MICROGLIAL GENE SILENCING USING DOUBLE-STRANDED SIRNA

BACKGROUND OF THE INVENTION

In many species, introduction of double-stranded RNA (dsRNA) induces potent and specific gene silencing. This phenomenon occurs in both plants and animals and has roles in viral defense and transposon silencing mechanisms. Short interfering RNAs (siRNAs), which are generally much shorter than the target gene, have been shown to be effective at gene silencing.

Microglia are a type of glial cell found in the central nervous system (CNS). Microglia are an essential component of the CNS immune system; however, microglia with dysregulated genes can also be a source of disease. For example, a disease state may precipitate as a result of overactive microglial genes or genes with reduced expression and/or activity in microglia. Therefore, silencing of effector genes or pathway regulatory genes may be needed to restore normal gene network function and ameliorate the disease state. Thus, there remains a need for new and improved therapeutics capable of permeating microglial cells and silencing microglial genes in order to restore genetic and biochemical pathway activity in microglia from a disease state towards a normal healthy state.

SUMMARY OF THE INVENTION

In an aspect, the invention features a method of delivering a branched small interfering RNA (siRNA) molecule to a microglial cell in a subject in need of microglial gene silencing. The method may include administering the branched siRNA molecule to the subject (e.g., to the central nervous system of the subject).

In some embodiments, the subject has been diagnosed as having a disease associated with expression of a dysregulated microglial gene or dysregulated microglial gene pathway. In some embodiments, the subject has been diagnosed as having a disease associated with expression and/or activity of a dysregulated microglial gene (e.g., altered expression and/or activity of a wild-type or mutated microglial gene).

In some embodiments, the dysregulated microglial gene exhibits increased expression and/or activity in microglial cells of the subject as compared to the expression and/or activity of the microglial gene in microglial cells of a reference subject. In some embodiments, the dysregulated microglial gene exhibits reduced expression and/or activity in microglial cells of the subject as compared to the expression and/or activity of the microglial gene in microglial cells of a reference subject.

In some embodiments, the microglial gene is a positive regulator of a gene for which increased expression and/or activity relative to the level of expression and/or activity observed in a reference subject is associated with a disease state.

In some embodiments, the microglial gene is a negative regulator of a gene for which decreased expression and/or activity relative to the level of expression and/or activity observed in a reference subject is associated with a disease state.

In some embodiments, the microglial gene is a splice isoform of a gene for which overexpression of the splice isoform relative to the expression of the splice isoform in a reference subject is associated with a disease state.

In some embodiments, the disease is a neuroinflammatory disease or a neurodegenerative disease. In some embodiments, the disease is Alzheimer’s disease. In some embodiments, the disease is Amyotrophic Lateral Sclerosis. In some embodiments, the disease is Parkinson’s disease. In some embodiments, the disease is frontotemporal dementia. In some embodiments, the disease is Huntington’s disease. In some embodiments, the disease is multiple sclerosis. In some embodiments, the disease is progressive supranuclear palsy.

In some embodiments, the dysregulated microglial gene is selected from the group consisting of ABCA7, ABI3, ADAM10, APOC1 , APOE, AXL, BIN1 , C1QA, C3, C90RF72, CASS4, CCL5, CD2AP, CD33, CD68, CLPTM1 , CLU, CR1 , CSF1 , CST7, CTSB, CTSD, CTSL, CXCL10, CXCL13, DSG2, ECHDC3, EPHA1 , FABP5, FERMT2, FTH1 , GNAS, GRN, HBEGF, HLA-DRB1 , HLA-DRB5, IFIT1 , IFIT3, IFITM3, IFNAR1 , IFNAR2, IGF1 , IL10RA, IL1A, IL1 B, IL1RAP, INPP5D, ITGAM, ITGAX, LILRB4, LPL, MEF2C, MMP12, MS4A4A, MS4A6A, NLRP3, NME8, NOS2, PICALM, PILRA, PLCG2, PTK2B, SCIMP, SLC24A4, SORL1 , SPI1 , SPP1 , SPPL2A, TBK1 , TNF, TREM2, TREML2, TYROBP, and ZCWPW1 .

In some embodiments, the subject is a mammal (e.g., a human).

In some embodiments, the branched siRNA is administered to the subject intrathecally, intracerebroventricularly, or intrastriatally.

In some embodiments, the siRNA molecule is di-branched. In some embodiments, the siRNA molecule is tri-branched. In some embodiments, the siRNA molecule is tetra-branched.

In some embodiments, the siRNA comprises (i) an antisense strand having complementarity to a portion of one or more of genes selected from the group consisting of APOE, BIN1 , C1 QA, C3,

C90RF72, CCL5, CD33, CLU/APOJ, CR1 , CXCL10, CXCL13, IFIT1 , IFIT3, IFITM3, IFNAR1 , IFNAR2, IL10RA, IL1 A, IL1 B, IL1 RAP, INPP5D, ITGAM, MEF2C, MMP12, NLRP3, NOS2, PILRA, PLCG2, PTK2B, SLC24A4, TBK1 , and TNF and (ii) a sense strand having complementarity to the antisense strand.

In some embodiments, the siRNA includes (i) an antisense strand having complementarity to a portion of a gene encoding a positive regulator of a gene for which increased expression and/or activity (relative, e.g., to the level of expression and/or activity observed in a reference subject) is associated with a disease state.

In some embodiments, the siRNA includes (i) an antisense strand having complementarity to a portion of a gene encoding a negative regulator of a gene for which decreased expression and/or activity (relative, e.g., to the level of expression and/or activity observed in a reference subject) is associated with a disease state.

In some embodiments, the siRNA includes (i) an antisense strand having complementarity to a splice isoform of a gene for which overexpression of the splice isoform relative to the expression of the splice isoform in a reference subject is associated with a disease state.

In any of the foregoing embodiments, the siRNA may also include (ii) a sense strand having complementarity to the antisense strand.

In some embodiment, the antisense strand has complementarity (e.g., at least 85% complementarity, such as 85% complementarity, 86% complementarity, 87% complementarity, 88% complementarity, 89% complementarity, 90% complementarity, 91% complementarity, 92% complementarity, 93% complementarity, 94% complementarity, 95% complementarity, 96% complementarity, 97% complementarity, 98% complementarity, 99% complementarity, or 100% complementarity) to a portion of at least 10 contiguous nucleotides of an mRNA molecule encoding one or more of the above genes. For example, the antisense strand may have complementarity to a portion of 10 contiguous nucleotides, 11 contiguous nucleotides, 12 contiguous nucleotides, 13 contiguous nucleotides, 14 contiguous nucleotides, 15 contiguous nucleotides, 16 contiguous nucleotides, 17 contiguous nucleotides, 18 contiguous nucleotides, 19 contiguous nucleotides, 20 contiguous nucleotides, 21 contiguous nucleotides, 22 contiguous nucleotides, 23 contiguous nucleotides, 24 contiguous nucleotides, 25 contiguous nucleotides, 26 contiguous nucleotides, 27 contiguous nucleotides, 28 contiguous nucleotides, 29 contiguous nucleotides, 30 contiguous nucleotides, 31 contiguous nucleotides, 32 contiguous nucleotides 33 contiguous nucleotides, 34 contiguous nucleotides, 35 contiguous nucleotides, 36 contiguous nucleotides, 37 contiguous nucleotides, 38 contiguous nucleotides, 39 contiguous nucleotides, 40 contiguous nucleotides, 41 contiguous nucleotides, 42 contiguous nucleotides, 43 contiguous nucleotides, 44 contiguous nucleotides, 45 contiguous nucleotides, 46 contiguous nucleotides, 47 contiguous nucleotides, 48 contiguous nucleotides, 49 contiguous nucleotides, or 50 contiguous nucleotides, or more, of an mRNA molecule encoding one or more of the above genes.

In some embodiments, the antisense strand has complementarity (e.g., at least 85% complementarity, such as 85% complementarity, 86% complementarity, 87% complementarity, 88% complementarity, 89% complementarity, 90% complementarity, 91% complementarity, 92% complementarity, 93% complementarity, 94% complementarity, 95% complementarity, 96% complementarity, 97% complementarity, 98% complementarity, 99% complementarity, or 100% complementarity) to a portion of from 10 to 50 contiguous nucleotides of an mRNA molecule encoding one or more of the above genes. For example, the antisense strand may have complementarity to a portion of from 11 contiguous nucleotides to 45 contiguous nucleotides, from 12 contiguous nucleotides to 40 contiguous nucleotides, from 13 contiguous nucleotides to 35 contiguous nucleotides, from 14 contiguous nucleotides to 30 contiguous nucleotides, from 15 contiguous nucleotides to 29 contiguous nucleotides, from 16 contiguous nucleotides to 28 contiguous nucleotides, from 17 contiguous nucleotides to 27 contiguous nucleotides, from 18 contiguous nucleotides to 26 contiguous nucleotides, or from 19 contiguous nucleotides to 22 contiguous nucleotides of an mRNA molecule encoding one or more of the above genes.

In some embodiments, the antisense strand comprises a region represented by the following chemical formula, in the 5'-to-3' direction:

Z-((A-P-)n(B-P-)m)q; wherein Z is a 5’ phosphorus stabilizing moiety; each A is, independently, a 2’-0-methyl (2'-0-Me) ribonucleoside; each B is, independently, a 2'-fluoro-ribonucleoside; each P is, independently, an internucleoside linkage selected from a phosphodiester linkage and a phosphorothioate linkage; n is an integer from 1 to 5 (e.g., 1 , 2, 3, 4, or 5); m is an integer from 1 to 5 (e.g., 1 , 2, 3, 4, or 5); and q is an integer between 1 and 15 (1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15). In some embodiments, the antisense strand has a structure represented by Formula A-l, wherein Formula A-l is, in the 5’-to-3’ direction:

A-B-(A’)j-C-P ² -D-P ¹ -(C’-P ¹ ) _k -C’

Formula A-l; wherein A is represented by the formula C-P ¹ -D-P ¹ ; each A’ is represented by the formula C-P ² -D-P ² ;

B is represented by the formula C-P ² -D-P ² -D-P ² -D-P ² ; each C is a 2’-0-methyl (2’-0-Me) ribonucleoside; each C’, independently, is a 2’-0-Me ribonucleoside or a 2’-fluoro (2’-F) ribonucleoside; each D is a 2’-F ribonucleoside; each P ¹ is a phosphorothioate internucleoside linkage; each P ² is a phosphodiester internucleoside linkage; j is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); and k is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7).

In some embodiments, the antisense strand has a structure represented by Formula A1 , wherein Formula A1 is, in the 5’-to-3’ direction:

A-S-B-S-A-O-B-O-B-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A -O-B-S-A-S-A-S-A-S-B-S-A

Formula A1; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the antisense strand has a structure represented by Formula A-ll, wherein Formula A-ll is, in the 5’-to-3’ direction:

A-B-(A’)j-C-P ² -D-P ¹ -(C-P ¹ ) _k -C’

Formula A-ll; wherein A is represented by the formula C-P ¹ -D-P ¹ ; each A’ is represented by the formula C-P ² -D-P ² ;

B is represented by the formula C-P ² -D-P ² -D-P ² -D-P ² ; each C is a 2’-0-methyl (2’-0-Me) ribonucleoside; each C’, independently, is a 2’-0-Me ribonucleoside or a 2’-fluoro (2’-F) ribonucleoside; each D is a 2’-F ribonucleoside; each P ¹ is a phosphorothioate internucleoside linkage; each P ² is a phosphodiester internucleoside linkage; j is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); and k is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7). In some embodiments, antisense strand has a structure represented by Formula A2, wherein Formula A2 is, in the 5’-to-3’ direction:

A-S-B-S-A-O-B-O-B-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A -O-B-S-A-S-A-S-A-S-A-S-A

Formula A2; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the sense strand has a structure represented by Formula S-lll, wherein Formula S-lll is, in the 5’-to-3’ direction:

E-(A’)m-F

Formula S-lll; wherein E is represented by the formula (C-P ¹ )2;

F is represented by the formula (C-P ² ) ₃ -D-P ¹ -C-P ¹ -C, (C-P ² ) ₃ -D-P ² -C-P ² -C, (C-P ² ) ₃ -D-P ¹ -C-P ¹ -D, or (C- P ² ) ₃ -D-P ² -C-P ² -D;

A’, C, D, P ¹ , and P ² are as defined in Formula II; and m is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7).

