAAGATTCTAAAATC

AAAAACCCAAAACACCAAA

R

TATTCTCTAAAATAAATTGTAACCAAACTGATATGTTATTAAAAAATCCCCTTTGCA TCAAGAGAAAGGAGCAGATGTGAT TTGTCAAGTCTGTAAACAG

Celera SNP ID: hCV2923662

Public SNP ID: rs6440006

SNP Chromosome Position: 142625381

SNP in Genomic Sequence: SEQ ID NO: 164

SNP Position Genomic: 46970

Related interrogated SNP: hCV2416397

Related interrogated SNP: hCV29279566

SNP Source: dbSNP; Celera; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (G,61|A,59)

SNP Type: INTRON

Context (SEQ ID NO: 340):

TGAGTAGCTTGGGGGGAGATCGGGAGGAGAGGCAGGGCAGAAACTAGAGGCCAGAAAGCC AGTTAAGCTACTACAACCCAC

CAAGGAAAAAGAGGGGCAG

R

AAAGGCCTGAAATGGATGATAACAATGAAATGGGAAAGGAATAGATGCAAAGGGAAG AACTGACAGAATCTGATGTCTCAG TGAAGGAACAGCTAAAGCT

Celera SNP ID: hCV8240179

Public SNP ID: rsl344674

SNP Chromosome Position: 142607876

SNP in Genomic Sequence: SEQ ID NO: 164

SNP Position Genomic: 29465

Related interrogated SNP: hCV2416397

Related interrogated SNP: hCV29279566

SNP Source: dbSNP; HapMap; ABI_Val HGBASE

Population (Allele, Count) : Caucasian (A, 130 |G, 96)

SNP Type: INTRON

Context (SEQ ID NO: 341):

ATGCAACTCCAGAAGCCAGCGGAAGGGGGTTCCTAATGGAGGGAGCCAGGCATGTCAGAC CGTGGAAGGTGAGGGATGAGC

TTAGGAAGACTGGTGGATT

S

ACAAGTGCAAAGTTACATTGTTGGTGTTTTCCTTTTTAAGGTAATATGACGTGTATG ATGAATATTAAGTGGTTTAATTTA CACAAATTAAACCACTCAA

Celera SNP ID: hCV8240181

Public SNP ID: rsl344672

SNP Chromosome Position: 142608395

SNP in Genomic Sequence: SEQ ID NO: 164

SNP Position Genomic: 29984

Related interrogated SNP: hCV2416397

Related interrogated SNP: hCV29279566

SNP Source: dbSNP; HGBASE

Population (Allele, Count) : Caucasian (C,130|G, 96)

SNP Type: INTRON

Context (SEQ ID NO: 342):

CCGAGGAGGCTGATGAGAAGCACGCAATTTTTTTAAATCATAAGTGAATGCATACCCTTG CCACTAGTAATCATGACAAAG

CTTAAGTAATTCAGGCATG

R

GCATGGTTTTCTGAAAGTATAAAACAGGATTTACTAGTTGAGAATGTCTGCCTAAAC AAGCTCATTGCTTTGAATATTTTC AACTATAGTTCACATTTGT

Celera SNP ID: hCVll795776 SNP Chromosome Position: 142585523

SNP in Genomic Sequence: SEQ ID NO: 164

SNP Position Genomic: 7112

Related interrogated SNP: hCV2416397

Related interrogated SNP: hCV29279566

SNP Source: dbSNP; Celera; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (G,127|A,95)

SNP Type: INTRON

Context (SEQ ID NO: 343):

GCCATATCATCTGGTAGCGAAGACTTGTTTTTGCCTCATTACAGCCTTAGATATTTCAAC ATCACCTTTCATTTCCAATTC

ATTTGCTTCTGGATGTTTG

Y

TTTTCATCACATTCAAAATATGATTTTACCTTTTTTTTTTTAACAAAACCAAAACCC CCCACAAACCCTAAAAACAAAAAC AACAACAACAAAACTCTGC

Celera SNP ID: hCVll795777

Public SNP ID: rs7632381

SNP Chromosome Position: 142588753

SNP in Genomic Sequence: SEQ ID NO: 164

SNP Position Genomic: 10342

Related interrogated SNP: hCV2416397

Related interrogated SNP: hCV29279566

SNP Source: dbSNP; Celera; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (T,129|C,97)

SNP Type: TRANSCRIPTION FACTOR BINDING SITE : INTRON : PSEUDOGENE

Context (SEQ ID NO: 344):

GATTGGGAATCGGACCCTAGTCCTGACCCTATGGGAACTTGATGATTTCCTTGATGCAAC ACCAAGCCCCTGGAATTGAAA

GGGACGTGCAAAGGCAGGG

M

CCTGCCCCCAGGGGTTTGCAGTCTCAGCCGCCTACTTCTGCAGTAGTAAGGTCTGCT CTGTTGGTACAACATACAACACAA CCGCCCGCCGTTAGCCACT

Celera SNP ID: hCVl6087675

Public SNP ID: rs2871960

SNP Chromosome Position: 142604504

SNP in Genomic Sequence: SEQ ID NO: 164

SNP Position Genomic: 26093

Related interrogated SNP: hCV2416397

Related interrogated SNP: hCV29279566

SNP Source: dbSNP; HapMap; HGBASE

Population (Allele, Count) : Caucasian (A, 129 |C, 97)

SNP Type: UTR5; INTRON

Context (SEQ ID NO: 345):

CCGGGGAGTCTAGAAACTTCTTTTGGTCACACTATGAGATCTTAGGCTTTTCTGTAGAGT TTTTTGGGTTTTTTTGTTTTG TTTTGTTTTGTTTTTGTTG

w

TATAAGGGAGTAGCTGAAGAAATTGGAGATGTATAGCCCAGGAAAGGGTAAACATTCAAA GGGCTGTCGTATGGCAAAGGC TACAGTTGAGGGCCCCTCA

Celera SNP ID: hCV31744961

Public SNP ID: rs6763927

SNP Chromosome Position: 142623056

SNP in Genomic Sequence: SEQ ID NO: 164

SNP Position Genomic: 44645

Related interrogated SNP: hCV2416397

Related interrogated SNP: hCV29279566

SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (A,62|T,58)

SNP Type: INTRON

Gene Number: 31

Gene Symbol : ZNF276 - 92822

Gene Name: zinc finger protein 276

Chromosome : 16

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 165): SNP Information

Context (SEQ ID NO: 346):

TTTAAACAAGTTTGTGCTTAATCTGTCCCAACTAAAATGGAGCTTATAAACTTACTTAGC AAGGAACCTCAAGGAGGGCTC

GTTCTTAACCATTTGCAAG

W

TGCCTCTGAAAAGAGCGGCCCTCCGCATTTGTGCCTCAGCAGCGTGTTTCTTACCAC TCTCTGTCAACTGAAAGAGTGCCA GCCAGGATATCTTCCTCTT

Celera SNP ID: hCVl2112567

Public SNP ID: rs7195906

SNP Chromosome Position: 88333848

SNP in Genomic Sequence: SEQ ID NO: 165

SNP Position Genomic: 28914

SNP Source: Applera

Population (Allele, Count) : Caucasian (A,25|T,15) African American (A,13|T,23) total (A,38|T,38)

SNP Type: MISSENSE MUTATION; TRANSCRIPTION FACTOR BINDING SITE;UTR3 ;INTRON

SNP Source: dbSNP; Celera; HapMap; ABI_Val

Popul ati on (Al 1 el e , Count) Caucasian (A,67|T,53)

SNP Type: MISSENSE MUTATION; TRANSCRIPTION FACTOR BINDING SITE:UTR3 :INTRON

Context (SEQ ID NO: 347):

TGCCCGCCCTTGGTGCTGGAGGCGGGCTTGGTGTCCGGCTCAAGTAGCCTTCCTCTGCTC TGGGACCAGTGGTTTATTTTC

CCGCAAACGCTGAGTGACT

Y

GGGGCCGGACAGTTCATAAATAATTGATTCCTTTCCCCACTAAAGCAGTCGAGGAGA TTTGTAATCCACTTTTTAGTGCAA CAAGAGCTCCATGTTATGC

Celera SNP ID: hCV3020887

Public SNP ID: rsl230

SNP Chromosome Position: 88332356

SNP in Genomic Sequence: SEQ ID NO: 165

SNP Position Genomic: 27422

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasi an (C,23|T,17) African American (C,8|T,28) total (C,31|T,45)

SNP Type: MICRORNA;UTR3

SNP Source: dbSNP; HapMap; HGBASE

Popul ati on (Al 1 el e , Count) Caucasian (C,133|T,93)

SNP Type: MICRORNA;UTR3

Context (SEQ ID NO: 348):

CCAGTGCACAACCCAAGACCGTGAACAAACAAGCCCTGCACCCCTGTGGACATGAAGGTG CCCGTGGGGTCTGAGTGGGGT

CCACAGGGGAGAAGTCCTG

M

GGGTGCCATGGTGACGGCGGTGGGGGCAGGGACGGTTCTGGGAACTCAGGATGTGCG GCCCTCATCTGCTATGAGCTGGCA TCTTTAACTGTGGCTTCCA

Celera SNP ID: hCV25922424

Public SNP ID: rsl2102297

SNP Chromosome Position: 88340263

SNP in Genomic Sequence: SEQ ID NO: 165

SNP Position Genomic: 35329

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source: Appl era

Popul ati on (Allele, Count) : Caucasian (A,17|C,21) African American (A,24|C,6) total (A,41|C,27)

SNP Type: INTRON

SNP Source: dbSNP; HapMap SN P Type: INTRON

Context (SEQ ID NO: 349):

GGTCGTGTGGGGCTGCGACCAGGGCCACGACTACACCATGGATACCAGCTCCAGCTGCAA GGCCTTCTTGCTGGACAGTGC

GCTGGCAGTCAAGTGGCCA

Y

GGGACAAAGAGACGGCGCCACGGCTGCCCCAGCACCGAGGGTGGAACCCTGGGGATG CCCCTCAGACCTCCCAGGGTAGAG GGACAGGGACCCCAGTTGG

Celera SNP ID: hCV25923374

Public SNP ID: rs6500437

SNP Chromosome Position: 88317399

SNP in Genomic Sequence: SEQ ID NO: 165

SNP Position Genomic: 12465

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: Appl era

Population (Allele, Count) : Caucasian (C,13|T,19) African American (C,19|T,9) total (C,32|T,28)

SNP Type: MISSENSE MUTATION ;UTR5; SILENT MUTATION

SNP Source: Appl era

Population (Allele, Count) : Caucasian (C,16|T,24) African American (C,18|T,12) total (C,34|T,36)

SNP Type: MISSENSE MUTATION ;UTR5; SILENT MUTATION

SNP Source: dbSNP; HapMap; ABI_Val

Popul ati on (Al 1 el e , Count) Caucasian (T,142|C,84)