In some embodiments, the sense strand has a structure represented by Formula S1 , wherein Formula S1 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-A-O-A-O-B-S-A -S-A

Formula S1; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the sense strand has a structure represented by Formula S2, wherein Formula S2 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-A-O-A-O-B-O-A -O-A

Formula S2; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage. In some embodiments, the sense strand has a structure represented by Formula S3, wherein Formula S3 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-A-O-A-O-B-S-A -S-B

Formula S3; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the sense strand has a structure represented by Formula S4, wherein Formula S4 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-A-O-A-O-B-O-A -O-B

Formula S4; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the antisense strand has a structure represented by Formula A-IV, wherein Formula A-IV is, in the 5’-to-3’ direction:

A-(A’)j-C-P ² -B-(C-P ¹ ) _k -C’

Formula A-IV; wherein A is represented by the formula C-P ¹ -D-P ¹ ; each A’ is represented by the formula C-P ² -D-P ² ;

B is represented by the formula D-P ¹ -C-P ¹ -D-P ¹ ; each C is a 2’-0-Me ribonucleoside; each C’, independently, is a 2’-0-Me ribonucleoside or a 2’-F ribonucleoside; each D is a 2’-F ribonucleoside; each P ¹ is a phosphorothioate internucleoside linkage; each P ² is a phosphodiester internucleoside linkage; j is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); and k is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7).

In some embodiments, the antisense strand has a structure represented by Formula A3, wherein Formula A3 is, in the 5’-to-3’ direction:

A-S-B-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A -O-B-S-A-S-B-S-A-S-A-S-A

Formula A3; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage. In some embodiments, the sense strand has a structure represented by Formula S-V, wherein Formula S-V is, in the 5’-to-3’ direction:

E-(A’) _m -C-P ² -F

Formula S-V; wherein E is represented by the formula (C-P ¹ )2;

F is represented by the formula D-P ¹ -C-P ¹ -C, D-P ² -C-P ² -C, D-P ¹ -C-P ¹ -D, or D-P ² -C-P ² -D;

A’, C, D, P ¹ and P ² are as defined in Formula IV; and m is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7).

In some embodiments, the sense strand has a structure represented by Formula S5, wherein Formula S5 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-S-A -S-A

Formula S5; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the sense strand has a structure represented by Formula S6, wherein Formula S6 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A -O-A

Formula S6; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the sense strand has a structure represented by Formula S7, wherein Formula S7 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-S-A -S-B

Formula S7; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the sense strand has a structure represented by Formula S8, wherein Formula S8 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A -O-B

Formula S8; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage. In some embodiments, the antisense strand has a structure represented by Formula A- VI, wherein Formula A- VI is, in the 5’-to-3’ direction:

A-Bj-E-B _k -E-F-Gi-D-P ¹ -C’

Formula A-VI; wherein A is represented by the formula C-P ¹ -D-P ¹ ; each B is represented by the formula C-P ² ; each C is a 2’-0-Me ribonucleoside; each C’, independently, is a 2’-0-Me ribonucleoside or a 2’-F ribonucleoside; each D is a 2’-F ribonucleoside; each E is represented by the formula D-P ² -C-P ² ;

F is represented by the formula D-P ¹ -C-P ¹ ; each G is represented by the formula C-P ¹ ; each P ¹ is a phosphorothioate internucleoside linkage; each P ² is a phosphodiester internucleoside linkage; j is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); k is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); and

I is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7).

In some embodiments, the antisense strand has a structure represented by Formula A4, wherein Formula A4 is, in the 5’-to-3’ direction:

A-S-B-S-A-O-A-O-A-O-B-O-A-O-A-O-A-O-A-O-A-O-A-O-A-O-B-O-A -O-B-S-A-S-A-S-A-S-B-S-A

Formula A4; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the sense strand has a structure represented by Formula S-VII, wherein Formula S-VII is, in the 5’-to-3’ direction:

H-Bm-ln-A’-Bo-H-C

Formula S-VII; wherein A’ is represented by the formula C-P ² -D-P ² ; each H is represented by the formula (C-P ¹ )2; each I is represented by the formula (D-P ² );

B, C, D, P ¹ and P ² are as defined in Formula VI; m is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); n is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); and o is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7). In some embodiments, the sense strand has a structure represented by Formula S9, wherein Formula S9 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-A-O-A-O-B-O-B-O-B-O-A-O-B-O-A-O-A-O-A-O-A-S-A -S-A

Formula S9; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the antisense strand also has a 5’ phosphorus stabilizing moiety at the 5’ end of the antisense strand.

In some embodiments, the sense strand also has a 5’ phosphorus stabilizing moiety at the 5’ end of the sense strand.

In some embodiments, each 5’-phosphorus stabilizing moiety is, independently represented by any one of Formula l-VIII: wherein Nuc represents a nucleobase, such as adenine, uracil, guanine, thymine, or cytosine, and R represents optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl (e.g., optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl), phenyl, benzyl, hydroxy, or hydrogen.

In some embodiments, Z is (E)-vinylphosphonate as represented in Formula III.

In some embodiments, n is from 1 to 4. In some embodiments, n is from 1 to 3. In some embodiments, n is from 1 to 2. In some embodiments, n is 1.

In some embodiments, m is from 1 to 4. In some embodiments, m is from 1 to 3. In some embodiments, m is from 1 to 2. In some embodiments, m is 1.

In some embodiments, n and m are each 1.

In some embodiments, 50% or more of the ribonucleotides in the antisense strand are 2'-0-Me ribonucleotides (e.g., 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand may be 2'-0-Me ribonucleotides).

In some embodiments, 60% or more of the ribonucleotides in the antisense strand are 2'-0-Me ribonucleotides (e.g., 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand may be 2'-0-Me ribonucleotides).

In some embodiments, 70% or more of the ribonucleotides in the antisense strand are 2'-0-Me ribonucleotides (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand may be 2'-0-Me ribonucleotides).

In some embodiments, 80% or more of the ribonucleotides in the antisense strand are 2'-0-Me ribonucleotides (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand may be 2'-0-Me ribonucleotides).

In some embodiments, 90% or more of the ribonucleotides in the antisense strand are 2'-0-Me ribonucleotides (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand may be 2'-0-Me ribonucleotides).

In some embodiments, 10% or less of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages. In some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

In some embodiments, 100% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

In some embodiments, 9 internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

In some embodiments, the length of the antisense strand is between 10 and 30 nucleotides (e.g., 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, or 30 nucleotides), 15 and 25 nucleotides (e.g., 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, or 25 nucleotides), or 18 and 23 nucleotides (e.g., 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, or 23 nucleotides). In some embodiments, the length of the antisense strand is 20 nucleotides. In some embodiments, the length of the antisense strand is 21 nucleotides. In some embodiments, the length of the antisense strand is 22 nucleotides. In some embodiments, the length of the antisense strand is 23 nucleotides. In some embodiments, the length of the antisense strand is 24 nucleotides. In some embodiments, the length of the antisense strand is 25 nucleotides. In some embodiments, the length of the antisense strand is 26 nucleotides. In some embodiments, the length of the antisense strand is 27 nucleotides. In some embodiments, the length of the antisense strand is 28 nucleotides. In some embodiments, the length of the antisense strand is 29 nucleotides. In some embodiments, the length of the antisense strand is 30 nucleotides. In some embodiments, the siRNA molecules of the branched compound are joined to one another by way of a linker (e.g., an ethylene glycol oligomer, such as tetraethylene glycol). In some embodiments, the siRNA molecules of the branched compound are joined to one another by way of a linker between the sense strand of one siRNA molecule and the sense strand of the other siRNA molecule. In some embodiments, the siRNA molecules are joined by way of linkers between the antisense strand of one siRNA molecule and the antisense strand of the other siRNA molecule. In some embodiments, the siRNA molecules of the branched compound are joined to one another by way of a linker between the sense strand of one siRNA molecule and the antisense strand of the other siRNA molecule.

In some embodiments, the length ofthe sense strand is between 12 and 30 nucleotides (e.g., 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, or 30 nucleotides), or 14 and 18 nucleotides (e.g., 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, or 18 nucleotides). In some embodiments, the length of the sense strand is 15 nucleotides.

In some embodiments, the length of the sense strand is 16 nucleotides. In some embodiments, the length of the sense strand is 17 nucleotides. In some embodiments, the length of the sense strand is 18 nucleotides. In some embodiments, the length of the sense strand is 19 nucleotides. In some embodiments, the length of the sense strand is 20 nucleotides. In some embodiments, the length of the sense strand is 21 nucleotides. In some embodiments, the length of the sense strand is 22 nucleotides. In some embodiments, the length of the sense strand is 23 nucleotides. In some embodiments, the length of the sense strand is 24 nucleotides. In some embodiments, the length of the sense strand is 25 nucleotides. In some embodiments, the length of the sense strand is 26 nucleotides. In some embodiments, the length of the sense strand is 27 nucleotides. In some embodiments, the length of the sense strand is 28 nucleotides. In some embodiments, the length of the sense strand is 29 nucleotides. In some embodiments, the length of the sense strand is 30 nucleotides.

In some embodiments, 4 internucleoside linkages are phosphorothioate linkages.

In some embodiments, the antisense strand is 18 nucleotides in length and the sense strand is

14 nucleotides in length.

In some embodiments, the antisense strand is 18 nucleotides in length and the sense strand is

15 nucleotides in length.

In some embodiments, the antisense strand is 18 nucleotides in length and the sense strand is

16 nucleotides in length.

In some embodiments, the antisense strand is 18 nucleotides in length and the sense strand is

17 nucleotides in length.

In some embodiments, the antisense strand is 18 nucleotides in length and the sense strand is

18 nucleotides in length.

In some embodiments, the antisense strand is 19 nucleotides in length and the sense strand is

14 nucleotides in length.

In some embodiments, the antisense strand is 19 nucleotides in length and the sense strand is

15 nucleotides in length. In some embodiments, the antisense strand is 19 nucleotides in length and the sense strand is

16 nucleotides in length.

In some embodiments, the antisense strand is 19 nucleotides in length and the sense strand is

17 nucleotides in length.

In some embodiments, the antisense strand is 19 nucleotides in length and the sense strand is

18 nucleotides in length.

In some embodiments, the antisense strand is 19 nucleotides in length and the sense strand is

19 nucleotides in length.

In some embodiments, the antisense strand is 20 nucleotides in length and the sense strand is

14 nucleotides in length.

In some embodiments, the antisense strand is 20 nucleotides in length and the sense strand is

15 nucleotides in length.

In some embodiments, the antisense strand is 20 nucleotides in length and the sense strand is

16 nucleotides in length.

In some embodiments, the antisense strand is 20 nucleotides in length and the sense strand is

17 nucleotides in length.

In some embodiments, the antisense strand is 20 nucleotides in length and the sense strand is

18 nucleotides in length.

In some embodiments, the antisense strand is 20 nucleotides in length and the sense strand is

19 nucleotides in length.

In some embodiments, the antisense strand is 20 nucleotides in length and the sense strand is

20 nucleotides in length.

In some embodiments, the antisense strand is 21 nucleotides in length and the sense strand is

14 nucleotides in length.

In some embodiments, the antisense strand is 21 nucleotides in length and the sense strand is

15 nucleotides in length.

In some embodiments, the antisense strand is 21 nucleotides in length and the sense strand is

16 nucleotides in length.

In some embodiments, the antisense strand is 21 nucleotides in length and the sense strand is

17 nucleotides in length.

In some embodiments, the antisense strand is 21 nucleotides in length and the sense strand is

18 nucleotides in length.

In some embodiments, the antisense strand is 21 nucleotides in length and the sense strand is

19 nucleotides in length.

In some embodiments, the antisense strand is 21 nucleotides in length and the sense strand is

20 nucleotides in length.

In some embodiments, the antisense strand is 21 nucleotides in length and the sense strand is

21 nucleotides in length.

In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is

14 nucleotides in length.

In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is

15 nucleotides in length. In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is

16 nucleotides in length.

In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is

17 nucleotides in length.

In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is

18 nucleotides in length.

In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is

19 nucleotides in length.

In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is

20 nucleotides in length.

In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is

21 nucleotides in length.

In some embodiments, the antisense strand is 22 nucleotides in length and the sense strand is

22 nucleotides in length.

In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is

14 nucleotides in length.

In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is

15 nucleotides in length.

In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is

16 nucleotides in length.

In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is

17 nucleotides in length.

In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is

18 nucleotides in length.

In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is

19 nucleotides in length.

In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is

20 nucleotides in length.

In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is

21 nucleotides in length.

In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is

22 nucleotides in length.

In some embodiments, the antisense strand is 23 nucleotides in length and the sense strand is

23 nucleotides in length.

In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is

14 nucleotides in length.

In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is

15 nucleotides in length.

In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is

16 nucleotides in length.

In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is

17 nucleotides in length. In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is

18 nucleotides in length.

In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is

19 nucleotides in length.

In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is

20 nucleotides in length.

In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is

21 nucleotides in length.

In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is

22 nucleotides in length.

In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is

23 nucleotides in length.

In some embodiments, the antisense strand is 24 nucleotides in length and the sense strand is

24 nucleotides in length.

In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is

14 nucleotides in length.

In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is

15 nucleotides in length.

In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is

16 nucleotides in length.

In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is

17 nucleotides in length.

In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is

18 nucleotides in length.

In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is

19 nucleotides in length.

In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is

20 nucleotides in length.

In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is

21 nucleotides in length.

In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is

22 nucleotides in length.

In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is

23 nucleotides in length.

In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is

24 nucleotides in length.

In some embodiments, the antisense strand is 25 nucleotides in length and the sense strand is

25 nucleotides in length.

In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is

14 nucleotides in length.

In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is

15 nucleotides in length. In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is

16 nucleotides in length.

In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is

17 nucleotides in length.

In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is

18 nucleotides in length.

In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is

19 nucleotides in length.

In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is

20 nucleotides in length.

In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is

21 nucleotides in length.

In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is

22 nucleotides in length.

In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is

23 nucleotides in length.

In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is

24 nucleotides in length.

In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is

25 nucleotides in length.

In some embodiments, the antisense strand is 26 nucleotides in length and the sense strand is

26 nucleotides in length.

In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is

14 nucleotides in length.

In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is

15 nucleotides in length.

In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is

16 nucleotides in length.

In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is

17 nucleotides in length.

In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is

18 nucleotides in length.

In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is

19 nucleotides in length.

In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is

20 nucleotides in length.

In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is

21 nucleotides in length.

In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is

22 nucleotides in length.

In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is

23 nucleotides in length. In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is

24 nucleotides in length.

In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is

25 nucleotides in length.

In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is

26 nucleotides in length.

In some embodiments, the antisense strand is 27 nucleotides in length and the sense strand is

27 nucleotides in length.

In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is

14 nucleotides in length.

In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is

15 nucleotides in length.

In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is

16 nucleotides in length.

In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is

17 nucleotides in length.

In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is

18 nucleotides in length.

In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is

19 nucleotides in length.

In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is

20 nucleotides in length.

In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is

21 nucleotides in length.

In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is

22 nucleotides in length.

In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is

23 nucleotides in length.

In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is

24 nucleotides in length.

In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is

25 nucleotides in length.

In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is

26 nucleotides in length.

In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is

27 nucleotides in length.

In some embodiments, the antisense strand is 28 nucleotides in length and the sense strand is

28 nucleotides in length.

In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is

14 nucleotides in length.

In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is

15 nucleotides in length. In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is

16 nucleotides in length.

In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is

17 nucleotides in length.

In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is

18 nucleotides in length.

In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is

19 nucleotides in length.

In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is

20 nucleotides in length.

In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is

21 nucleotides in length.

In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is

22 nucleotides in length.

In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is

23 nucleotides in length.

In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is

24 nucleotides in length.

In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is

25 nucleotides in length.

In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is

26 nucleotides in length.

In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is

27 nucleotides in length.

In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is

28 nucleotides in length.

In some embodiments, the antisense strand is 29 nucleotides in length and the sense strand is

29 nucleotides in length.

In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

14 nucleotides in length.

In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

15 nucleotides in length.

In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

16 nucleotides in length.

In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

17 nucleotides in length.

In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

18 nucleotides in length.

In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

19 nucleotides in length.

In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

20 nucleotides in length. In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

21 nucleotides in length.

In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

22 nucleotides in length.

In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

23 nucleotides in length.

In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

24 nucleotides in length.

In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

25 nucleotides in length.

In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

26 nucleotides in length.

In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

27 nucleotides in length.

In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

28 nucleotides in length.

In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

29 nucleotides in length.

In some embodiments, the antisense strand is 30 nucleotides in length and the sense strand is

30 nucleotides in length.

In another aspect, the invention features a branched siRNA molecule including a sense strand and an antisense strand, wherein the antisense strand includes a region having complementarity to a segment of contiguous nucleotides within a gene selected from the group consisting of APOE, BIN1 , C1QA, C3, C90RF72, CCL5, CD33, CLU/APOJ, CR1 , CXCL10, CXCL13, IFIT1 , IFIT3, IFITM3, IFNAR1 , IFNAR2, IL10RA, IL1A, IL1B, IL1RAP, INPP5D, ITGAM, MEF2C, MMP12, NLRP3, NOS2, PILRA,

PLCG2, PTK2B, SLC24A4, TBK1 , and TNF.

In some embodiments, the antisense strand has complementarity to a portion of a gene encoding a positive regulator of a gene for which increased expression and/or activity relative to the level of expression and/or activity observed in a reference subject is associated with a disease state.

In some embodiments, the antisense strand has complementarity to a portion of a gene encoding a negative regulator of a gene for which decreased expression and/or activity relative to the level of expression and/or activity observed in a reference subject is associated with a disease state.

In some embodiments, the antisense strand has complementarity to a splice isoform of a gene for which overexpression of the splice isoform relative to the expression of the splice isoform in a reference subject is associated with a disease state.

In some embodiments, the sense strand has complementarity to the antisense strand.

In some embodiments, the siRNA molecule is di-branched. In some embodiments, the siRNA molecule is tri-branched. In some embodiments, the siRNA molecule is tetra-branched.

In some embodiments, the antisense strand of the branched siRNA has the following Formula in the 5'-to-3' direction:

Z-((A-P-)n(B-P-)m)q; wherein Z is a 5' phosphorus stabilizing moiety; each A is, independently, a 2'-0-Me ribonucleoside; each B is, independently, a 2'-fluoro-ribonucleoside; each P is, independently, an internucleoside linkage selected from a phosphodiester linkage and a phosphorothioate linkage; n is an integer from 1 to 5 (e.g.,

1 , 2, 3, 4, or 5); m is an integer from 1 to 5 (e.g., 1 , 2, 3, 4, or 5); and q is an integer between 1 and 15 (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15).

In some embodiments, the antisense strand has a structure represented by Formula A-l, wherein Formula A-l is, in the 5’-to-3’ direction:

A-B-(A’)j-C-P ² -D-P ¹ -(C’-P ¹ )k-C’

Formula A-l; wherein A is represented by the formula C-P ¹ -D-P ¹ ; each A’ is represented by the formula C-P ² -D-P ² ;

B is represented by the formula C-P ² -D-P ² -D-P ² -D-P ² ; each C is a 2’-0-methyl (2’-0-Me) ribonucleoside; each C’, independently, is a 2’-0-Me ribonucleoside or a 2’-fluoro (2’-F) ribonucleoside; each D is a 2’-F ribonucleoside; each P ¹ is a phosphorothioate internucleoside linkage; each P ² is a phosphodiester internucleoside linkage; j is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); and k is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7).

In some embodiments, the antisense strand has a structure represented by Formula A1 , wherein Formula A1 is, in the 5’-to-3’ direction:

A-S-B-S-A-O-B-O-B-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A -O-B-S-A-S-A-S-A-S-B-S-A

Formula A1; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the antisense strand has a structure represented by Formula A-ll, wherein Formula A-ll is, in the 5’-to-3’ direction:

A-B-(A’)j-C-P ² -D-P ¹ -(C-P ¹ ) _k -C’

Formula A-ll; wherein A is represented by the formula C-P ¹ -D-P ¹ ; each A’ is represented by the formula C-P ² -D-P ² ;

B is represented by the formula C-P ² -D-P ² -D-P ² -D-P ² ; each C is a 2’-0-methyl (2’-0-Me) ribonucleoside; each C’, independently, is a 2’-0-Me ribonucleoside or a 2’-fluoro (2’-F) ribonucleoside; each D is a 2’-F ribonucleoside; each P ¹ is a phosphorothioate internucleoside linkage; each P ² is a phosphodiester internucleoside linkage; j is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); and k is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7).

In some embodiments, antisense strand has a structure represented by Formula A2, wherein Formula A2 is, in the 5’-to-3’ direction:

A-S-B-S-A-O-B-O-B-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A -O-B-S-A-S-A-S-A-S-A-S-A

Formula A2; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the sense strand has a structure represented by Formula S-lll, wherein Formula S-lll is, in the 5’-to-3’ direction:

E-(A’)m-F

Formula S-lll; wherein E is represented by the formula (C-P ¹ )2;

F is represented by the formula (C-P ² ) ₃ -D-P ¹ -C-P ¹ -C, (C-P ² ) ₃ -D-P ² -C-P ² -C, (C-P ² ) ₃ -D-P ¹ -C-P ¹ -D, or (C- P ² ) ₃ -D-P ² -C-P ² -D;

A’, C, D, P ¹ , and P ² are as defined in Formula II; and m is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7).

In some embodiments, the sense strand has a structure represented by Formula S1 , wherein Formula S1 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-A-O-A-O-B-S-A -S-A

Formula S1; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the sense strand has a structure represented by Formula S2, wherein Formula S2 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-A-O-A-O-B-O-A -O-A

Formula S2; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage. In some embodiments, the sense strand has a structure represented by Formula S3, wherein Formula S3 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-A-O-A-O-B-S-A -S-B

Formula S3; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the sense strand has a structure represented by Formula S4, wherein Formula S4 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-A-O-A-O-B-O-A -O-B

Formula S4; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the antisense strand has a structure represented by Formula A-IV, wherein Formula A-IV is, in the 5’-to-3’ direction:

A-(A’)j-C-P ² -B-(C-P ¹ ) _k -C’

Formula A-IV; wherein A is represented by the formula C-P ¹ -D-P ¹ ; each A’ is represented by the formula C-P ² -D-P ² ;

B is represented by the formula D-P ¹ -C-P ¹ -D-P ¹ ; each C is a 2’-0-Me ribonucleoside; each C’, independently, is a 2’-0-Me ribonucleoside or a 2’-F ribonucleoside; each D is a 2’-F ribonucleoside; each P ¹ is a phosphorothioate internucleoside linkage; each P ² is a phosphodiester internucleoside linkage; j is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); and k is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7).