SNP Type: MISSENSE MUTATION :UTR5: SILENT MUTATION

Context (SEQ ID NO: 350):

TGGAGGTACCTGTAAAAAGCGAAAGGCAGCAGCCTGGTGTGCTGATCCGGGGCCACACGG AGGAGGAGCCGCCCCAGCCTG

AGGTCTGCAACACCAAGAA

R

TGGCTCAGGCAACTCTGGACATCTCTGCCTATTATCAGTGCTGGGGACACCCCTGGG GGTCGGGACGTGTACCCTGGGAGG CCTGGCTGTGGGGATAGTG

Celera SNP ID: hCV7518972

Public SNP ID: rsl061646

SNP Chromosome Position: 88333478

SNP in Genomic Sequence: SEQ ID NO: 165

SNP Position Genomic: 28544

Related interrogated SNP: hCVl2112711

Related interrogated SNP: hCV31692807

Related interrogated SNP: hCV3275471

SNP Source: Appl era

Popul ati on (Allele, Count) : Caucasian (A,12|G,20) African American (A,24|G,14) total (A, 361G, 34)

SNP Type: TRANSCRIPTION FACTOR BINDING

SITE ; MICRORNA; UTR3 ; INTRON

SNP Source: dbSNP; HapMap; ABI_Val ; HGBASE

Popul ati on (Allele, Count) : Caucasian (G, 142 | A, 84)

SNP Type: TRANSCRIPTION FACTOR BINDING

SITE ; MICRORNA; UTR3 ; INTRON

Context (SEQ ID NO: 351):

TGAGCTGTCTCACTGCAAGCTTATCTGGGGCTGTCCCTCAGCACATGAATCAAGGCTACT GCAGCATGAACACAGAAGGCA

CCACTTGAAGGCTGACAGC

M

TTTACGCTGGGCTGTGATGAGGATAAAAATAAGCTGAAGAAACGCACTTCAAGCCTG GGCAACACAGTGAGACCCCCATCT CTTTTAATTTTTACTTTAA

Celera SNP ID: hCV3020893

Public SNP ID: rs6500439

SNP Chromosome Position: 88335776

SNP in Genomic Sequence: SEQ ID NO: 165

SNP Position Genomic: 30842

Related Interrogated SNP: hCVll951343 Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source: dbSNP; Celera; HapMap

Population (Allele, Count) : Caucasian (A,64|C,52)

SNP Type: TRANSCRIPTION FACTOR BINDING SITE : INTRON

Context (SEQ ID NO: 352):

TGGGCTGCTAGGGGAGCCTGCTGAGCTCTGGCGGGAGCTGAGGTGAAGTCTCTGCTCCGA AGTCCCAAGAAAGCATAGTCA

GGCGCAAGTGGGCCACAGT

Y

ATGCTCTCGTGACGGGGCACAGGCAGCCACCGTACAGCCTCCAGCCAGTGCACAACC CAAGACCGTGAACAAACAAGCCCT GCACCCCTGTGGACATGAA

Celera SNP ID: hCV31692619

Public SNP ID: rsl2102290

SNP Chromosome Position: 88340118

SNP in Genomic Sequence: SEQ ID NO: 165

SNP Position Genomic: 35184

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (C,68|T,52)

SNP Type: INTRON

Context (SEQ ID NO: 353):

GTGAAGGGACCACACTCCTCTGAGCTGGGAACGAAACAGTGAAGAGACCACACTGCCCTG AGCTGGGAATGCCTGGTCCTT

GGATGCCCTCAGCTGAGAG

R

TGGCGTTCTAAACACCGAAGAGTTCATTTCTCACGAATTCCACCAACTGAGCTACAA CTCGGTGCAAATGCAGCCTGCTTG GGGAGCTCCCTGGGGAACA

Celera SNP ID: hCV31692620

Public SNP ID: rsl2922302

SNP Chromosome Position: 88339784

SNP in Genomic Sequence: SEQ ID NO: 165

SNP Position Genomic: 34850

Related interrogated SNP: hCVll951343

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCVl2112715

Related interrogated SNP: hCV2590883

Related interrogated SNP: hCV26871795

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source: dbSNP

Population (Allele, Count) : Caucasian (G,67|A,51)

SNP Type: INTRON

Gene Number: 32

Gene Symbol : ADPGK - 83440

Gene Name: ADP-dependent glucoki

Chromosome : 15

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 166)

SNP Information

Context (SEQ ID NO: 354):

TAGGTCAAGACAACAGATGCTGAATGTCAAAATGGGTTGGGGGGCTGGCAAAGAGGGCAC AGTTCTCCCTTCTAGACCATA AGTGCCTCTAAGGCAAAGA GATGTTTCCTATCTCCTCCCTTCTGTTTCATCACCTGTAAAATGTTTTCTAAGGTTTTCT CTAGCTTTACATTATGTGCAT CAGCTGTTATAAGAGCTAA

Celera SNP ID: hCV2902199

Public SNP ID: rsl2594844

SNP Chromosome Position: 70858060

SNP in Genomic Sequence: SEQ ID NO: 166

SNP Position Genomic: 37297

Related interrogated SNP: hCV25628122

SNP Source: dbSNP; Celera; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (C,206|G, 18)

SNP Type: INTRON

Context (SEQ ID NO: 355):

CCACCTCATCAGAACTTCCCCATCCTGGTCATCTACCTTCCCGCAGTTCATCCTACCCAG CCTACCTGACCATGCCATCCC

TTTCGACAAAGATATTCAC

R

CAGGAACAGATTTGGGCTACCTTGGAAAAGAAGCCAAAGAGCCAGTCAGATCTTTAT GAAGCCATGAAAGCCATCTTCCCT AGAGTTGCCTGTCACTTCT

Celera SNP ID: hCVl5965703

Public SNP ID: rs2278543

SNP Chromosome Position: 70864255

SNP in Genomic Sequence: SEQ ID NO: 166

SNP Position Genomic: 43492

Related interrogated SNP: hCV25628122

SNP Source: dbSNP; HapMap; ABI_Val ; HGBASE

Population (Allele, Count) : Caucasian (A, 209 |G, 17)

SNP Type: UTR5; INTRON

Context (SEQ ID NO: 356):

GTGCAGCATCAAAACCAGTAAACGGACATTGGTGCAAGGTGTATGTATAGTTTTGTGCCG TCTTATTATATATGGAGATTC

GGGTAATCACCACTCAATC

M

AGTTGCAAGAACTGTCCCATCACCACGAAGATCTCCCTCATGCTATCCCTTTAGTCA CACCCAACCCCCATCCTCTACCAT TCCTAGACCCTGGCAGCCA

Celera SNP ID: hCV27934522

Public SNP ID: rs4777543

SNP Chromosome Position: 70869647

SNP in Genomic Sequence: SEQ ID NO: 166

SNP Position Genomic: 48884

Related interrogated SNP: hCV25628122

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (A , 109 |C, 11)

SNP Type: INTRON

Context (SEQ ID NO: 357):

CTGCTCTAATCCAAACCTTAATCATTATACAGGAAAACAGCGATAACTTTCTTGTTGGCC TCCCCCTTCAGGCCTATTCTA

CTCATAGCAAGAGAAACTT

Y

TTACTCAGGTGTTACTGTGAACATGGCAACGATTTTTAATTCTACTTAAACCAAACA ATTTAAGTCTTGAAGACACTCCCC TACTGACTCTCATCTAGTG

Celera SNP ID: hDV70763118

Public SNP ID: rsl6957293

SNP Chromosome Position: 70850572

SNP in Genomic Sequence: SEQ ID NO: 166

SNP Position Genomic: 29809

Related interrogated SNP: hCV25628122

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (C,207|T,17)

SNP Type: INTRON

Gene Number: 33

Gene Symbol : BBS4 - 585

Gene Name: Bardet-Bi edl syndrome 4

Chromosome : 15

OMIM NUMBER: 600374

OMIM Information: Bardet-Bi edl syndrome 4, 209900 (3)

Genomic Sequence (SEQ ID NO: 167) SN P Information

Context (SEQ ID NO: 358):

TGCTGCCTGGCATTGTGAGCACAATGAGGATAGAAAAAAAATTCCACAAGAGAGGACTGG TGAAACTGTGTGTGTTCTAGG

CTGACTTGGTTTATAAAGC

R

TTGTTCTTTAATTTTATCAGTGTGACCAAGACAGTCATGCAAAACATTCTATAGGTT CTTTCTTAGGACTTTTACCCTAAG AAAGGAATCTGAATTCTAA

Celera SNP ID: hCV25628122

Public SNP ID: rs3759870

SNP Chromosome Position: 70807021

SNP in Genomic Sequence: SEQ ID NO: 167

SNP Position Genomic: 51433

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasi an (A, 34 IG, 4) African American (A,36|G,0) total (A, 701G, 4)

SNP Type: INTRON

SNP Source: dbSNP; HapMap; ABI_Val HGBASE

Popul ati on (Al 1 el e , Count) Caucasian (A, 209 |G, 17)

SNP Type: INTRON

Context (SEQ ID NO: 359):

CCTATTTTTAAATTTCTTTTTTCCTTATTATTGATTTGTGAGACTTCTTAATATATTCTG AATGTACGTCCTTTGTCTGTT

ATATATGTGGTAAGTATTT

Y

CCCCCAGCCTGTGTTTTACTACTTTCATTTTATTAAGGTATCTTTTGATGATCAAAA GTTTTAATTTTGATGAAGGCCAAT TTACTATTATTTTTCTTTT

Celera SNP ID: hCV2902254

Public SNP ID: rs4777528

SNP Chromosome Position: 70780102

SNP in Genomic Sequence: SEQ ID NO: 167

SNP Position Genomic: 24514

Related interrogated SNP: hCV25628122

SNP Source: dbSNP; Celera; HapMap; ABI_Val ; HGBASE

Popul ati on (Allele, Count) : Caucasian (C,108|T,10)

SNP Type: INTRON

Context (SEQ ID NO: 360):

TGGGCTGTTATTTGCTTACAAAAGTTGTGGGAGTAGATGGGGTGTGGATTGGATGGTTGT TGGGACAGGATGATTAGTACC

TAATTCTGTCTGCACTTAC

R

TATGATTGAAATTCTCCCTAGGATGTAGAACTAAAAAAGAAAAAAAAAATCCCAATA CTCTCTGTCTTAAGTTAGGTAATC TACTCAACCTCTCTGAGCT

Celera SNP ID: hCV29508987

Public SNP ID: rs4777529

SNP Chromosome Position: 70800829

SNP in Genomic Sequence: SEQ ID NO: 167

SNP Position Genomic: 45241

Related interrogated SNP: hCV25628122

SNP Source: dbSNP; HapMap; ABI_Val ; HGBASE

Popul ati on (Allele, Count) : Caucasian (G, 110 | A, 10)

SNP Type: INTRON

Context (SEQ ID NO: 361):