In some embodiments, the antisense strand has a structure represented by Formula A3, wherein Formula A3 is, in the 5’-to-3’ direction:

A-S-B-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A -O-B-S-A-S-B-S-A-S-A-S-A

Formula A3; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage. In some embodiments, the sense strand has a structure represented by Formula S-V, wherein Formula S-V is, in the 5’-to-3’ direction:

E-(A’) _m -C-P ² -F

Formula S-V; wherein E is represented by the formula (C-P ¹ )2;

F is represented by the formula D-P ¹ -C-P ¹ -C, D-P ² -C-P ² -C, D-P ¹ -C-P ¹ -D, or D-P ² -C-P ² -D;

A’, C, D, P ¹ and P ² are as defined in Formula IV; and m is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7).

In some embodiments, the sense strand has a structure represented by Formula S5, wherein Formula S5 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-S-A -S-A

Formula S5; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the sense strand has a structure represented by Formula S6, wherein Formula S6 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A -O-A

Formula S6; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the sense strand has a structure represented by Formula S7, wherein Formula S7 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-S-A -S-B

Formula S7; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the sense strand has a structure represented by Formula S8, wherein Formula S8 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A -O-B

Formula S8; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage. In some embodiments, the antisense strand has a structure represented by Formula A- VI, wherein Formula A- VI is, in the 5’-to-3’ direction:

A-Bj-E-B _k -E-F-Gi-D-P ¹ -C’

Formula A-VI; wherein A is represented by the formula C-P ¹ -D-P ¹ ; each B is represented by the formula C-P ² ; each C is a 2’-0-Me ribonucleoside; each C’, independently, is a 2’-0-Me ribonucleoside or a 2’-F ribonucleoside; each D is a 2’-F ribonucleoside; each E is represented by the formula D-P ² -C-P ² ;

F is represented by the formula D-P ¹ -C-P ¹ ; each G is represented by the formula C-P ¹ ; each P ¹ is a phosphorothioate internucleoside linkage; each P ² is a phosphodiester internucleoside linkage; j is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); k is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); and

I is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7).

In some embodiments, the antisense strand has a structure represented by Formula A4, wherein Formula A4 is, in the 5’-to-3’ direction:

A-S-B-S-A-O-A-O-A-O-B-O-A-O-A-O-A-O-A-O-A-O-A-O-A-O-B-O-A -O-B-S-A-S-A-S-A-S-B-S-A

Formula A4; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the sense strand has a structure represented by Formula S-VII, wherein Formula S-VII is, in the 5’-to-3’ direction:

H-Bm-ln-A’-Bo-H-C

Formula S-VII; wherein A’ is represented by the formula C-P ² -D-P ² ; each H is represented by the formula (C-P ¹ )2; each I is represented by the formula (D-P ² );

B, C, D, P ¹ and P ² are as defined in Formula VI; m is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); n is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); and o is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7). In some embodiments, the sense strand has a structure represented by Formula S9, wherein Formula S9 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-A-O-A-O-B-O-B-O-B-O-A-O-B-O-A-O-A-O-A-O-A-S-A -S-A

Formula S9; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments, the antisense strand also has a 5’ phosphorus stabilizing moiety at the 5’ end of the antisense strand.

In some embodiments, the sense strand also has a 5’ phosphorus stabilizing moiety at the 5’ end of the sense strand.

In some embodiments, each 5’-phosphorus stabilizing moiety is, independently, represented by any one of Formula l-VIII: wherein Nuc represents a nucleobase, such as adenine, uracil, guanine, thymine, or cytosine, and R represents optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl (e.g., optionally substituted C1 -C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2- C6 alkynyl), phenyl, benzyl, hydroxy, or hydrogen.

In some embodiments, Z is (E)-vinylphosphonate as represented in Formula III.

In some embodiments, each P is independently selected from phosphodiester and phosphorothioate.

In some embodiments, n is from 1 to 4 (e.g., 1 , 2, 3, or 4), 1 to 3 (e.g., 1 , 2, or 3), or 1 to 2. In some embodiments, n is 1.

In some embodiments, m is from 1 to 4 (e.g., 1 , 2, 3, or 4), 1 to 3 (e.g., 1 , 2, or 3), or 1 to 2. In some embodiments, m is 1.

In some embodiments, n and m are each 1. In some embodiments, 50% or more of the ribonucleotides in the antisense strand are 2'-0-Me ribonucleotides (e.g., 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%,

82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand may be 2'-0-Me ribonucleotides).

In some embodiments, 60% or more of the ribonucleotides in the antisense strand are 2'-0-Me ribonucleotides (e.g., 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,

92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand may be 2'-0-Me ribonucleotides).

In some embodiments, 70% or more of the ribonucleotides in the antisense strand are 2'-0-Me ribonucleotides (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand may be 2'-0-Me ribonucleotides).

In some embodiments, 80% or more of the ribonucleotides in the antisense strand are 2'-0-Me ribonucleotides (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand may be 2'-0-Me ribonucleotides).

In some embodiments, 90% or more of the ribonucleotides in the antisense strand are 2'-0-Me ribonucleotides (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the ribonucleotides in the antisense strand may be 2'-0-Me ribonucleotides).

In some embodiments, 10% or less of the internucleoside linkages are phosphodiester linkages or phosphorothioate. In some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the internucleoside linkages are phosphodiester linkages or phosphorothioate. In some embodiments, 100% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

In some embodiments, the length of the antisense strand is between 10 and 30 nucleotides (e.g., 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, or 30 nucleotides), 15 and 25 nucleotides (e.g., 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, or 25 nucleotides), or 18 and 23 nucleotides (e.g., 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, or 23 nucleotides). In some embodiments, the length of the antisense strand is 21 nucleotides. In some embodiments, the length of the antisense strand is 22 nucleotides. In some embodiments, the length of the antisense strand is 23 nucleotides. In some embodiments, the length of the antisense strand is 24 nucleotides. In some embodiments, the length of the antisense strand is 25 nucleotides. In some embodiments, the length of the antisense strand is 26 nucleotides. In some embodiments, the length of the antisense strand is 27 nucleotides. In some embodiments, the length of the antisense strand is 28 nucleotides. In some embodiments, the length of the antisense strand is 29 nucleotides. In some embodiments, the length of the antisense strand is 30 nucleotides.

In some embodiments, 9 internucleoside linkages are phosphorothioate. In some embodiments, the sense strand of the branched siRNA has the following formula in the

5'-to-3' direction:

Y-((A-P-)n(B-P-)m)qL-((B-P-)m(A-P-)n)q; wherein Y is a hydrophobic moiety (e.g., cholesterol, vitamin D, or tocopherol); L is a linker; each A is, independently, a 2'-0-Me ribonucleoside; each B is, independently, a 2'-fluoro-ribonucleoside; each P is, independently, an internucleoside linkage selected from a phosphodiester linkage and a phosphorothioate linkage; n is an integer from 1 to 5 (1 , 2, 3, 4, or 5); m is an integer from 1 to 5 (1 , 2, 3, 4, or 5); and q is an integer between 1 and 15 (1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, or 15).

In some embodiments, Y is cholesterol.

In some embodiments, Y tocopherol.

In some embodiments, L is an ethylene glycol oligomer.

In some embodiments, L is tetraethylene glycol.

In some embodiments, each P is independently selected from phosphodiester and phosphorothioate.

In some embodiments, n is from 1 to 4 (e.g., 1 , 2, 3, or 4), 1 to 3 (e.g., 1 , 2, or 3), or 1 to 2. In some embodiments, n is 1.

In some embodiments, m is from 1 to 4 (e.g., 1 , 2, 3, or 4), 1 to 3 (e.g., 1 , 2, or 3), or 1 to 2. In some embodiments, m is 1.

In some embodiments, n and m are each 1.

In some embodiments, 10% or less of the ribonucleosides are 2'-0-Me ribonucleoside.

In some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the ribonucleosides are 2'-0-Me ribonucleoside.

In some embodiments, 10% or less of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages. In some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages. In some embodiments, 100% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

In some embodiments, the length ofthe sense strand is between 12 and 30 nucleotides (e.g., 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 , nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, or 30 nucleotides), or 14 and 18 nucleotides (e.g., 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides). In some embodiments, the length ofthe sense strand is 16 nucleotides. In some embodiments, the length ofthe sense strand is 17 nucleotides. In some embodiments, the length ofthe sense strand is 18 nucleotides. In some embodiments, the length ofthe sense strand is 19 nucleotides. In some embodiments, the length ofthe sense strand is 20 nucleotides. In some embodiments, the length of the sense strand is 21 nucleotides. In some embodiments, the length ofthe sense strand is 22 nucleotides. In some embodiments, the length ofthe sense strand is 23 nucleotides. In some embodiments, the length ofthe sense strand is 24 nucleotides. In some embodiments, the length ofthe sense strand is 25 nucleotides. In some embodiments, the length of the sense strand is 26 nucleotides. In some embodiments, the length of the sense strand is 27 nucleotides. In some embodiments, the length of the sense strand is 28 nucleotides. In some embodiments, the length of the sense strand is 29 nucleotides. In some embodiments, the length of the sense strand is 30 nucleotides.

In some embodiments, 4 internucleoside linkages are phosphorothioate.

In another aspect, the invention features a method of treating a subject diagnosed as having a disease associated with expression of a dysregulated microglial gene (e.g., wild-type or mutated microglial gene), the method includes administering to the subject the branched siRNA molecule of any one of the above aspects or embodiments.

In some embodiments, the dysregulated microglial gene is selected from the group consisting of ABCA7, ABI3, ADAM10, APOC1 , APOE, AXL, BIN1 , C1QA, C3, C90RF72, CASS4, CCL5, CD2AP, CD33, CD68, CLPTM1 , CLU, CR1 , CSF1 , CST7, CTSB, CTSD, CTSL, CXCL10, CXCL13, DSG2, ECHDC3, EPHA1 , FABP5, FERMT2, FTH1 , GNAS, GRN, HBEGF, HLA-DRB1 , HLA-DRB5, IFIT1 , IFIT3, IFITM3, IFNAR1 , IFNAR2, IGF1 , IL10RA, IL1A, IL1B, IL1RAP, INPP5D, ITGAM, ITGAX, LILRB4, LPL, MEF2C, MMP12, MS4A4A, MS4A6A, NLRP3, NME8, NOS2, PICALM, PILRA, PLCG2, PTK2B, SCIMP, SLC24A4, SORL1 , SPI1 , SPP1 , SPPL2A, TBK1 , TNF, TREM2, TREML2, TYROBP, and ZCWPW1.

In some embodiments, the dysregulated microglial gene exhibits increased expression and/or activity in microglial cells of the subject as compared to the expression and/or activity of the same gene in microglial cells of a reference subject.

In some embodiments, the dysregulated microglial gene exhibits reduced expression and/or activity in microglial cells of the subject as compared to the expression and/or activity of the same gene in microglial cells of a reference subject.

In some embodiments, the administering of the branched siRNA molecule to the subject results in silencing of gene in the subject.

In some embodiments, the silencing of a gene comprises silencing any one of the genes selected from the group consisting of APOE, BIN1 , C1QA, C3, C90RF72, CCL5, CD33, CLU/APOJ, CR1 , CXCL10, CXCL13, IFIT1 , IFIT3, IFITM3, IFNAR1 , IFNAR2, IL10RA, IL1A, IL1B, IL1RAP, INPP5D,

ITGAM, MEF2C, MMP12, NLRP3, NOS2, PILRA, PLCG2, PTK2B, SLC24A4, TBK1 , and TNF.

In some embodiments, silencing of a gene comprises silencing of a positive regulator of a gene for which increased expression and/or activity relative to the level of expression and/or activity observed in a reference subject is associated with a disease state.

In some embodiments, silencing of a gene comprises silencing of a negative regulator of a gene for which decreased expression and/or activity relative to the level of expression and/or activity observed in a reference subject is associated with a disease state.

In some embodiments, silencing of a gene comprises silencing of a splice isoform of a gene for which overexpression of the splice isoform relative to the expression of the splice isoform in a reference subject is associated with a disease state.

In some embodiments, the subject is a human.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D are a series of fluorescence images of brain and spinal cord tissue of cynomolgus macaques treated with a single intrathecal injection of Cy3-labeled di-siRNA of the disclosure. Fluorescence images were acquired from representative regions of the brain, including cortex (FIG. 1A), hippocampus (FIG. 1 B), caudate nucleus (FIG 1C), and of the spinal cord (FIG. 1D). Microglia cells (Iba1 channel), di-siRNAs (Cy3 channel), and cell nuclei (DAPI) were labeled. White arrows indicate colocalization of Cy3 di-siRNA signal within microglial cells labeled with the Iba1 antibody. Scale bars = 20 pm.

DEFINITIONS

Unless otherwise defined herein, scientific, and technical terms used herein have the meanings that are commonly understood by those of ordinary skill in the art. In the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

The use of "or" means "and/or" unless stated otherwise. The use of the term "including," as well as other forms, such as "includes" and "included," is not limiting.

As used herein, the term "nucleic acids" refers to RNA or DNA molecules consisting of a chain of ribonucleotides or deoxyribonucleotides, respectively. As used herein, the term "therapeutic nucleic acid" refers to a nucleic acid molecule (e.g., ribonucleic acid) that has partial or complete complementarity to, and interacts with, a disease-associated target mRNA and mediates silencing of expression of the mRNA.

As used herein, the term "carrier nucleic acid" refers to a nucleic acid molecule (e.g., ribonucleic acid) that has sequence complementarity with, and hybridizes with, a therapeutic nucleic acid. As used herein, the term "3' end" refers to the end of the nucleic acid that contains an unmodified hydroxyl group at the 3' carbon of the ribose ring.

As used herein, the term "nucleoside" refers to a molecule made up of a heterocyclic base and its sugar.

As used herein, the term "nucleotide" refers to a nucleoside having a phosphate group on its 3' or 5' sugar hydroxyl group.

As used herein, the term "siRNA" refers to small interfering RNA duplexes that induce the RNA interference (RNAi) pathway. siRNA molecules can vary in length (generally, between 18-30 base pairs) and contain varying degrees of complementarity to their target mRNA. The term "siRNA" includes duplexes of two separate strands, as well as single strands that optionally form hairpin structures comprising a duplex region.

As used herein, the term "antisense strand" refers to the strand of the siRNA duplex that contains some degree of complementarity to the target gene.

As used herein, the term "sense strand" refers to the strand of the siRNA duplex that contains complementarity to the antisense strand.

As used herein, the terms "chemically modified nucleotide" or "nucleotide analog" or "altered nucleotide" or "modified nucleotide" refer to a non-standard nucleotide, including non-naturally occurring ribonucleotides or deoxyribonucleotides. Exemplary nucleotide analogs are modified at any position so as to alter certain chemical properties of the nucleotide yet retain the ability of the nucleotide analog to perform its intended function.

As used herein, the term "metabolically stabilized" refers to RNA molecules that contain ribonucleotides that have been chemically modified from 2'-hydroxyl groups to 2'-0-methyl groups. As used herein, the term "phosphorothioate" refers to the phosphate group of a nucleotide that is modified by substituting one or more of the oxygens of the phosphate group with sulfur.

As used herein, the term "ethylene glycol chain" refers to a carbon chain with the formula ((CH ₂ OH) ₂ ).

As used herein, “alkyl” refers to a saturated hydrocarbon group. Alkyl groups may be acyclic or cyclic and contain only C and H when unsubstituted. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed and described; thus, for example, “butyl” is meant to include n-butyl, sec-butyl, and /so-butyl. Examples of alkyl include ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. In some embodiments, alkyl may be substituted.

Suitable substituents that may be introduced into an alkyl group include, for example, hydroxy, alkoxy, amino, alkylamino, and halo, among others.

As used herein, “alkenyl” refers to an acyclic or cyclic unsaturated hydrocarbon group having at least one site of olefinic unsaturation (i.e. , having at least one moiety of the formula C=C). Alkenyl groups contain only C and H when unsubstituted. When an alkenyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed and described; thus, for example, “butenyl” is meant to include n-butenyl, sec-butenyl, and /so-butenyl. Examples of alkenyl include -CH=CH ₂ , -CH ₂ -CH=CH ₂ , and -CH ₂ -CH=CH-CH=CH ₂ . In some embodiments, alkenyl may be substituted. Suitable substituents that may be introduced into an alkenyl group include, for example, hydroxy, alkoxy, amino, alkylamino, and halo, among others.

As used herein, “alkynyl” refers to an acyclic or cyclic unsaturated hydrocarbon group having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula CºC). Alkynyl groups contain only C and H when unsubstituted. When an alkynyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed and described; thus, for example, “pentynyl” is meant to include n-pentynyl, sec-pentynyl, /so-pentynyl, and fe/f-pentynyl. Examples of alkynyl include -CºCH and -CºC-CH3. In some embodiments, alkynyl may be substituted. Suitable substituents that may be introduced into an alkynyl group include, for example, hydroxy, alkoxy, amino, alkylamino, and halo, among others.

As used herein the term "phenyl" denotes a monocyclic arene in which one hydrogen atom from a carbon atom of the ring has been removed. A phenyl group can be unsubstituted or substituted with one or more suitable substituents, wherein the substituent replaces an H of the phenyl group.

As used herein, the term “benzyl” refers to monovalent radical obtained when a hydrogen atom attached to the methyl group of toluene is removed. A benzyl generally has the formula of phenyl-CH ₂ -.

A benzyl group can be unsubstituted or substituted with one or more suitable substituents. For example, the substituent may replace an H of the phenyl component and/or an H of the methylene (-CH ₂ -) component.

As used herein, the term "amide" refers to an alkyl or aromatic group that is attached to an amino-carbonyl functional group.

As used herein, the term "internucleoside" and "internucleotide" refer to the bonds between nucleosides and nucleotides, respectively. As used herein, the term "triazol" refers to heterocyclic compounds with the formula (C2H3N3), having a five-membered ring of two carbons and three nitrogens, the positions of which can change resulting in multiple isomers.

As used herein, the term "terminal group" refers to the group at which a carbon chain or nucleic acid ends.

As used herein, the term "lipophilic amino acid" refers to an amino acid comprising a hydrophobic moiety (e.g., an alkyl chain or an aromatic ring).

As used herein, the term "antagomiRs" refers to nucleic acids that can function as inhibitors of miRNA activity.

As used herein, the term "gapmers" refers to chimeric antisense nucleic acids that contain a central block of deoxynucleotide monomers sufficiently long to induce RNase H cleavage. The deoxynucleotide block is flanked by ribonucleotide monomers or ribonucleotide monomers containing modifications.

As used herein, the term "mixmers" refers to nucleic acids that are comprised of a mix of locked nucleic acids (LNAs) and DNA.

As used herein, the term "guide RNAs" refers to nucleic acids that have sequence complementarity to a specific sequence in the genome immediately or 1 base pair upstream of the protospacer adjacent motif (PAM) sequence as used in CRISPR/Cas9 gene editing systems.

Alternatively, “guide RNAs” may refer to nucleic acids that have sequence complementarity (e.g., are antisense) to a specific messenger RNA (mRNA) sequence. In this context, a guide RNA may also have sequence complementarity to a “passenger RNA” sequence of equal or shorter length, which is identical or substantially identical to the sequence of mRNA to which the guide RNA hybridizes.

As used herein, the term "target of delivery" refers to the organ or part of the body that is desired to deliver the branched oligonucleotide compositions to.

As used herein, the term “branched siRNA” refers to a compound containing two or more double- stranded siRNA molecules covalently bound to one another. Branched siRNA molecules may be “di- branched,” also referred to herein as “di-siRNA,” wherein the siRNA molecule comprises 2 siRNA molecules covalently bound to one another, e.g., by way of a linker. Branched siRNA molecules may be “tri-branched,” also referred to herein as “tri-siRNA,” wherein the siRNA molecule comprises 3 siRNA molecules covalently bound to one another, e.g., by way of a linker. Branched siRNA molecules may be “tetra-branched,” also referred to herein as “tetra-siRNA,” wherein the siRNA molecule comprises 4 siRNA molecules covalently bound to one another, e.g., by way of a linker.

As used herein, the term “5' phosphorus stabilizing moiety” refers to a terminal phosphate group that includes phosphates as well as modified phosphates (e.g., phosphorothioates, phosphodiesters, phosphonates). The phosphate moiety can be located at either terminus but is preferred at the 5'- terminal nucleoside. In one aspect, the terminal phosphate is unmodified having the formula -O- P(=0)(0H)0H. In another aspect, the terminal phosphate is modified such that one or more of the O and OH groups are replaced with H, O, S, N(R’), or alkyl where R’ is H, an amino protecting group, or unsubstituted or substituted alkyl. In some embodiments, the 5' and or 3' terminal group can comprise from 1 to 3 phosphate moieties that are each, independently, unmodified (di- or tri-phosphates) or modified. As used herein, the term “between X and Y” is inclusive of the values of X and Y. For example, “between X and Y” refers to the range of values between the value of X and the value of Y, as well as the value of X and the value of Y.

As used herein, an "amino acid" refers to a molecule containing amine and carboxyl functional groups and a side chain specific to the amino acid. :

In some embodiments the amino acid is chosen from the group of proteinogenic amino acids. In other embodiments, the amino acid is an L-amino acid or a D-amino acid. In other embodiments, the amino acid is a synthetic amino acid (e.g., a beta-amino acid).

It is understood that certain internucleotide linkages provided herein, including, e.g., phosphodiester and phosphorothioate, comprise a formal charge of -1 at physiological pH, and that said formal charge will be balanced by a cationic moiety, e.g., an alkali metal such as sodium or potassium, an alkali earth metal such as calcium or magnesium, or an ammonium or guanidinium ion.

The phosphate group of the nucleotide may also be modified, e.g., by substituting one or more of the oxygens of the phosphate group with sulfur (e.g., phosphorothioates), or by making other substitutions which allow the nucleotide to perform its intended function such as described in, for example, Eckstein, Antisense Nucleic Acid Drug Dev. 2000 Apr. 10(2):117-21 , Rusckowski et al. Antisense Nucleic Acid Drug Dev. 2000 Oct. 10(5):333-45, Stein, Antisense Nucleic Acid Drug Dev. 2001 Oct. 11 (5): 317-25, Vorobjev et al. Antisense Nucleic Acid Drug Dev. 2001 Apr. 11 (2):77-85, and U.S.

Pat. No. 5,684,143. Certain of the above- referenced modifications (e.g., phosphate group modifications) preferably decrease the rate of hydrolysis of, for example, polynucleotides comprising said analogs in vivo or in vitro.