AATCACAACAAGGGAGTTGAAATTTTAAGAAACTGAATGAACTAATACTTTACTAGGCAT TATTAATACTCTAGGTTTTTT

TACATATGATTCTTGTCCA

Y

GTCTGCTTTTTCATTACTATTTGTTTTCTTTTTTTTTTCAGACAGAGTCTCACTCTG TTGCCCAGGCTGGAGTGCAGTGGC GCTATCTTGGCTCACTGCA

Celera SNP ID: hDV77042816

Public SNP ID: rs4776611

SNP Chromosome Position: 70791241

SNP in Genomic Sequence: SEQ ID NO: 167

SNP Position Genomic: 35653

Related interrogated SNP: hCV25628122

SNP Source: CDX; dbSNP

Popul ati on (Allele, Count) : Caucasian (C,107|T,9) Gene Number: 34

Gene Symbol : ADAP2 - 55803

Gene Name: centaurin, alpha

Chromosome: 17

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 168):

SNP Information

Context (SEQ ID NO: 362):

TATGTATAAAATTGCCAGTATTTGCCAGTTGTCTATTTGCAAAAATGGCAATTTCACATG GTTAAACCTGATTACAAGAAT

GCTCATAGCAGCACTATTT

K

TATTAGCCAAAACCTCAATGGCAGATTATTGTGTATATATTGAATAAACGTTTCACC CAGTAACATGGGTAAATCCCACAA ATATGATGTTGAATGAAAG

Celera SNP ID: hCVll612362

Public SNP ID: rs9911989

SNP Chromosome Position: 26261828

SNP in Genomic Sequence: SEQ ID NO: 168

SNP Position Genomic: 1052

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; Celera

Population (Allele, Count) : Caucasian (G,202|T,24)

SNP Type: TRANSCRIPTION FACTOR BINDING SITE : INTRON

Context (SEQ ID NO: 363):

GTAGGGGCAGCGTAGACAAGGTCCTCAAATAACCTTTTCACCAGGTAGACTGGAATAACG GGGAGAGATGCGAAGTGTTTG

AGGAGCTCAGCGGGGAAAC

R

GGGCAGGCAAGGGATTAGGTAAAGGCGAGGGAGGAGGAGATTGCGTTGGCGCTGGAG CGGTATTCCTCTTAGAAGGGATAA AGGGAGATGAATGTAGCGC

Celera SNP ID: hCVl5877773

Public SNP ID: rs2269916

SNP Chromosome Position: 26257889

SNP in Genomic Sequence: SEQ ID NO: 168

SNP Position Genomic: 4991

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap; ABI_Val HGBASE

Population (Allele, Count) : Caucasian (A, 202 |G, 24)

SNP Type: UTR5; INTRON

Context (SEQ ID NO: 364):

ATGTAAGGAGAGTGGAAAGAAAAGAATTATTTCTGGAAGATGGGGAGCCAGTTTTGTGAA AAACGGGGAATTCAGGAGGGA

GGGAAAGGTGATGAGTTTG

Y

GTTTTTATGAGGCAGCAATGGGTTGATTGTTTGTGTCTGGAAGGCAGTGGGGATGTA GGGGAATCATAAGTATTAATAAAA TGTGCTGGTCGGGAGCAGT

Celera SNP ID: hCV30384549

Public SNP ID: rs9889755

SNP Chromosome Position: 26258631

SNP in Genomic Sequence: SEQ ID NO: 168

SNP Position Genomic: 4249

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (C,202|T,24)

SNP Type: INTRON

Context (SEQ ID NO: 365):

AAAAAGGAAAACACTTTGTGATCCCAAGTCCTCTCACTTTATTGATTATTATTTTTTACC GATCCTCATTTCTTTGTTTAT

TTAGCAAACATTTGTTGAA

W

CCCTGCTATGTGGCATGCAGGTGCTAGGGATACAACAGAGAACACAACTGACCCTGT CCTCATGAAGCATAGAAGTGTGAC AGACCAGTAAACCAGCAAG

Celera SNP ID: hCV30239993 SNP Chromosome Position: 26267481

SNP in Genomic Sequence: SEQ ID NO: 168

SNP Position Genomic: 4601

Related interrogated SNP: hCV27849348

SNP Source: dbSNP

Population (Allele, Count) : Caucasian (A , 200 |T, 26)

SNP Type: INTRON

Context (SEQ ID NO: 366):

CACCTGGTCAAAAGTAAGACTTGAATTTAGGCATGGAGGCAGGAGTTTGCTCCACCAACC AATGGAGGCTGGGCTGGATGA

TGTTGTAGAGGAGAGAGCT

R

GGGTAGGAGAAGGGGCAGCATGAGCGAGATACAATGGCATGGAGTTGGATAGCTCTG TGTTCAAAGGATGTGGACAGATCA CACACCAAGCACATCCCAG

Celera SNP ID: hCV29590899

Public SNP ID: rs9895684

SNP Chromosome Position: 26266726

SNP in Genomic Sequence: SEQ ID NO: 168

SNP Position Genomic: 3846

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (G,202|A,24)

SNP Type: INTRON

Context (SEQ ID NO: 367):

TGGAGGCAGAGGTTGCAGTGAGCCGAGATTGCACCACTGCATTCCAGCCTGGGCGATAAG AGAGAGACTCCGTCTCAAAGA

AAACCAAAAAACAAAAAAC

R

CCACATTGCAATACCACTACACACCCATGAGAATACCTACTGGAAATCTCATACATT GCTGATGGAAGTGTGGGTTGGTTG AATCACTTTGAAAAGCTGG

Celera SNP ID: hCV29626991

Public SNP ID: rs9913782

SNP Chromosome Position: 26261510

SNP in Genomic Sequence: SEQ ID NO: 168

SNP Position Genomic: 1370

Related interrogated SNP: hCV27849348

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (A , 202 |G, 24)

SNP Type: INTRON

Gene Number: 35

Gene Symbol : ELKl - 2002

Gene Name: ELKl, member of ETS oncogene family

Chromosome : X

OMIM NUMBER: 311040

OMIM Information:

Genomic Sequence (SEQ ID NO: 169)

SNP Information

Context (SEQ ID NO: 368):

AGGCAAGCCGGCCTCTTCAGCCTCCAGACAGGCCTCCAAGGGGCTTGGACTGGTGCTCCT GCTCCCCGAGGGGGGCGCTGC

TGCCCCTGCAGGAGCTGCA

Y

TGGGGAGCACCACAGCAGGCCGAGGATGAGGGGGTGGCTGCGGCTGCAGAGACTGGA TGGTGAAGGTGGAATAGAGGCCCG AGCGCATGTACTCGTTCCG

Celera SNP ID: hCV8938091

Public SNP ID: rsl059579

SNP Chromosome Position: 47383344

SNP in Genomic Sequence: SEQ ID NO: 169

SNP Position Genomic: 13480

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasian (C,37|T,1) African American (C,27|T,11) total (C,64|T,12)

SNP Type: MISSENSE MUTATION; ESE; INTRON

SNP Source: Appl era ; Cel era ; HGBASE ; dbSNP SNP Type: MISSENSE MUTATION; ESE; INTRON

Gene Number: 36

Gene Symbol : HDAC8 - 55869

Gene Name: hi stone deacetyl

Chromosome : x

OMIM NUMBER: 300269

OMIM Informati

Genomic Sequence (SEQ ID NO: 170)

SNP Information

Context (SEQ ID NO: 369):

ATCAAGACATACTGCAACCACAAAGTTCCATCTCACTTAGATGTGGATGAAAAAAGATCT CTTGCTAAATTATTTTCTGTG

ACCTTAAAAGAAATTTGTT

M

CACTTTTCATCTTTCAAGGGTCATCTTGATAGTTACCTTAACAAACCTTTCTCAGCT ATTTATTATTGAGAAAGCCCATTC TTAAATTTTAAGTCACAAA

Celera SNP ID: hDV81070728

Public SNP ID: rs41459646

SNP Chromosome Position: 65878630

SNP in Genomic Sequence: SEQ ID NO: 170

SNP Position Genomic: 5577461

Related interrogated SNP: hCV8722378

SNP Source: dbSNP

Population (Allele, Count) : Caucasian (A, 198 |C, 28)

SNP Type: UTR3;INTRONIC INDEL

Gene Number: 37

Gene Symbol : LETMl - 3954

Gene Name: leucine zi pper-EF-hand containing transmembrane protein 1

Chromosome : 4

OMIM NUMBER: 604407

OMIM Information:

Genomic Sequence (SEQ ID NO: 171)

SNP Information

Context (SEQ ID NO: 370):

AGGCCTCAACGCCCATGTCTTTGCAGCCGAGGAGGAGCTGGTGGAGGCTGACGAGGCGGG CAGTGTGTATGCAGGCATCCT

CAGCTACGGGGTGGGCTTC

Y

TCCTGTTCATCCTGGTGGTGGCGGCTGTGACGCTCTGCCGCCTGCGCAGCCCCCCCA AGAAAGGCCTGGGCTCCCCCACCG TGCACAAGATCTCCCGCTT

Celera SNP ID: hDV71078050

Public SNP ID: rsl7881656

SNP Chromosome Position: 1775929

SNP in Genomic Sequence: SEQ ID NO: 171

SNP Position Genomic: 1371

SNP Source: ABI_Val ;Celera;HGBASE;dbSNP

Popul ati on (Al 1 el e , Count) no_pop (C,-|T,-)

SNP Type: MISSENSE MUTATION; TRANSCRIPTION FACTOR BINDING SITE ;UTR5; INTRON

Gene Number: 38

Gene Symbol : LOC645811 - 645811

Gene Name: similar to ciliary rootlet coi 1 ed-coi 1 , rootl eti n Chromosome : 16

OMIM NUMBER:

OMIM Informati

Genomic Sequence (SEQ ID NO: 172): SNP Information

Context (SEQ ID NO: 371):

CTCTGAGGGGCCAGGCCACCAAGTTAATCTCAGTCTCAAACAGAAATGAGACACCTGGGA AGAGTGTGAAATGGGCATCCC

CCGTCCCACTCAGCCCACT

K

TGAGGACTGGAAGACGCCACCCCGGGTTCAGCAGTGCCCCAAATTCACGTCCCCTCA GAACACAAGAACTTGACCTTGTCT GGAAACAGGGTCTTTGCCA

Celera SNP ID: hCVl256109

Public SNP ID: rsll861094

SNP Chromosome Position: 1416535

SNP in Genomic Sequence: SEQ ID NO: 172

SNP Position Genomic: 3010

Related interrogated SNP: hCV25995019

SNP Source: dbSNP; Celera; HapMap

Population (Allele, Count) : Caucasian (G,223|T,1)

SNP Type: TRANSCRIPTION FACTOR BINDING SITE : INTRON

Context (SEQ ID NO: 372):