As used herein, the term “complementary” refers to two nucleotides that form canonical Watson- Crick base pairs. For the avoidance of doubt, Watson-Crick base pairs in the context of the present disclosure include adenine-thymine, adenine-uracil, and cytosine-guanine base pairs. A proper Watson- Crick base pair is referred to in this context as a “match,” while each unpaired nucleotide, and each incorrectly paired nucleotide, is referred to as a “mismatch.” Alignment for purposes of determining percent nucleic acid sequence complementarity can be achieved in various ways that are within the capabilities of one of skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, or Megalign software.

As used herein, the term “percent (%) sequence complementarity” with respect to a reference polynucleotide sequence is defined as the percentage of nucleic acids in a candidate sequence that are complementary to the nucleic acids in the reference polynucleotide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence complementarity. A given nucleotide is considered to be “complementary” to a reference nucleotide as described herein if the two nucleotides form canonical Watson-Crick base pairs. For the avoidance of doubt, Watson-Crick base pairs in the context of the present disclosure include adenine-thymine, adenine-uracil, and cytosine-guanine base pairs. A proper Watson-Crick base pair is referred to in this context as a “match,” while each unpaired nucleotide, and each incorrectly paired nucleotide, is referred to as a “mismatch.” Alignment for purposes of determining percent nucleic acid sequence complementarity can be achieved in various ways that are within the capabilities of one of skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, or Megalign software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal complementarity over the full length of the sequences being compared. As an illustration, the percent sequence complementarity of a given nucleic acid sequence, A, to a given nucleic acid sequence, B, (which can alternatively be phrased as a given nucleic acid sequence, A that has a certain percent complementarity to a given nucleic acid sequence, B) is calculated as follows:

100 multiplied by (the fraction X/Y) where X is the number of complementary base pairs in an alignment (e.g., as executed by computer software, such as BLAST) in that program’s alignment of A and B, and where Y is the total number of nucleic acids in B. It will be appreciated that where the length of nucleic acid sequence A is not equal to the length of nucleic acid sequence B, the percent sequence complementarity of A to B will not equal the percent sequence complementarity of B to A. As used herein, a query nucleic acid sequence is considered to be “completely complementary” to a reference nucleic acid sequence if the query nucleic acid sequence has 100% sequence complementarity to the reference nucleic acid sequence.

The term “gene silencing” refers to the suppression of gene expression, e.g., transgene, heterologous gene and/or endogenous gene expression, which may be mediated through processes that affect transcription and/or through processes that affect post-transcriptional mechanisms. In some embodiments, gene silencing occurs when an RNAi molecule initiates the inhibition or degradation of the mRNA transcribed from a gene of interest in a sequence-specific manner via RNA interference, thereby preventing translation of the gene's product.

The phrase “overactive disease driver gene,” as used herein, refers to a microglial gene having increased activity and/or expression that contributes to or causes a disease state in a subject (e.g., a human). The disease state may be caused or exacerbated by the overactive disease driver gene directly or by way of an intermediate gene(s).

The term “negative regulator,” as used herein, refers to a microglial gene that negatively regulates (e.g., reduces or inhibits) the expression and/or activity of another microglial gene or set of genes (e.g., dysregulated microglial gene ordysregulated microglial gene pathway).

The term “positive regulator,” as used herein, refers to a microglial gene that positively regulates (e.g., increases or saturates) the expression and/or activity of another microglial gene or set of microglial genes (e.g., dysregulated microglial gene ordysregulated microglial gene pathway).

The term “phosphate moiety” as used herein, refers to a terminal phosphate group that includes phosphates as well as modified phosphates. The phosphate moiety can be located at either terminus but is preferred at the 5'-terminal nucleoside. In one aspect, the terminal phosphate is unmodified having the formula — O — P(=0)(0H)0H. In another aspect, the terminal phosphate is modified such that one or more of the O and OH groups are replaced with H, O, S, N(R’) or alkyl where R’ is H, an amino protecting group or unsubstituted or substituted alkyl. In some embodiments, the 5' and or 3' terminal group can comprise from 1 to 3 phosphate moieties that are each, independently, unmodified (di or tri-phosphates) or modified.

In the context of this invention, the term "oligonucleotide" refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics thereof. This term includes oligonucleotides composed of naturally-occurring nucleobases, sugars and covalent internucleoside (backbone) linkages as well as oligonucleotides having non-naturally-occurring portions that function similarly. Such modified or substituted oligonucleotides are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target and increased stability in the presence of nucleases.

As used herein, the term “reference subject” refers to a healthy control subject of the same or similar, e.g., age, sex, geographical region, and/or education level as a subject treated with a composition of the disclosure. A healthy reference subject is one that does not suffer from a disease associated with expression of a dysregulated microglial gene or a dysregulated microglial gene pathway. Moreover, a healthy reference subject is one that does not suffer from a disease associated with altered (e.g., increased or decreased) expression and/or activity of a microglial gene.

As used herein, the terms “treat,” “treated,” or “treating” mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

Genes described herein

As used herein, the term “ABCA7” refers to the gene encoding Phospholipid-transporting ATPase ABCA7. The terms “ABCA7” and "Phospholipid-transporting ATPase ABCA7" include wild-type forms of the ABCA7 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type ABCA7. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type ABCA7 nucleic acid sequence (e.g., SEQ ID NO: 1 , European Nucleotide Archive (ENA) accession number AF250238). SEQ ID NO: 1 is a wild-type gene sequence encoding ABCA7 protein, and is shown below:

ATGGCCTTCTGGACACAGCTGATGCTGCTGCTCTGGAAGAATTTCATGTATCGCCGG AGA

CAGCCGGTCCAGCTCCTGGTCGAATTGCTGTGGCCTCTCTTCCTCTTCTTCATCCTG GTG

GCTGTTCGCCACTCCCACCCGCCCCTGGAGCACCATGAATGCCACTTCCCAAACAAG CCA

CTGCCATCGGCGGGCACCGTGCCCTGGCTCCAGGGTCTCATCTGTAATGTGAACAAC ACC

TGCTTTCCGCAGCTGACACCGGGCGAGGAGCCCGGGCGCCTGAGCAACTTCAACGAC TCC

CTGGTCTCCCGGCTGCTAGCCGATGCCCGCACTGTGCTGGGAGGGGCCAGTGCCCAC AGG

ACGCTGGCTGGCCTAGGGAAGCTGATCGCCACGCTGAGGGCTGCACGCAGCACGGCC CAG

CCTCAACCAACCAAGCAGTCTCCACTGGAACCACCCATGCTGGATGTCGCGGAGCTG CTG

ACGTCACTGCTGCGCACGGAATCCCTGGGGTTGGCACTGGGCCAAGCCCAGGAGCCC TTG

CACAGCTT GTT GGAGGCCGCT GAGGACCT GGCCCAGGAGCTCCTGGCGCTGCGCAGCCT G GTGGAGCTTCGGGCACTGCTGCAGAGACCCCGAGGGACCAGCGGCCCCCTGGAGTTGCTG

TCAGAGGCCCTCTGCAGTGTCAGGGGACCTAGCAGCACAGTGGGCCCCTCCCTCAAC TGG

TACGAGGCTAGT GACCT GAT GGAGCT GGTGGGGCAGGAGCCAGAATCCGCCCT GCCAGAC

AGCAGCCTGAGCCCCGCCTGCTCGGAGCTGATTGGAGCCCTGGACAGCCACCCGCTG TCC

CGCCTGCTCTGGAGACGCCTGAAGCCTCTGATCCTCGGGAAGCTACTCTTTGCACCA GAT

ACACCTTTTACCCGGAAGCTCATGGCCCAGGTCAACCGGACCTTCGAGGAGCTCACC CTG

CTGAGGGATGTCCGGGAGGTGTGGGAGATGCTGGGACCCCGGATCTTCACCTTCATG AAC

G ACAGTTCCAAT GT GGCCATGCT GCAGCGGCTCCT GCAGATGCAGGAT G AAGG AAGAAGG

CAGCCCAGACCTGGAGGCCGGGACCACATGGAGGCCCTGCGATCCTTTCTGGACCCT GGG

AGCGGTGGCTACAGCTGGCAGGACGCACACGCTGATGTGGGGCACCTGGTGGGCACG CTG

GGCCGAGTGACGGAGTGCCTGTCCTTGGACAAGCTGGAGGCGGCACCCTCAGAGGCA GCC

CTGGTGTCGCGGGCCCTGCAACTGCTCGCGGAACATCGATTCTGGGCCGGCGTCGTC TTC

TTGGGACCTGAGGACTCTTCAGACCCCACAGAGCACCCAACCCCAGACCTGGGCCCC GGC

CACGT GCGCATC AAAATCCGCATGGACATT G ACGT GGTCACGAGG ACC AAT AAG AT CAGG

GACAGGTTTTGGGACCCTGGCCCAGCCGCGGACCCCCTGACCGACCTGCGCTACGTG TGG

GGCGGCTTCGTGTACCTGCAAGACCTGGTGGAGCGTGCAGCCGTCCGCGTGCTCAGC GGC

GCCAACCCCCGGGCCGGCCTCTACCTGCAGCAGATGCCCTATCCGTGCTATGTGGAC GAC

GTGTTCCTGCGTGTGCTGAGCCGGTCGCTGCCGCTCTTCCTGACGCTGGCCTGGATC TAC

TCCGTGACACTGACAGTGAAGGCCGTGGTGCGGGAGAAGGAGACGCGGCTGCGGGAC ACC

ATGCGCGCCATGGGGCTCAGCCGCGCGGTGCTCTGGCTAGGCTGGTTCCTCAGCTGC CTC

GGGCCCTTCCTGCTCAGCGCCGCACTGCTGGTTCTGGTGCTCAAGCTGGGAGACATC CTC

CCCTACAGCCACCCGGGCGTGGTCTTCCTGTTCTTGGCAGCCTTCGCGGTGGCCACG GTG

ACCCAGAGCTTCCTGCTCAGCGCCTTCTTCTCCCGCGCCAACCTGGCTGCGGCCTGC GGC

GGCCTGGCCTACTTCTCCCTCTACCTGCCCTACGTGCTGTGTGTGGCTTGGCGGGAC CGG

CTGCCCGCGGGTGGCCGCGTGGCCGCGAGCCTGCTGTCGCCCGTGGCCTTCGGCTTC GGC

TGCGAGAGCCTGGCTCTGCTGGAGGAGCAGGGCGAGGGCGCGCAGTGGCACAACGTG GGC

ACCCGGCCTACGGCAGACGTCTTCAGCCTGGCCCAGGTCTCTGGCCTTCTGCTGCTG GAC

GCGGCGCTCTACGGCCTCGCCACCTGGTACCTGGAAGCTGTGTGCCCAGGCCAGTAC GGG

ATCCCTGAACCATGGAATTTTCCTTTTCGGAGGAGCTACTGGTGCGGACCTCGGCCC CCC

AAGAGTCCAGCCCCTTGCCCCACCCCGCTGGACCCAAAGGTGCTGGTAGAAGAGGCA CCG

CCCGGCCTGAGTCCTGGCGTCTCCGTTCGCAGCCTGGAGAAGCGCTTTCCTGGAAGC CCG

CAGCCAGCCCTGCGGGGGCTCAGCCTGGACTTCTACCAGGGCCACATCACCGCCTTC CTG

GGCCACAACGGGGCCGGCAAGACCACCACCCTGTCCATCTTGAGTGGCCTCTTCCCA CCC

AGTGGTGGCTCTGCCTTCATCCTGGGCCACGACGTCCGCTCCAGCATGGCCGCCATC CGG

CCCCACCTGGGCGTCTGTCCTCAGTACAACGTGCTGTTTGACATGCTGACCGTGGAC GAG

CACGTCTGGTTCTATGGGCGGCTGAAGGGTCTGAGTGCCGCTGTAGTGGGCCCCGAG CAG

GACCGTCTGCTGCAGGATGTGGGGCTGGTCTCCAAGCAGAGTGTGCAGACTCGCCAC CTC

TCTGGTGGGATGCAACGGAAGCTGTCCGTGGCCATTGCCTTTGTGGGCGGCTCCCAA GTT

GTTATCCTGGACGAGCCTACGGCTGGCGTGGATCCTGCTTCCCGCCGCGGTATTTGG GAG

CTGCTGCTCAAATACCGAGAAGGTCGCACGCTGATCCTCTCCACCCACCACCTGGAT GAG

GCAGAGCTGCTGGGAGACCGTGTGGCTGTGGTGGCAGGTGGCCGCTTGTGCTGCTGT GGC

TCCCCACTCTTCCTGCGCCGTCACCTGGGCTCCGGCTACTACCTGACGCTGGTGAAG GCC CGCCT GCCCCT GACCACCAAT GAGAAGGCTGACACT GACAT GGAGGGCAGTGTGGACACC

AGGCAGGAAAAGAAGAATGGCAGCCAGGGCAGCAGAGTCGGCACTCCTCAGCTGCTG GCC

CT GGTACAGCACT GGGT GCCCGGGGCACGGCT GGTGGAGGAGCT GCCACACGAGCT GGTG

CTGGTGCTGCCCTACACGGGTGCCCATGACGGCAGCTTCGCCACACTCTTCCGAGAG CTA

GACACGCGGCTGGCGGAGCTGAGGCTCACTGGCTACGGGATCTCCGACACCAGCCTC GAG

GAGATCTTCCTGAAGGTGGTGGAGGAGTGTGCTGCGGACACAGATATGGAGGATGGC AGC

TGCGGGCAGCACCTATGCACAGGCATTGCTGGCCTAGACGTAACCCTGCGGCTCAAG ATG

CCGCCACAGGAGACAGCGCTGGAGAACGGGGAACCAGCTGGGTCAGCCCCAGAGACT GAC

CAGGGCTCTGGGCCAGACGCCGTGGGCCGGGTACAGGGCTGGGCACTGACCCGCCAG CAG

CTCCAGGCCCTGCTTCTCAAGCGCTTTCTGCTTGCCCGCCGCAGCCGCCGCGGCCTG TTC

GCCCAGATCGTGCTGCCTGCCCTCTTTGTGGGCCTGGCCCTCGTGTTCAGCCTCATC GTG

CCTCCTTTCGGGCACTACCCGGCTCTGCGGCTCAGTCCCACCATGTACGGTGCTCAG GTG

TCCTTCTTCAGTGAGGACGCCCCAGGGGACCCTGGACGTGCCCGGCTGCTCGAGGCG CTG

CTGCAGGAGGCAGGACTGGAGGAGCCCCCAGTGCAGCATAGCTCCCACAGGTTCTCG GCA

CCAGAAGTTCCTGCTGAAGTGGCCAAGGTCTTGGCCAGTGGCAACTGGACCCCAGAG TCT

CCATCCCCAGCCTGCCAGTGTAGCCAGCCCGGTGCCCGGCGCCTGCTGCCCGACTGC CCG

GCTGCAGCTGGTGGTCCCCCTCCGCCCCAGGCAGTGACCGGCTCTGGGGAAGTGGTT CAG

AACCTGACAGGCCGGAACCTGTCTGACTTCCTGGTCAAGACCTACCCGCGCCTGGTG CGC

CAGGGCCTGAAGACTAAGAAGTGGGTGAATGAGGTCAGGTACGGAGGCTTCTCGCTG GGG

GGCCGAGACCCAGGCCTGCCCTCGGGCCAAGAGTTGGGCCGCTCAGTGGAGGAGTTG TGG

GCGCTGCTGAGTCCCCTGCCTGGCGGGGCCCTCGACCGTGTCCTGAAAAACCTCACA GCC

TGGGCTCACAGCCTGGACGCTCAGGACAGTCTCAAGATCTGGTTCAACAACAAAGGC TGG

CACTCCATGGTGGCCTTTGTCAACCGAGCCAGCAACGCAATCCTCCGTGCTCACCTG CCC

CCAGGCCGGGCCCGCCACGCCCACAGCATCACCACACTCAACCACCCCTTGAACCTC ACC

AAGGAGCAGCTGTTTGAGGCTGCATTGATGGCCTCCTCGGTGGACGTCCTCGTCTCC ATC

TGTGTGGTCTTTGCCATGTCCTTTGTCCCGGCCAGCTTCACTCTTGTCCTCATTGAG GAG

CGAGTCACCCGAGCCAAGCACCTGCAGCTCATGGGGGGCCTGTCCCCCACCCTCTAC TGG

CTTGGCAACTTTCTCTGGGACATGTGTAACTACTTGGTGCCAGCATGCATCGTGGTG CTC

ATCTTTCTGGCCTTCCAGCAGAGGGCATATGTGGCCCCTGCCAACCTGCCTGCTCTC CTG

CTGTTGCTACTACTGTATGGCTGGTCGATCACACCGCTCATGTACCCAGCCTCCTTC TTC

TTCTCCGTGCCCAGCACAGCCTATGTGGTGCTCACCTGCATAAACCTCTTTATTGGC ATC

AATGGAAGCATGGCCACCTTTGTGCTTGAGCTCTTCTCTGATCAGAAGCTGCAGGAG GTG

AGCCGGATCTTGAAACAGGTCTTCCTTATCTTCCCCCACTTCTGCTTGGGCCGGGGG CTT

ATTGACATGGTGCGGAACCAGGCCATGGCTGATGCCTTTGAGCGCTTGGGAGACAGG CAG

TTCCAGTCACCCCTGCGCTGGGAGGTGGTCGGCAAGAACCTCTTGGCCATGGTGATA CAG

GGGCCCCTCTTCCTTCTCTTCACACTACTGCTGCAGCACCGAAGCCAACTCCTGCCA CAG

CCCAGGGTGAGGTCTCTGCCACTCCTGGGAGAGGAGGACGAGGATGTAGCCCGTGAA CGG

GAGCGGGTGGTCCAAGGAGCCACCCAGGGGGATGTGTTGGTGCTGAGGAACTTGACC AAG

GTATACCGTGGGCAGAGGATGCCAGCTGTTGACCGCTTGTGCCTGGGGATTCCCCCT GGT

GAGTGTTTTGGGCTGCTGGGTGTGAATGGAGCAGGGAAGACGTCCACGTTTCGCATG GTG

ACGGGGGACACATTGGCCAGCAGGGGCGAGGCTGTGCTGGCAGGCCACAGCGTGGCC CGG

GAACCCAGTGCTGCGCACCTCAGCATGGGATACTGCCCTCAATCCGATGCCATCTTT GAG CTGCTGACGGGCCGCGAGCACCTGGAGCTGCTTGCGCGCCTGCGCGGTGTCCCGGAGGCC

CAGGTTGCCCAGACCGCTGGCTCGGGCCTGGCGCGTCTGGGACTCTCATGGTACGCA GAC

CGGCCTGCAGGCACCTACAGCGGAGGGAACAAACGCAAGCTGGCGACGGCCCTGGCG CTG

GTTGGGGACCCAGCCGTGGTGTTTCTGGACGAGCCGACCACAGGCATGGACCCCAGC GCG

CGGCGCTTCCTTTGGAACAGCCTTTTGGCCGTGGTGCGGGAGGGCCGTTCAGTGATG CTC

ACCTCCCATAGCATGGAGGAGTGTGAAGCGCTCTGCTCGCGCCTAGCCATCATGGTG AAT

GGGCGGTTCCGCTGCCTGGGCAGCCCGCAACATCTCAAGGGCAGATTCGCGGCGGGT CAC

ACACTGACCCTGCGGGTGCCCGCCGCAAGGTCCCAGCCGGCAGCGGCCTTCGTGGCG GCC

GAGTTCCCTGGGTCGGAGCTGCGCGAGGCACATGGAGGCCGCCTGCGCTTCCAGCTG CCG

CCGGGAGGGCGCTGCGCCCTGGCGCGCGTCTTTGGAGAGCTGGCGGTGCACGGCGCA GAG

CACGGCGTGGAGGACTTTTCCGTGAGCCAGACGATGCTGGAGGAGGTATTCTTGTAC TTC

TCCAAGGACCAGGGGAAGGACGAGGACACCGAAGAGCAGAAGGAGGCAGGAGTGGGA GTG

GACCCCGCGCCAGGCCTGCAGCACCCCAAACGCGTCAGCCAGTTCCTCGATGACCCT AGC

ACTGCCGAGACTGTGCTCTGAGCCTCCCTCCCCTGCGGGGCCGCGGGGAGGCCCTGG GAA

TGGCAAGGGCAAGGTAGAGTGCCTAGGAGCCCTGGACTCAGGCTGGCAGAGGGGCTG GTG

CCCTGGAGAAAATAAAGAGAAGGCTGGAGAGAAGCCGTGCTTGGTGAA

(SEQ ID NO: 1)

As used herein, the term “ABI3” refers to the gene encoding ABI gene family member 3. The terms “ABI3” and "ABI gene family member 3" include wild-type forms of the ABI3 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type ABI3. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type ABI3 nucleic acid sequence (e.g., SEQ ID NO: 2, ENA accession number AF037886). SEQ ID NO: 2 is a wild-type gene sequence encoding ABI3 protein, and is shown below:

TCCTATCCACCCTCCACTCCCCTGTCCCTTGGTGACTCATCCCTGAGCTTCCCAAGG AAG

CCCCCACCCTCTGCCCTTTCCTCCCGCCTTCCATGAGTGGAAAATCCACCTCCGCCC CCT

ATAGCAGGCCAGCCCCCTTCCTCCCCAGTCTCCGACCCCATCCCCCAGCCGACCAGT TTC

CTCTCCAGGACCAGGGAGCAATCACAGCTGCCCCGACCTTGGCTTCCTCTGCTGGGT GGG

ATTGGGGGCTGGGCCCCCAAATGGGCCCCTGGCTTCCCCCTTCCTCTGGGCAGGGGA CAG

AGAGACACAGGCTCGGGGAGCAGGACTGACTTCCTCTTGTCCCGGAATGAGCATGCC TGC

CCTTTGCAAGCAGGTTTGGGTCTCACGCAGAGGAAACCAAAAGCAATAAGAGGGAGG GAA

GGCAGAGCAACCAATCAAGGGCAGGGTGAGACTCAAAACGAGCGGGCTCCCTGGGGA GCC

AGACAGAGGCTGGGGGTGATGGCGGAGCTACAGCAGCTGCAGGAGTTTGAGATCCCC ACT

GGCCGGGAGGCTCTGAGGGGCAACCACAGTGCCCTGCTGCGGGTCGCTGACTACTGC GAG

GACAACTATGTGCAGGCCACAGACAAGCGGAAGGCGCTGGAGGAGACCATGGCCTTC ACT

ACCCAGGCACTGGCCAGCGTGGCCTACCAGGTGGGCAACCTGGCCGGGCACACTCTG CGC

ATGTTGGACCTGCAGGGGGCCGCCCTGCGGCAGGTGGAAGCCCGTGTAAGCACGCTG GGC

CAGATGGTGAACATGCATATGGAGAAGGTGGCCCGAAGGGAGATCGGCACCTTAGCC ACT

GTCCAGCGGCTGCCCCCCGGCCAGAAGGTCATCGCCCCAGAGAACCTACCCCCTCTC ACG CCCT ACT GCAGG AG ACCCCT CAACTTTGGCT GCCT GG ACG AC ATTGGCCATGGG AT CAAG