ATGCCCGCCGAGCCCCCGCACACGCCTCCTTCACGAGGGGCTGGGTCTCATTTCCTCACC CTTGGCGTCCAGGACAGTGAC

CAGCACCGACGAGGCCGAG

Y

TGAGGTCCACCTGCGCCCGAAGCCTGGGCTGGCCATTTCCTGCCGCCCGCGCCTTTC AGGACAGAACACAGGGGCCCAGAG GCCCTTCTGGGTCCTCCAC

Celera SNP ID: hCV32105505

Public SNP ID: rsll645222

SNP Chromosome Position: 1418455

SNP in Genomic Sequence: SEQ ID NO: 172

SNP Position Genomic: 4930

Related interrogated SNP: hCV25995019

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (C,221|T,1)

SNP Type: MISSENSE MUTATION

Gene Number: 39

Gene Symbol : LYRM5 - 144363

Gene Name: LYR motif containing 5

Chromosome : 12

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 173)

SNP Information

Context (SEQ ID NO: 373):

GACAGTGGAATTGGAAACTTTCGGATAAAACACTGTAACCCAGTTAGCTCTGTGGGGGTG TGGGGGGAGAGATGGGCCCTC

AACATATCTGCAGATAACT

K

TTTTTTCCCCTAAATTCATCTAAATTACCTATCATTATCCCAAACAGGCACTTCAAA CTATTAAACTAAAACACAGATCTT AATCTAGTTATGACTATTC

Celera SNP ID: hDV75942727

Public SNP ID: rs34719539

SNP Chromosome Position: 25249931

SNP in Genomic Sequence: SEQ ID NO: 173

SNP Position Genomic: 20448

SNP Source: CDX;dbSNP

Popul ati on (Al 1 el e , Count) no_pop (G, T -)

SNP Type: MICR0RNA;UTR3 UTR3

Gene Number: 40

Gene Symbol : NFKBl - 4790

Gene Name: nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (

pl05)

Chromosome : 4 OMIM Information:

Genomic Sequence (SEQ ID NO: 174)

SNP Information

Context (SEQ ID NO: 374):

TTTGGAACTTTCTCCAGGACACGGTGTTTTTTAGTACACTGTGTCTAAACATTGGGTATA AAGAAAAGCATAAGGAATGTG

TTTAATGAGTAGCATTACT

G

CAAAAAAAAAAAAAATGTAGTCCTACACCAACATGTGGTTCTTCGTATCCTGCAGTT TGCCATTGTCTTCAAAACTCCAAA GTATAAAGATATTAATATT

Celera SNP ID: hDV89365167

Public SNP ID:

SNP Chromosome Position: 103724821

SNP in Genomic Sequence: SEQ ID NO: 174

SNP Position Genomic: 93303

SNP Source: CDX

Population (Allele, Count) : no_pop (G,-| ,-)

SNP Type: INTRONIC INDEL

Gene Number: 41

Gene Symbol : SLC23A3 - 151295

Gene Name: solute carrier family 23 (nucleobase transporters) member 3

Chromosome :

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 175)

SNP Information

Context (SEQ ID NO: 375):

TCATGCCACACCTGTTGAAGATCTGAAACCAACAAGGCATAGCCCTGCTTGGTGATAAAA ACCTTGGCCAAGAGGGAGTTC

TCTGCAAGCTGTAGCCACG

Y

CCATGGCTGCATCAACAGGCCTTGCTCCAGTTCTTCCATCTGCAAAAAAGTCCTCAT TTAGTAAAGAGCCTCAGGGTCATG CTGGCCTAGGGAGGGCACC

Celera SNP ID: hCV25636054

Public SNP ID: rs34689457

SNP Chromosome Position: 219731289

SNP in Genomic Sequence: SEQ ID NO: 175

SNP Position Genomic: 6858

SNP Source: Appl era

Popul ati on (Al 1 el e , Count) Caucasi an (C,40|T,0) African American (C,32|T,6) total (C,72|T,6)

SNP Type: MISSENSE MUTATION ; MICRORNA; UTR5 ; UTR3

SNP Source: Appl era; dbSNP

Popul ati on (Al 1 el e , Count) no_pop (C,-|T,-)

SNP Type: MISSENSE MUTATION ; MICRORNA; UTR5 ; UTR3

Gene Number: 42

Gene Symbol : SPIRE2 - 84501

Gene Name: spire homolog 2 (Drosophila)

Chromosome : 16

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 176)

SNP Information

Context (SEQ ID NO: 376):

CAAGGGAGCGCTATTACTGAAGGTTATTTTAACAGAAACAAGTCATCACATAAGGACGTG AAGGATCAGAAAATAACTTAC W

CCCTATCTCCCACTCTCAAACTGGGGGGAGAAGGAGGTACCTAGAAAATTGTTCTCCCGT CTGCTCTCCTGGGCACACCAC AGCCTGTCTCACTACTTCC

Celera SNP ID: hCV31692756

Public SNP ID: rsll076632

SNP Chromosome Position: 88408038

SNP in Genomic Sequence: SEQ ID NO: 176

SNP Position Genomic: 4370

Related interrogated SNP: hCVl2112567

Related interrogated SNP: hCV3020887

Related interrogated SNP: hCV30590701

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (A,66|T,54)

SNP Type: TRANSCRIPTION FACTOR BINDING SITE ; INTRON

Gene Number: 43

Gene Symbol : Chrl:65877906. 65951124

Gene Name:

Chromosome :

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 177)

SNP Information

Context (SEQ ID NO: 377):

TGAGGGGAAGGGGTTTTGTATAAAAAGGAAGCATGGGGAATTCAAGAGGAGGTGGATGTG TGATGGAAATGTTCTCTATAG

AATCGTGACGCTATGCATG

Y

GTCAAAACCCATCAAACTGTATGCCATAAAAGTGAATTTTACTGCATGTAAGTTAAA AATCTCAGCCAGGATATGGGAACA ATATGGAAAGCCGGCTGTG

Celera SNP ID: hCVl01179

Public SNP ID: rsll809917

SNP Chromosome Position: 65919425

SNP in Genomic Sequence: SEQ ID NO: 177

SNP Position Genomic: 41519

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; Celera; HapMap

Population (Allele, Count) : Caucasian (T,103|C,13)

SNP Type: INTERGENIC : UNKNOWN

Context (SEQ ID NO: 378):

GACACAAATACATATATTTTAAAGCAAAACATATGTCTATGTGTGATAACCTATCTTTAT GAAATTCTCTTTAGTACATAT

TTTGCCTACAGCTCCAAAG

M

CTGTGTTTCCAGGCACTGTAATTCCATGGGAAGGCTGTCAGGGAAAATTTTTTACTC TGTAATGGATAAATACTTTGTAGT AAAGCTGCACTAGACTTCT

Celera SNP ID: hCVl03609

Public SNP ID: rsll812068

SNP Chromosome Position: 65897906

SNP in Genomic Sequence: SEQ ID NO: 177

SNP Position Genomic: 20000

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; Celera; HapMap

Population (Allele, Count) : Caucasian (C, 194 | A, 32)

SNP Type: INTERGENIC : UNKNOWN

Context (SEQ ID NO: 379):

GAAAACTGCAGAAAAGTATCACTCCTGAACATAAACTCTAAAATTCCTAATAAAATTTTA GCAAATTATCCCAACATATAA

AAGGATTATATATCATAAC

R

AAGCAGAGTTTATTCCAAACATGGCAGGTTACTTTAACATCCTCAAAATGTTATATA TAACACCTTACACATGATCCAGCT ATTTCACCCAGAGATATGA

Celera SNP ID: hCV414483

Public SNP ID: rsll807752

SNP Chromosome Position: 65911163 SNP Position Genomic: 33257

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; Celera; HapMap

Population (Allele, Count) : Caucasian (A , 195 |G, 29)

SNP Type: INTERGENIC : UNKNOWN

Context (SEQ ID NO: 380):

GTCTGTGATAATGCCTGGTACATAATAGACCTTTGGTAAATTTCTATTGCATGTAATTGA ACGAAGTCGATTTGAGTGAAA

TGTTTAGGAAAACGAAGCG

Y

TGACATTGCTTGTATTTCACAAGATAGTTAAAAATGAATTAACGAGGAAAATTCTGG TTTGAGAATCATTTTCTCTACCTC TTTATAACTATTTGAAATG

Celera SNP ID: hCVl5785472

Public SNP ID: rs2375803

SNP Chromosome Position: 65925477

SNP in Genomic Sequence: SEQ ID NO: 177

SNP Position Genomic: 47571

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; Celera; HapMap;

Population (Allele, Count) : Caucasian (T,198|C,28)

SNP Type: INTERGENIC : UNKNOWN

Context (SEQ ID NO: 381):

CTTTGGTAAATTTCTATTGCATGTAATTGAACGAAGTCGATTTGAGTGAAATGTTTAGGA AAACGAAGCGTTGACATTGCT

TGTATTTCACAAGATAGTT

R

AAAATGAATTAACGAGGAAAATTCTGGTTTGAGAATCATTTTCTCTACCTCTTTATA ACTATTTGAAATGACAGCATTCCC CATAATAGATTCTCTTTAT

Celera SNP ID: hCVl5785473

Public SNP ID: rs2375804

SNP Chromosome Position: 65925507

SNP in Genomic Sequence: SEQ ID NO: 177

SNP Position Genomic: 47601

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; Celera; HapMap;

Population (Allele, Count) : Caucasian (A , 107 |G, 13)

SNP Type: INTERGENIC : UNKNOWN

Context (SEQ ID NO: 382):

GTAGCTATAACCATCTGCTTTAAGTTGTTAACAACTTAGCTTCAAATTGGATACTAAATC TCTACACTTTTATTCCCTCCA

CCCCACTTTGTGTTCTTGA

R

GTCAGAGTTTCTGTCTTTTTATGTTGTTTATTCATTAACAATTTTTTGTATTGTAGT CATTCTTAACATTTTTGTCTTTTA ACTTTTATATTAGTGTTAA

Celera SNP ID: hCVl5844618

Public SNP ID: rs2186244

SNP Chromosome Position: 65904121

SNP in Genomic Sequence: SEQ ID NO: 177

SNP Position Genomic: 26215

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; Celera; HapMap; ABI_Val HGBASE

Population (Allele, Count) : Caucasian (G, 102 | A, 12)

SNP Type: INTERGENIC : UNKNOWN

Context (SEQ ID NO: 383):

ATGAATCACATAACCGATACGGAGGGAGGTGGGGAAGTCAGGGTTTAAACTGAATGGATG CTGTAAGACTCAAGACAAAAG

AACTGTATATAAACACTGT

R

CTTGAGAAATTTGTTTTTTTTAAATTTTTAATTTTTCTGGCTATATAGTAGGTGTAT ATATTTATGGGGTATTTGGGATAT TTTGCTACATGCATACAAT

Celera SNP ID: hCV26465906

Public SNP ID: rsll809410

SNP Chromosome Position: 65919656

SNP in Genomic Sequence: SEQ ID NO: 177

SNP Position Genomic: 41750

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; Celera; HapMap

Population (Allele, Count) : Caucasian (A , 103 |G, 13) Context (SEQ ID NO: 384):

AAGCACAAAACTGGGCAGCTGTTTGGGCAGACACTGAGCTAGGTTCAGGAGTTTTTTTTT CACACCCCATTGGCATGTGGA

TCACCAGCAAGACAGTACT

K

TTCACTCCCATGGAAAAGGGGCTGAAACCAGGGGGCCAAGTGGTCTAGCTCAGCAGA TCCCATTCCCATGGAGGCCAGCAA GTTAAGATCCACTGGCTTG

Celera SNP ID: hCV26465940

Public SNP ID: rsl938493

SNP Chromosome Position: 65890407

SNP in Genomic Sequence: SEQ ID NO: 177

SNP Position Genomic: 12501

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; HapMap; HGBASE

Population (Allele, Count) : Caucasian (G,198|T,28)

SNP Type: INTERGENIC ; UNKNOWN

Context (SEQ ID NO: 385):

GAAAGATCTAAGCTACCAAATATCAGTGAAGTAGAAATAGCTAACCTAAACATTGCAATA TCTATTTACAAAATTGAATTT

GTAGTTAAAAATCTGCACA

R

AAAGAAAACTTCAGCACAGTTGGCTTCAATAGTGAATTCTACTAAACATTTAAGGAA ATAATAATAACACCAATTCCACAG AAATTCTTCCATTAAAACC

Celera SNP ID: hCV30405525

Public SNP ID: rs7339965

SNP Chromosome Position: 65909423

SNP in Genomic Sequence: SEQ ID NO: 177

SNP Position Genomic: 31517

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (G, 107 | A, 13)

SNP Type: INTERGENIC ; UNKNOWN

Context (SEQ ID NO: 386):

CACTGTAGTTGACACTGAGGCTATAGACATGAGAATCGGATGCAGTGCTTGCGCTCCAGT AGCCCCACCTCCTGTTGGAGA

CACAGTCAGCAGTGGTGTA

M

GTGCTGTAGAGGGATGACGAAGGCTCTCTAGGAGTCTAGGACAGAGAGGGTCAGAGG CTTCTTTAGGCTAAGGCAGAGAAG GAATAGGAATTAACCAGAC

Celera SNP ID: hDV70949557

Public SNP ID: rsl7407229

SNP Chromosome Position: 65928560

SNP in Genomic Sequence: SEQ ID NO: 177

SNP Position Genomic: 50654

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (A,107|C, ID

SNP Type: INTERGENIC ; UNKNOWN

Context (SEQ ID NO: 387):

TGTCGAACTTGAAAAGCTGGGTGTCCGTGTTGACCCCTGCTTCTCCCTCATGTCCCATAT ACAAATAAGTCCACTAGATTA

AATCTCTTCATTCAATTTA

Y

GTATTTCTATCATTACTGTCACAACTCTAGTCTGGCCCACTATAATTTCCAACAGCT TCCTCAAAGGCATCTTACCTTCCA ATGATGCTGTTCTAAACAT

Celera SNP ID: hDV70949568

Public SNP ID: rsl7407322

SNP Chromosome Position: 65931124

SNP in Genomic Sequence: SEQ ID NO: 177

SNP Position Genomic: 53218

Related interrogated SNP: hCV8722378

SNP Source: dbSNP; HapMap

Population (Allele, Count) : Caucasian (C,106|T,12)

SNP Type: INTERGENIC ; UNKNOWN

Context (SEQ ID NO: 388):

ATCAAGACATACTGCAACCACAAAGTTCCATCTCACTTAGATGTGGATGAAAAAAGATCT CTTGCTAAATTATTTTCTGTG ACCTTAAAAGAAATTTGTT CACTTTTCATCTTTCAAGGGTCATCTTGATAGTTACCTTAACAAACCTTTCTCAGCTATT TATTATTGAGAAAGCCCATTC TTAAATTTTAAGTCACAAA

Celera SNP ID: hDV81070728

Public SNP ID: rs41459646

SNP Chromosome Position: 65878630

SNP in Genomic Sequence: SEQ ID NO: 177

SNP Position Genomic: 724

Related interrogated SNP: hCV8722378

SNP Source: dbSNP

Population (Allele, Count) : Caucasian (A, 198 |C, 28)

SNP Type: UTR3;INTRONIC INDEL

Gene Number: 44

Gene Symbol : Chr3:142566899. 142586899

Gene Name:

Chromosome :

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 178)

SNP Information

Context (SEQ ID NO: 389):

CTACCACAGTCTGCCTTGCAGCCTATGTCATTTGCCACTTTTCCTTTGTTAAAAAACACA TGGTTTACAGTTCCCTTTTCC

TTCCAGCTCTTTCCTGGAG

R

GTAACCCCAGTTTGGTCCACAAGGCTTGCTGCCCAATCTTTGCCAACAGGTATGTAC TCCTTTCTCATGTCCTACACAGAT GCTAATGGATGGACGTGAG

Celera SNP ID: hCV29279566

Public SNP ID: rs6764769

SNP Chromosome Position: 142582970

SNP in Genomic Sequence: SEQ ID NO: 178

SNP Position Genomic: 16071

SNP Source: dbSNP; HapMap; ABI_Val

Popul ati on (Al 1 el e , Count) Caucasian (A, 130 |G, 96)

SNP Type: UTR5: PSEUDOGENE

Context (SEQ ID NO: 390):

GTTCATTTACTTCCTGGTGGTCACTCAGAGATTTAATGGCAAAGGTTGAACTAGACAAAG GGCCCAGAGTCACCCAACCTT

TAGGTAAGAGACAAAAGGC

R

CCAATGAGAAGATTCACTCCTGAGGCAACGCCCTGCCTCAGCCAAGGAGCTCTTACC TGCCCTCAGATAGGCATGCCCGTA CTTCAAGACACTCTTGGGC

Celera SNP ID: hCV2923639

Public SNP ID: rs6440003

SNP Chromosome Position: 142576899

SNP in Genomic Sequence: SEQ ID NO: 178

SNP Position Genomic: 10000

Related interrogated SNP: hCV2416397

Related interrogated SNP: hCV29279566

SNP Source: dbSNP; Celera; HapMap

Popul ati on (Allele, Count) : Caucasian (G, 130 | A, 96)

SNP Type: INTRON

Context (SEQ ID NO: 391):

CCGAGGAGGCTGATGAGAAGCACGCAATTTTTTTAAATCATAAGTGAATGCATACCCTTG CCACTAGTAATCATGACAAAG

CTTAAGTAATTCAGGCATG

R

GCATGGTTTTCTGAAAGTATAAAACAGGATTTACTAGTTGAGAATGTCTGCCTAAAC AAGCTCATTGCTTTGAATATTTTC AACTATAGTTCACATTTGT

Celera SNP ID: hCVll795776

Public SNP ID: rs6763931

SNP Chromosome Position: 142585523

SNP in Genomic Sequence: SEQ ID NO: 178

SNP Position Genomic: 18624

Related Interrogated SNP: hCV2416397 SNP Source: dbSNP; Celera; HapMap; ABI_Val

Population (Allele, Count) : Caucasian (G,127|A,95)

SNP Type: INTRON

Gene Number: 4 5

Gene Symbol : Chr7:603357..623357

Gene Name:

Chromosome : 7

OMIM NUMBER:

OMIM Information:

Genomic Sequence (SEQ ID NO: 179):

SNP Information

Context (SEQ ID NO: 392):

CCCAGGTTCAAGCGATTCTCCTGCCTCAGCCTCTGGAGCAGCTGGGATTACAGGCACCCG CCACCACACCCAGCTAATTTT

TATTTTTAGTAGAGACAGG

R

TTTCACCATGCTGGTCACCTGGACCACCAGGCTGGTCTCGAACCCCTGACCTCAGGT GATCTGCCCACCTCAGCCTCCCAA AGTGCTGGGATTACAGGCG

Celera SNP ID: hDV88213973

Public SNP ID:

SNP Chromosome Position: 613357

SNP in Genomic Sequence: SEQ ID NO: 179

SNP Position Genomic: 10000

SNP Source: CDX

Population (Allele, Count) : no_pop (A,-|G,-)

SNP Type: MISSENSE MUTATION; INTRON

Interrogated SNP Interrogated SNP

(hCV #) (rs #) LD SNP (hCV #) LD SNP (rs #) Threshold r ² r ² hCV1 1951343 rs1800337 hCV1 1951325 rs 1800335 0.9 1 hCV1 1951343 rs1800337 hCV121 12567 rs7195906 0.9 0.9303 hCV1 1951343 rs1800337 hCV121 12715 rs1800287 0.9 1 hCV1 1951343 rs1800337 hCV121 12716 rs6500453 0.9 1 hCV1 1951343 rs1800337 hCV2590883 rs6500450 0.9 1 hCV1 1951343 rs1800337 hCV2590894 rs6500449 0.9 1 hCV1 1951343 rs1800337 hCV2590902 rs8046243 0.9 1 hCV1 1951343 rs1800337 hCV2590905 rs12448860 0.9 1 hCV1 1951343 rs1800337 hCV25922424 rs12102297 0.9 0.9599 hCV1 1951343 rs1800337 hCV26871795 rs6500441 0.9 1 hCV1 1951343 rs1800337 hCV27475628 rs3743859 0.9 1 hCV1 1951343 rs1800337 hCV27897055 rs4785595 0.9 1 hCV1 1951343 rs1800337 hCV3020887 rs1230 0.9 0.9807 hCV1 1951343 rs1800337 hCV3020893 rs6500439 0.9 0.929 hCV1 1951343 rs1800337 hCV30590701 rs7190823 0.9 0.9619 hCV1 1951343 rs1800337 hCV31692619 rs12102290 0.9 0.9644 hCV1 1951343 rs1800337 hCV31692620 rs12922302 0.9 0.9638 hCV1 1951343 rs1800337 hCV31692774 rs12599799 0.9 1 hCV1 1951343 rs1800337 hCV31692777 rs10852623 0.9 0.9619 hCV1 1951343 rs1800337 hCV31692778 rs1 1076626 0.9 1 hCV1 1951343 rs1800337 hCV31692794 rs12709094 0.9 0.9807 hCV1 1951343 rs1800337 hCV31692807 rs7187436 0.9 0.925 hCV1 1951343 rs1800337 hCV31692816 rs12599180 0.9 1 hCV1 1951343 rs1800337 hCV31692827 rs7203907 0.9 0.9591 hCV1 1951343 rs1800337 hCV7518999 rs886952 0.9 1 hCV1 1951343 rs1800337 hCV7519008 rs886950 0.9 0.9807 hCV1 1951343 rs1800337 hDV77251247 rs8045232 0.9 1 hCV121 12567 rs7195906 hCV1 1951325 rs 1800335 0.9 0.9321 hCV121 12567 rs7195906 hCV1 1951343 rs1800337 0.9 0.9303 hCV121 12567 rs7195906 hCV121 12715 rs1800287 0.9 0.9272 hCV121 12567 rs7195906 hCV121 12716 rs6500453 0.9 0.9635 hCV121 12567 rs7195906 hCV2590840 rs1 1076631 0.9 0.9668 hCV121 12567 rs7195906 hCV2590844 rs1 1076628 0.9 0.9647 hCV121 12567 rs7195906 hCV2590883 rs6500450 0.9 0.9303 hCV121 12567 rs7195906 hCV2590894 rs6500449 0.9 0.9335 hCV121 12567 rs7195906 hCV2590902 rs8046243 0.9 0.9329 hCV121 12567 rs7195906 hCV2590905 rs12448860 0.9 0.9344 hCV121 12567 rs7195906 hCV25922424 rs12102297 0.9 0.9622 hCV121 12567 rs7195906 hCV26871795 rs6500441 0.9 0.9303 hCV121 12567 rs7195906 hCV27475628 rs3743859 0.9 0.9303 hCV121 12567 rs7195906 hCV27897055 rs4785595 0.9 0.9303 hCV121 12567 rs7195906 hCV3020887 rs1230 0.9 0.9646 hCV121 12567 rs7195906 hCV3020893 rs6500439 0.9 1 hCV121 12567 rs7195906 hCV30590701 rs7190823 0.9 0.9646 hCV121 12567 rs7195906 hCV31692619 rs12102290 0.9 0.9667 hCV121 12567 rs7195906 hCV31692620 rs12922302 0.9 0.9661 hCV121 12567 rs7195906 hCV31692756 rs1 1076632 0.9 0.9668 hCV121 12567 rs7195906 hCV31692774 rs12599799 0.9 0.9344 hCV121 12567 rs7195906 hCV31692777 rs10852623 0.9 0.9646 hCV121 12567 rs7195906 hCV31692778 rs1 1076626 0.9 0.9344 hCV121 12567 rs7195906 hCV31692794 rs12709094 0.9 0.9646 hCV121 12567 rs7195906 hCV31692816 rs12599180 0.9 0.929 hCV121 12567 rs7195906 hCV31692827 rs7203907 0.9 0.9621 hCV121 12567 rs7195906 hCV7518999 rs886952 0.9 0.9344 Interrogated SNP Interrogated SNP

(hCV #) (rs #) LD SNP (hCV #) LD SNP (rs #) Threshold r ² r ² hCV121 12567 rs7195906 hCV7519008 rs886950 0.9 0.9646 hCV121 12567 rs7195906 hDV77251247 rs8045232 0.9 0.9318 hCV121 1271 1 rs6500452 hCV158351 13 rs21591 13 0.9 1 hCV121 1271 1 rs6500452 hCV16172654 rs2238529 0.9 1 hCV121 1271 1 rs6500452 hCV16174688 rs2239360 0.9 0.9594 hCV121 1271 1 rs6500452 hCV2590884 rs1800330 0.9 0.9596 hCV121 1271 1 rs6500452 hCV2590886 rs8049660 0.9 0.9596 hCV121 1271 1 rs6500452 hCV25923374 rs6500437 0.9 0.9216 hCV121 1271 1 rs6500452 hCV26871766 rs12709096 0.9 1 hCV121 1271 1 rs6500452 hCV26871781 rs2016571 0.9 0.9637 hCV121 1271 1 rs6500452 hCV27897053 rs4785722 0.9 1 hCV121 1271 1 rs6500452 hCV31692786 rs8051231 0.9 1 hCV121 1271 1 rs6500452 hCV31692807 rs7187436 0.9 0.9615 hCV121 1271 1 rs6500452 hCV31692841 rs 7201028 0.9 0.9289 hCV121 1271 1 rs6500452 hCV31692842 rs7195752 0.9 0.9289 hCV121 1271 1 rs6500452 hCV3275469 rs 1006547 0.9 0.9794 hCV121 1271 1 rs6500452 hCV3275471 rs3785275 0.9 0.9637 hCV121 1271 1 rs6500452 hCV3275489 rs1 1860203 0.9 1 hCV121 1271 1 rs6500452 hCV7518972 rs1061646 0.9 0.9216 hCV121 1271 1 rs6500452 hCV7519014 rs 1007931 0.9 0.9598 hCV121 1271 1 rs6500452 hCV7519028 rs 1057042 0.9 0.9637 hCV121 12715 rs1800287 hCV1 1951325 rs 1800335 0.9 1 hCV121 12715 rs1800287 hCV1 1951343 rs1800337 0.9 1 hCV121 12715 rs1800287 hCV121 12567 rs7195906 0.9 0.9272 hCV121 12715 rs1800287 hCV121 12716 rs6500453 0.9 1 hCV121 12715 rs1800287 hCV2590883 rs6500450 0.9 1 hCV121 12715 rs1800287 hCV2590894 rs6500449 0.9 1 hCV121 12715 rs1800287 hCV2590902 rs8046243 0.9 1 hCV121 12715 rs1800287 hCV2590905 rs12448860 0.9 1 hCV121 12715 rs1800287 hCV25922424 rs12102297 0.9 0.96 hCV121 12715 rs1800287 hCV26871795 rs6500441 0.9 1 hCV121 12715 rs1800287 hCV27475628 rs3743859 0.9 1 hCV121 12715 rs1800287 hCV27897055 rs4785595 0.9 1 hCV121 12715 rs1800287 hCV3020887 rs1230 0.9 0.9608 hCV121 12715 rs1800287 hCV3020893 rs6500439 0.9 0.9258 hCV121 12715 rs1800287 hCV30590701 rs7190823 0.9 0.9608 hCV121 12715 rs1800287 hCV31692619 rs12102290 0.9 0.9629 hCV121 12715 rs1800287 hCV31692620 rs12922302 0.9 0.9622 hCV121 12715 rs1800287 hCV31692774 rs12599799 0.9 1 hCV121 12715 rs1800287 hCV31692777 rs10852623 0.9 0.9608 hCV121 12715 rs1800287 hCV31692778 rs1 1076626 0.9 1 hCV121 12715 rs1800287 hCV31692794 rs12709094 0.9 0.9608 hCV121 12715 rs1800287 hCV31692807 rs7187436 0.9 0.9197 hCV121 12715 rs1800287 hCV31692816 rs12599180 0.9 1 hCV121 12715 rs1800287 hCV31692827 rs7203907 0.9 0.9592 hCV121 12715 rs1800287 hCV7518999 rs886952 0.9 1 hCV121 12715 rs1800287 hCV7519008 rs886950 0.9 0.9608 hCV121 12715 rs1800287 hDV77251247 rs8045232 0.9 1 hCV2416397 rs 724016 hCV1 1795776 rs6763931 0.9 1 hCV2416397 rs 724016 hCV1 1795777 rs7632381 0.9 0.9807 hCV2416397 rs 724016 hCV16087675 rs2871960 0.9 0.9807 hCV2416397 rs 724016 hCV2923639 rs6440003 0.9 1 hCV2416397 rs 724016 hCV2923645 rs6808936 0.9 1 hCV2416397 rs 724016 hCV2923649 rs 1582874 0.9 1 Interrogated SNP Interrogated SNP

(hCV #) (rs #) LD SNP (hCV #) LD SNP (rs #) Threshold r ² r ² hCV2416397 rs 724016 hCV2923655 rs1991431 0.9 1 hCV2416397 rs 724016 hCV2923661 rs9846396 0.9 1 hCV2416397 rs 724016 hCV2923662 rs6440006 0.9 0.9641 hCV2416397 rs 724016 hCV29279566 rs6764769 0.9 1 hCV2416397 rs 724016 hCV31744961 rs6763927 0.9 1 hCV2416397 rs 724016 hCV8240179 rs 1344674 0.9 1 hCV2416397 rs 724016 hCV8240181 rs 1344672 0.9 1 hCV25628122 rs3759870 hCV15965703 rs2278543 0.9 1 hCV25628122 rs3759870 hCV27934522 rs4777543 0.9 0.9002 hCV25628122 rs3759870 hCV2902199 rs 12594844 0.9 0.9396 hCV25628122 rs3759870 hCV2902254 rs4777528 0.9 1 hCV25628122 rs3759870 hCV29508987 rs4777529 0.9 1 hCV25628122 rs3759870 hDV707631 18 rs16957293 0.9 1 hCV25628122 rs3759870 hDV77042816 rs477661 1 0.9 1 hCV2590883 rs6500450 hCV1 1951325 rs 1800335 0.9 1 hCV2590883 rs6500450 hCV1 1951343 rs1800337 0.9 1 hCV2590883 rs6500450 hCV121 12567 rs7195906 0.9 0.9303 hCV2590883 rs6500450 hCV121 12715 rs1800287 0.9 1 hCV2590883 rs6500450 hCV121 12716 rs6500453 0.9 1 hCV2590883 rs6500450 hCV2590894 rs6500449 0.9 1 hCV2590883 rs6500450 hCV2590902 rs8046243 0.9 1 hCV2590883 rs6500450 hCV2590905 rs12448860 0.9 1 hCV2590883 rs6500450 hCV25922424 rs12102297 0.9 0.9599 hCV2590883 rs6500450 hCV26871795 rs6500441 0.9 1 hCV2590883 rs6500450 hCV27475628 rs3743859 0.9 1 hCV2590883 rs6500450 hCV27897055 rs4785595 0.9 1 hCV2590883 rs6500450 hCV3020887 rs1230 0.9 0.9805 hCV2590883 rs6500450 hCV3020893 rs6500439 0.9 0.929 hCV2590883 rs6500450 hCV30590701 rs7190823 0.9 0.9614 hCV2590883 rs6500450 hCV31692619 rs12102290 0.9 0.9644 hCV2590883 rs6500450 hCV31692620 rs12922302 0.9 0.9638 hCV2590883 rs6500450 hCV31692774 rs12599799 0.9 1 hCV2590883 rs6500450 hCV31692777 rs10852623 0.9 0.9614 hCV2590883 rs6500450 hCV31692778 rs1 1076626 0.9 1 hCV2590883 rs6500450 hCV31692794 rs12709094 0.9 0.9805 hCV2590883 rs6500450 hCV31692807 rs7187436 0.9 0.925 hCV2590883 rs6500450 hCV31692816 rs12599180 0.9 1 hCV2590883 rs6500450 hCV31692827 rs7203907 0.9 0.9591 hCV2590883 rs6500450 hCV7518999 rs886952 0.9 1 hCV2590883 rs6500450 hCV7519008 rs886950 0.9 0.9805 hCV2590883 rs6500450 hDV77251247 rs8045232 0.9 1 hCV2590886 rs8049660 hCV121 1271 1 rs6500452 0.9 0.9596 hCV2590886 rs8049660 hCV158351 13 rs21591 13 0.9 1 hCV2590886 rs8049660 hCV16172654 rs2238529 0.9 1 hCV2590886 rs8049660 hCV16174688 rs2239360 0.9 1 hCV2590886 rs8049660 hCV2590884 rs1800330 0.9 1 hCV2590886 rs8049660 hCV26871766 rs12709096 0.9 1 hCV2590886 rs8049660 hCV26871781 rs2016571 0.9 0.9637 hCV2590886 rs8049660 hCV27897053 rs4785722 0.9 0.9596 hCV2590886 rs8049660 hCV31692786 rs8051231 0.9 1 hCV2590886 rs8049660 hCV31692807 rs7187436 0.9 0.9615 hCV2590886 rs8049660 hCV31692841 rs 7201028 0.9 0.9289 hCV2590886 rs8049660 hCV31692842 rs7195752 0.9 0.9289 hCV2590886 rs8049660 hCV3275469 rs 1006547 0.9 0.9386 Interrogated SNP Interrogated SNP

(hCV #) (rs #) LD SNP (hCV #) LD SNP (rs #) Threshold r ² r ² hCV2590886 rs8049660 hCV3275471 rs3785275 0.9 0.9637 hCV2590886 rs8049660 hCV3275489 rs1 1860203 0.9 1 hCV2590886 rs8049660 hCV7519014 rs 1007931 0.9 1 hCV2590886 rs8049660 hCV7519028 rs 1057042 0.9 0.9637 hCV25922338 rs3729910 hCV1 1733314 rs 1892847 0.9 1 hCV25922338 rs3729910 hCV29249403 rs7286558 0.9 1 hCV25922338 rs3729910 hCV31649955 rs7285387 0.9 1 hCV25922338 rs3729910 hCV7626903 rs 13058 0.9 1 hCV25922338 rs3729910 hDV71012676 rs17821423 0.9 1 hCV25995019 rs9282731 hCV1256109 rs1 1861094 0.9 1 hCV25995019 rs9282731 hCV15793839 rs3087468 0.9 1 hCV25995019 rs9282731 hCV32105457 rs 13332460 0.9 1 hCV25995019 rs9282731 hCV32105505 rs1 1645222 0.9 1 hCV25995019 rs9282731 hCV32396801 rs321 1977 0.9 1 hCV25995019 rs9282731 hDV750281 1 1 rs1 1551373 0.9 1 hCV26871795 rs6500441 hCV1 1951325 rs 1800335 0.9 1 hCV26871795 rs6500441 hCV1 1951343 rs1800337 0.9 1 hCV26871795 rs6500441 hCV121 12567 rs7195906 0.9 0.9303 hCV26871795 rs6500441 hCV121 12715 rs1800287 0.9 1 hCV26871795 rs6500441 hCV121 12716 rs6500453 0.9 1 hCV26871795 rs6500441 hCV2590844 rs1 1076628 0.9 0.9066 hCV26871795 rs6500441 hCV2590883 rs6500450 0.9 1 hCV26871795 rs6500441 hCV2590894 rs6500449 0.9 1 hCV26871795 rs6500441 hCV2590902 rs8046243 0.9 1 hCV26871795 rs6500441 hCV2590905 rs12448860 0.9 1 hCV26871795 rs6500441 hCV25922424 rs12102297 0.9 0.9599 hCV26871795 rs6500441 hCV27475628 rs3743859 0.9 1 hCV26871795 rs6500441 hCV27897055 rs4785595 0.9 1 hCV26871795 rs6500441 hCV3020887 rs1230 0.9 0.9805 hCV26871795 rs6500441 hCV3020893 rs6500439 0.9 0.929 hCV26871795 rs6500441 hCV30590701 rs7190823 0.9 0.9805 hCV26871795 rs6500441 hCV31692619 rs12102290 0.9 0.9644 hCV26871795 rs6500441 hCV31692620 rs12922302 0.9 0.9638 hCV26871795 rs6500441 hCV31692774 rs12599799 0.9 1 hCV26871795 rs6500441 hCV31692777 rs10852623 0.9 0.9805 hCV26871795 rs6500441 hCV31692778 rs1 1076626 0.9 1 hCV26871795 rs6500441 hCV31692794 rs12709094 0.9 0.9805 hCV26871795 rs6500441 hCV31692807 rs7187436 0.9 0.925 hCV26871795 rs6500441 hCV31692816 rs12599180 0.9 1 hCV26871795 rs6500441 hCV31692827 rs7203907 0.9 0.9591 hCV26871795 rs6500441 hCV7518999 rs886952 0.9 1 hCV26871795 rs6500441 hCV7519008 rs886950 0.9 0.9805 hCV26871795 rs6500441 hDV77251247 rs8045232 0.9 1 hCV27849348 rs9910051 hCV1 1413173 rs2433 0.9 0.9138 hCV27849348 rs9910051 hCV1 1612362 rs991 1989 0.9 0.9138 hCV27849348 rs9910051 hCV1 1616069 rs1 1658435 0.9 0.9138 hCV27849348 rs9910051 hCV1 1616097 rs1 1651858 0.9 0.9138 hCV27849348 rs9910051 hCV1 1627478 rs9899349 0.9 0.9138 hCV27849348 rs9910051 hCV148865 rs4131618 0.9 0.913 hCV27849348 rs9910051 hCV15877773 rs2269916 0.9 0.9138 hCV27849348 rs9910051 hCV1955740 rs3764421 0.9 0.9138 hCV27849348 rs9910051 hCV1955744 rs1 1655623 0.9 0.9138 hCV27849348 rs9910051 hCV1955747 rs999798 0.9 1 hCV27849348 rs9910051 hCV25642628 rs9896095 0.9 0.9138 Interrogated SNP Interrogated SNP

(hCV #) (rs #) LD SNP (hCV #) LD SNP (rs #) Threshold r ² r ² hCV27849348 rs9910051 hCV26024164 rs1 1656462 0.9 0.9199 hCV27849348 rs9910051 hCV26030672 rs1 1650305 0.9 0.9138 hCV27849348 rs9910051 hCV26030673 rs1 1654914 0.9 0.9133 hCV27849348 rs9910051 hCV27493873 rs3816780 0.9 0.9137 hCV27849348 rs9910051 hCV29590899 rs9895684 0.9 0.9138 hCV27849348 rs9910051 hCV29626991 rs9913782 0.9 0.9138 hCV27849348 rs9910051 hCV29663173 rs9914271 0.9 0.9138 hCV27849348 rs9910051 hCV29859378 rs9914242 0.9 0.9135 hCV27849348 rs9910051 hCV30075535 rs7342938 0.9 1 hCV27849348 rs9910051 hCV30239993 rs9891656 0.9 1 hCV27849348 rs9910051 hCV30327630 rs9898858 0.9 0.9199 hCV27849348 rs9910051 hCV30384549 rs9889755 0.9 0.9138 hCV27849348 rs9910051 hCV30507741 rs9915139 0.9 0.9138 hCV27849348 rs9910051 hCV30615799 rs6505215 0.9 1 hCV27849348 rs9910051 hCV30662630 rs1 1652409 0.9 0.9199 hCV27849348 rs9910051 hCV30664356 rs12103588 0.9 0.9138 hCV27849348 rs9910051 hCV30679094 rs1 1651802 0.9 0.9074 hCV27849348 rs9910051 hCV3068661 1 rs1 1657270 0.9 0.9138 hCV27849348 rs9910051 hCV30686614 rs1 1080138 0.9 0.9138 hCV27849348 rs9910051 hCV516198 rs1 1650271 0.9 0.9199 hCV27849348 rs9910051 hCV7472194 rs999796 0.9 1 hCV27849348 rs9910051 hDV76805555 rs36056619 0.9 0.9138 hCV27849348 rs9910051 hDV7731 1325 rs9909497 0.9 0.9138 hCV29279566 rs6764769 hCV1 1795776 rs6763931 0.9 1 hCV29279566 rs6764769 hCV1 1795777 rs7632381 0.9 0.981 hCV29279566 rs6764769 hCV16087675 rs2871960 0.9 0.981 hCV29279566 rs6764769 hCV2416397 rs 724016 0.9 1 hCV29279566 rs6764769 hCV2923639 rs6440003 0.9 1 hCV29279566 rs6764769 hCV2923645 rs6808936 0.9 1 hCV29279566 rs6764769 hCV2923649 rs 1582874 0.9 1 hCV29279566 rs6764769 hCV2923655 rs1991431 0.9 1 hCV29279566 rs6764769 hCV2923661 rs9846396 0.9 1 hCV29279566 rs6764769 hCV2923662 rs6440006 0.9 0.9648 hCV29279566 rs6764769 hCV31744961 rs6763927 0.9 1 hCV29279566 rs6764769 hCV8240179 rs 1344674 0.9 1 hCV29279566 rs6764769 hCV8240181 rs 1344672 0.9 1 hCV29670713 rs9282734 hCV1 1329931 rs 1464931 0.9 1 hCV29670713 rs9282734 hCV1 1329934 rs1534152 0.9 1 hCV29670713 rs9282734 hCV29250463 rs6953668 0.9 1 hCV3020887 rs1230 hCV1 1951325 rs 1800335 0.9 0.9631 hCV3020887 rs1230 hCV1 1951343 rs1800337 0.9 0.9807 hCV3020887 rs1230 hCV121 12567 rs7195906 0.9 0.9646 hCV3020887 rs1230 hCV121 12715 rs1800287 0.9 0.9608 hCV3020887 rs1230 hCV121 12716 rs6500453 0.9 0.9608 hCV3020887 rs1230 hCV2590840 rs1 1076631 0.9 0.9305 hCV3020887 rs1230 hCV2590844 rs1 1076628 0.9 0.9081 hCV3020887 rs1230 hCV2590883 rs6500450 0.9 0.9805 hCV3020887 rs1230 hCV2590894 rs6500449 0.9 0.9639 hCV3020887 rs1230 hCV2590902 rs8046243 0.9 0.9636 hCV3020887 rs1230 hCV2590905 rs12448860 0.9 0.9644 hCV3020887 rs1230 hCV25922424 rs12102297 0.9 1 hCV3020887 rs1230 hCV26871795 rs6500441 0.9 0.9805 hCV3020887 rs1230 hCV27475628 rs3743859 0.9 0.9807 hCV3020887 rs1230 hCV27897055 rs4785595 0.9 0.9805 Interrogated SNP Interrogated SNP

(hCV #) (rs #) LD SNP (hCV #) LD SNP (rs #) Threshold r ² r ² hCV3020887 rs1230 hCV3020893 rs6500439 0.9 0.9639 hCV3020887 rs1230 hCV30590701 rs7190823 0.9 0.9808 hCV3020887 rs1230 hCV31692619 rs12102290 0.9 1 hCV3020887 rs1230 hCV31692620 rs12922302 0.9 1 hCV3020887 rs1230 hCV31692756 rs1 1076632 0.9 0.9305 hCV3020887 rs1230 hCV31692774 rs12599799 0.9 0.9644 hCV3020887 rs1230 hCV31692777 rs10852623 0.9 0.9808 hCV3020887 rs1230 hCV31692778 rs1 1076626 0.9 0.9644 hCV3020887 rs1230 hCV31692794 rs12709094 0.9 1 hCV3020887 rs1230 hCV31692816 rs12599180 0.9 0.9805 hCV3020887 rs1230 hCV31692827 rs7203907 0.9 1 hCV3020887 rs1230 hCV7518999 rs886952 0.9 0.9644 hCV3020887 rs1230 hCV7519008 rs886950 0.9 1 hCV3020887 rs1230 hDV77251247 rs8045232 0.9 0.9638 hCV30590701 rs7190823 hCV1 1951325 rs 1800335 0.9 0.9631 hCV30590701 rs7190823 hCV1 1951343 rs1800337 0.9 0.9619 hCV30590701 rs7190823 hCV121 12567 rs7195906 0.9 0.9646 hCV30590701 rs7190823 hCV121 12715 rs1800287 0.9 0.9608 hCV30590701 rs7190823 hCV121 12716 rs6500453 0.9 0.9608 hCV30590701 rs7190823 hCV2590840 rs1 1076631 0.9 0.9305 hCV30590701 rs7190823 hCV2590844 rs1 1076628 0.9 0.9259 hCV30590701 rs7190823 hCV2590883 rs6500450 0.9 0.9614 hCV30590701 rs7190823 hCV2590894 rs6500449 0.9 0.9639 hCV30590701 rs7190823 hCV2590902 rs8046243 0.9 0.9636 hCV30590701 rs7190823 hCV2590905 rs12448860 0.9 0.9644 hCV30590701 rs7190823 hCV25922424 rs12102297 0.9 1 hCV30590701 rs7190823 hCV26871795 rs6500441 0.9 0.9805 hCV30590701 rs7190823 hCV27475628 rs3743859 0.9 0.9619 hCV30590701 rs7190823 hCV27897055 rs4785595 0.9 0.9615 hCV30590701 rs7190823 hCV3020887 rs1230 0.9 0.9808 hCV30590701 rs7190823 hCV3020893 rs6500439 0.9 0.9639 hCV30590701 rs7190823 hCV31692619 rs12102290 0.9 1 hCV30590701 rs7190823 hCV31692620 rs12922302 0.9 1 hCV30590701 rs7190823 hCV31692756 rs1 1076632 0.9 0.9305 hCV30590701 rs7190823 hCV31692774 rs12599799 0.9 0.9644 hCV30590701 rs7190823 hCV31692777 rs10852623 0.9 1 hCV30590701 rs7190823 hCV31692778 rs1 1076626 0.9 0.9644 hCV30590701 rs7190823 hCV31692794 rs12709094 0.9 0.9808 hCV30590701 rs7190823 hCV31692816 rs12599180 0.9 0.9615 hCV30590701 rs7190823 hCV31692827 rs7203907 0.9 1 hCV30590701 rs7190823 hCV7518999 rs886952 0.9 0.9644 hCV30590701 rs7190823 hCV7519008 rs886950 0.9 0.9808 hCV30590701 rs7190823 hDV77251247 rs8045232 0.9 0.9638 hCV31692807 rs7187436 hCV1 1951325 rs 1800335 0.9 0.9252 hCV31692807 rs7187436 hCV1 1951343 rs1800337 0.9 0.925 hCV31692807 rs7187436 hCV121 1271 1 rs6500452 0.9 0.9615 hCV31692807 rs7187436 hCV121 12715 rs1800287 0.9 0.9197 hCV31692807 rs7187436 hCV121 12716 rs6500453 0.9 0.9224 hCV31692807 rs7187436 hCV158351 13 rs21591 13 0.9 0.963 hCV31692807 rs7187436 hCV16172654 rs2238529 0.9 1 hCV31692807 rs7187436 hCV16174688 rs2239360 0.9 0.9607 hCV31692807 rs7187436 hCV2590883 rs6500450 0.9 0.925 hCV31692807 rs7187436 hCV2590884 rs1800330 0.9 0.9615 hCV31692807 rs7187436 hCV2590886 rs8049660 0.9 0.9615 Interrogated SNP Interrogated SNP

(hCV #) (rs #) LD SNP (hCV #) LD SNP (rs #) Threshold r ² r ² hCV31692807 rs7187436 hCV2590894 rs6500449 0.9 0.9271 hCV31692807 rs7187436 hCV2590902 rs8046243 0.9 0.9262 hCV31692807 rs7187436 hCV2590905 rs12448860 0.9 0.928 hCV31692807 rs7187436 hCV25923374 rs6500437 0.9 0.9229 hCV31692807 rs7187436 hCV26871766 rs12709096 0.9 0.9625 hCV31692807 rs7187436 hCV26871781 rs2016571 0.9 0.926 hCV31692807 rs7187436 hCV26871795 rs6500441 0.9 0.925 hCV31692807 rs7187436 hCV27475628 rs3743859 0.9 0.925 hCV31692807 rs7187436 hCV27897053 rs4785722 0.9 0.9615 hCV31692807 rs7187436 hCV27897055 rs4785595 0.9 0.925 hCV31692807 rs7187436 hCV31692774 rs12599799 0.9 0.928 hCV31692807 rs7187436 hCV31692778 rs1 1076626 0.9 0.928 hCV31692807 rs7187436 hCV31692786 rs8051231 0.9 0.9619 hCV31692807 rs7187436 hCV31692816 rs12599180 0.9 0.961 1 hCV31692807 rs7187436 hCV31692841 rs 7201028 0.9 0.926 hCV31692807 rs7187436 hCV31692842 rs7195752 0.9 0.926 hCV31692807 rs7187436 hCV3275469 rs 1006547 0.9 0.9214 hCV31692807 rs7187436 hCV3275471 rs3785275 0.9 0.926 hCV31692807 rs7187436 hCV3275489 rs1 1860203 0.9 0.9579 hCV31692807 rs7187436 hCV7518972 rs1061646 0.9 0.9229 hCV31692807 rs7187436 hCV7518999 rs886952 0.9 0.928 hCV31692807 rs7187436 hCV7519014 rs 1007931 0.9 0.9615 hCV31692807 rs7187436 hCV7519028 rs 1057042 0.9 0.926 hCV31692807 rs7187436 hDV77251247 rs8045232 0.9 0.9266 hCV3275471 rs3785275 hCV121 1271 1 rs6500452 0.9 0.9637 hCV3275471 rs3785275 hCV158351 13 rs21591 13 0.9 0.9655 hCV3275471 rs3785275 hCV16172654 rs2238529 0.9 0.9587 hCV3275471 rs3785275 hCV16174688 rs2239360 0.9 0.963 hCV3275471 rs3785275 hCV2590884 rs1800330 0.9 0.9637 hCV3275471 rs3785275 hCV2590886 rs8049660 0.9 0.9637 hCV3275471 rs3785275 hCV25923374 rs6500437 0.9 0.9639 hCV3275471 rs3785275 hCV26871766 rs12709096 0.9 0.9651 hCV3275471 rs3785275 hCV26871781 rs2016571 0.9 1 hCV3275471 rs3785275 hCV27897053 rs4785722 0.9 0.9637 hCV3275471 rs3785275 hCV31692786 rs8051231 0.9 0.9646 hCV3275471 rs3785275 hCV31692807 rs7187436 0.9 0.926 hCV3275471 rs3785275 hCV31692841 rs 7201028 0.9 0.9658 hCV3275471 rs3785275 hCV31692842 rs7195752 0.9 0.9658 hCV3275471 rs3785275 hCV3275469 rs 1006547 0.9 1 hCV3275471 rs3785275 hCV3275489 rs1 1860203 0.9 0.9612 hCV3275471 rs3785275 hCV7518972 rs1061646 0.9 0.9639 hCV3275471 rs3785275 hCV7519014 rs 1007931 0.9 0.9637 hCV3275471 rs3785275 hCV7519028 rs 1057042 0.9 1 hCV7600023 rs 1092331 hCV1 1659170 rs1088677 0.9 1 hCV7600023 rs 1092331 hCV15934307 rs2184634 0.9 0.9185 hCV7600023 rs 1092331 hCV32090053 rs12589100 0.9 0.9192 hCV7600023 rs 1092331 hCV7600032 rs1088679 0.9 0.9186 hCV7600023 rs 1092331 hCV7600033 rs1088680 0.9 1 hCV7600023 rs 1092331 hDV70867209 rs17098729 0.9 0.9192 hCV7600023 rs 1092331 hDV70928489 rs 17256254 0.9 0.9192 hCV7626903 rs13058 hCV1 1733314 rs 1892847 0.9 1 hCV7626903 rs13058 hCV25922338 rs3729910 0.9 1 hCV7626903 rs13058 hCV29249403 rs7286558 0.9 1 hCV7626903 rs13058 hCV31649955 rs7285387 0.9 1 Interrogated SNP Interrogated SNP

(hCV #) (rs #) LD SNP (hCV #) LD SNP (rs #) Threshold r ² r ² hCV7626903 rs13058 hDV71012676 rs17821423 0.9 1 hCV8722378 rs8179183 hCV101 179 rs1 1809917 0.9 0.9142 hCV8722378 rs8179183 hCV103609 rs1 1812068 0.9 0.9138 hCV8722378 rs8179183 hCV15785472 rs2375803 0.9 0.9138 hCV8722378 rs8179183 hCV15785473 rs2375804 0.9 0.9145 hCV8722378 rs8179183 hCV15785939 rs2376018 0.9 1 hCV8722378 rs8179183 hCV15844618 rs2186244 0.9 0.9078 hCV8722378 rs8179183 hCV25597196 rs3828034 0.9 1 hCV8722378 rs8179183 hCV25597209 rs3790437 0.9 1 hCV8722378 rs8179183 hCV26465906 rs1 1809410 0.9 0.9142 hCV8722378 rs8179183 hCV26465940 rs 1938493 0.9 0.9138 hCV8722378 rs8179183 hCV26465953 rs4606347 0.9 1 hCV8722378 rs8179183 hCV30009175 rs7545475 0.9 1 hCV8722378 rs8179183 hCV30405525 rs7339965 0.9 0.9145 hCV8722378 rs8179183 hCV31223419 rs12077336 0.9 1 hCV8722378 rs8179183 hCV414483 rs1 1807752 0.9 0.9138 hCV8722378 rs8179183 hDV70888487 rs17127838 0.9 0.9138 hCV8722378 rs8179183 hDV70949464 rs 17406429 0.9 1 hCV8722378 rs8179183 hDV70949557 rs 17407229 0.9 0.9007 hCV8722378 rs8179183 hDV70949568 rs 17407322 0.9 0.9081 hCV8722378 rs8179183 hDV70950526 rs17415296 0.9 0.9138 hCV8722378 rs8179183 hDV71040566 rs6661050 0.9 1 hCV8722378 rs8179183 hDV71040668 rs6665672 0.9 1 hCV8722378 rs8179183 hDV81070728 rs41459646 0.9 0.9138