GACCTCAGCACGCAGCTGTCAAGAACAGGCACCCTGTCTCGAAAGAGCATCAAGGCC CCT

GCCACACCCGCCTCCGCCACCTTGGGGAGACCACCCCGGATTCCCGAGCCAGTGCAC CTG

CCGGTGGTGCCCGACGGCAGACTCTCCGCCGCCTCCTCTGCGTCTTCCCTGGCCTCG GCC

GGCAGCGCCGAAGGTGTCGGTGGGGCCCCCACGCCCAAGGGGCAGGCAGCACCTCCA GCC

CCACCTCTCCCCAGCTCCTTGGACCCACCTCCTCCACCAGCAGCCGTCGAGGTGTTC CAG

CGGCCTCCCACGCTGGAGGAGTTGTCCCCACCCCCACCGGACGAAGAGCTGCCCCTG CCA

CTGGACCTGCCTCCTCCTCCACCCCTGGATGGAGATGAATTGGGGCTGCCTCCACCC CCA

CCAGGATTTGGGCCTGATGAGCCCAGCTGGGTGCCTGCCTCATACTTGGAGAAAGTG GTG

ACACTGTACCCATACACCAGCCAGAAGGACAATGAGCTCTCCTTCTCTGAGGGCACT GTC

ATCTGTGTCACTCGCCGCTACTCCGATGGCTGGTGCGAGGGCGTCAGCTCAGAGGGG ACT

GGATTCTTCCCTGGGAACTATGTGGAGCCCAGCTGCTGACAGCCCAGGGCTCTCTGG GCA

GCTGATGTCTGCACTGAGTGGGTTTCATGAGCCCCAAGCCAAAACCAGCTCCAGTCA CAG

CTGGACTGGGTCTGCCCACCTCTTGGGCTGTGAGCTGTGTTCTGTCCTTCCTCCCAT CGG

AGGGAGAAGGGGTCCTGGGGAGAGAGAATTTATCCAGAGGCCTGCTGCAGATGGGGA AGA

GCTGGAAACCAAGAAGTTTGTCAACAGAGGACCCCTACTCCATGCAGGACAGGGTCT CCT

GCTGCAAGTCCCAACTTTGAATAAAACAGATGATGTCCTGTGACTGCCCCACAGAGA TAA

GGGGCCAGGAGGGATTGAAAGGCATCCCAGTTCTAAGGCTGCTGCTAATTACAGCCC CCA

ACCTCCAACCCACCAGCTGACCTAGAAGCAGCATCTTCCCATTTCCTCAGTACCCAC AAA

GTGCAGCCCACATT GG ACCCC AG ACACCCCT CTGCAGCC ATT G ACT GCAACTT GTTCTTT

T GCCCATTAAAAAAAAAAAAAAAAAAAAA

(SEQ ID NO: 2)

As used herein, the term “ADAM10” refers to the gene encoding ADAM Metallopeptidase Domain 10. The terms “ADAM10” and " ADAM Metallopeptidase Domain 10" include wild-type forms of the ADAM10 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type ADAM10. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type ADAM 10 nucleic acid sequence (e.g., SEQ ID NO: 3, NCBI Reference Sequence: NM_001110.3). SEQ ID NO: 3 is a wild-type gene sequence encoding ADAM10 protein, and is shown below:

GCGGCGGCAGGCCTAGCAGCACGGGAACCGTCCCCCGCGCGCATGCGCGCGCCCCTG AAGCGCC

TGGGGGACGGGTAGGGGCGGGAGGTAGGGGCGCGGCTCCGCGTGCCAGTTGGGTGCC CGCGCG

TCACGTGGTGAGGAAGGAGGCGGAGGTCTGAGTTTCGAAGGAGGGGGGGAGAGAAGA GGGAACG

AGCAAGGGAAGGAAAGCGGGGAAAGGAGGAAGGAAACGAACGAGGGGGAGGGAGGTC CCTGTTTT

GGAGGAGCTAGGAGCGTTGCCGGCCCCTGAAGTGGAGCGAGAGGGAGGTGCTTCGCC GTTTCTCC

TGCCAGGGGAGGTCCCGGCTTCCCGTGGAGGCTCCGGACCAAGCCCCTTCAGCTTCT CCCTCCGG

ATCGATGTGCTGCTGTTAACCCGTGAGGAGGCGGCGGCGGCGGCAGCGGCAGCGGAA GATGGTGT

TGCTGAGAGTGTTAATTCTGCTCCTCTCCTGGGCGGCGGGGATGGGAGGTCAGTATG GGAATCCTT

T AAATAAAT AT AT CAGAC ATTAT G AAGG ATT AT CTT ACAAT GTGGATTCATT ACACCAAAAACACCAGC

GTGCCAAAAGAGCAGTCTCACATGAAGACCAATTTTTACGTCTAGATTTCCATGCCC ATGGAAGACAT TTCAACCTACGAATGAAGAGGGACACTTCCCTTTTCAGTGATGAATTTAAAGTAGAAACA TCAAATAA

AGTACTTGATTATGATACCTCTCATATTTACACTGGACATATTTATGGTGAAGAAGG AAGTTTTAGCCA

TGGGTCTGTTATTGATGGAAGATTTGAAGGATTCATCCAGACTCGTGGTGGCACATT TTATGTTGAGC

CAGCAG AG AG AT AT ATT AAAGACCG AACT CTGCC ATTT CACT CTGTC ATTTAT CAT GAAGAT GAT ATTA

ACTATCCCCATAAATACGGTCCTCAGGGGGGCTGTGCAGATCATTCAGTATTTGAAA GAATGAGGAA

ATACCAGAT G ACT GGTGTAGAGGAAGT AACACAG AT ACCT CAAGAAGAACAT GCTGCT AATGGTCCA

G AACTTCT G AGG AAAAAACGT AC AACTTC AGCT G AAAAAAAT ACTTGT C AG CTTT AT ATT C AG ACT G A

TCATTTGTTCTTTAAATATTACGGAACACGAGAAGCTGTGATTGCCCAGATATCCAG TCATGTTAAAG

CGATTGATACAATTTACCAGACCACAGACTTCTCCGGAATCCGTAACATCAGTTTCA TGGTGAAACGC

ATAAGAATCAATACAACTGCTGATGAGAAGGACCCTACAAATCCTTTCCGTTTCCCA AATATTGGTGT

G G AG AAGTTT CTG G AATT G AATT CT G AGC AG AAT CAT G ATG ACT ACTGTTT GGCCTATGTCTT C AC AG

ACCGAGATTTTGATGATGGCGTACTTGGTCTGGCTTGGGTTGGAGCACCTTCAGGAA GCTCTGGAG

G AAT ATGT G AAAAAAGT AAACT CT ATT C AG AT G GT AAG AAG AAGTCCTT AAAC ACT G G AATT ATT ACT

GTTCAGAACTATGGGTCTCATGTACCTCCCAAAGTCTCTCACATTACTTTTGCTCAC GAAGTTGGACA

TAACTTTGGATCCCCACATGATTCTGGAACAGAGTGCACACCAGGAGAATCTAAGAA TTTGGGTCAA

AAAGAAAATGGCAATTACATCATGTATGCAAGAGCAACATCTGGGGACAAACTTAAC AACAATAAATT

CT CACT CT GT AGTATTAG AAATAT AAGCCAAGTTCTT G AG AAG AAG AG AAACAACT GTTTTGTT GAAT

CTGGCCAACCTATTTGTGGAAATGGAATGGTAGAACAAGGTGAAGAATGTGATTGTG GCTATAGTGA

CCAGTGTAAAGATGAATGCTGCTTCGATGCAAATCAACCAGAGGGAAGAAAATGCAA ACTGAAACCT

GGGAAACAGTGCAGTCCAAGTCAAGGTCCTTGTTGTACAGCACAGTGTGCATTCAAG TCAAAGTCTG

AGAAGTGTCGGGATGATTCAGACTGTGCAAGGGAAGGAATATGTAATGGCTTCACAG CTCTCTGCCC

AGCATCT G ACCCT AAACCAAACTT CACAG ACT GT AAT AGGC AT AC AC AAGTGT GCATT AATGGGCAAT

GTGCAGGTTCTATCTGTGAGAAATATGGCTTAGAGGAGTGTACGTGTGCCAGTTCTG ATGGCAAAGA

TGATAAAGAATTATGCCATGTATGCTGTATGAAGAAAATGGACCCATCAACTTGTGC CAGTACAGGGT

CTGTGCAGTGGAGTAGGCACTTCAGTGGTCGAACCATCACCCTGCAACCTGGATCCC CTTGCAACG

ATTTTAGAGGTTACTGTGATGTTTTCATGCGGTGCAGATTAGTAGATGCTGATGGTC CTCTAGCTAGG

CTTAAAAAAGCAATTTTTAGTCCAGAGCTCTATGAAAACATTGCTGAATGGATTGTG GCTCATTGGTG

GGCAGTATTACTTATGGGAATTGCTCTGATCATGCTAATGGCTGGATTTATTAAGAT ATGCAGTGTTC

ATACTCCAAGTAGTAATCCAAAGTTGCCTCCTCCTAAACCACTTCCAGGCACTTTAA AGAGGAGGAG

ACCTCCACAGCCCATTCAGCAACCCCAGCGTCAGCGGCCCCGAGAGAGTTATCAAAT GGGACACAT

GAGACGCTAACTGCAGCTTTTGCCTTGGTTCTTCCTAGTGCCTACAATGGGAAAACT TCACTCCAAA

GAGAAACCTATTAAGTCATCATCTCCAAACTAAACCCTCACAAGTAACAGTTGAAGA AAAAATGGCAA

GAGATCATATCCTCAGACCAGGTGGAATTACTTAAATTTTAAAGCCTGAAAATTCCA ATTTGGGGGTG

G G AGGT GG AAAAG G AACCC AATTTT CTT AT G AAC AG AT ATTTTT AACTT AAT G G C AC AAAGT CTT AG A

ATATTATTATGTGCCCCGTGTTCCCTGTTCTTCGTTGCTGCATTTTCTTCACTTGCA GGCAAACTTGG

CTCTCAATAAACTTTTACCACAAATTGAAATAAATATATTTTTTTCAACTGCCAATC AAGGCTAGGAGG

CTCGACC ACCT CAAC ATT GG AG ACATC ACTT GCC AAT GT ACAT ACCTT GTTATATGCAG ACAT GT ATT

TCTTACGTAC ACTGTACTTCTGTGT GC AATTGTAAAC AG AAATT G C AAT AT G GAT GTTT CTTTGTATT A

T AAAATTTTTCCG CT CTT AATT AAAAATT ACT GTTT AATT G AC AT ACT C AG GAT AAC AG AG AAT G GTG G

TATTCAGTGGTCCAGGATTCTGTAATGCTTTACACAGGCAGTTTTGAAATGAAAATC AATTTACCTTTC

TGTTACGATGGAGTTGGTTTTGATACTCATTTTTTCTTTATCACATGGCTGCTACGG GCACAAGTGAC

T ATACT G AAG AAC AC AG TT AAGT GTT GT GCAAACTGGACAT AGCAGCACAT ACT ACTTCAG AGTT CAT GATGTAGATGTCTGGTTTCTGCTTACGTCTTTTAAACTTTCTAATTCAATTCCATTTTTC AATTAATAGG T G AAATTTT ATT CAT G CTTT GAT AG AAATT ATGTC AAT G AAAT GATT CTTTTT ATTT GTAGCCTACTTAT TTGTGTTTTTCATATATCTGAAATATGCTAATTATGTTTTCTGTCTGATATGGAAAAGAA AAGCTGTGT CTTT AT C AAAAT ATTT AAACG GTTTTTT C AG CAT AT CAT C ACT GAT C ATT G GT AACC ACT A AAG AT GAG T AATTT GCTTAAGT AGTAGTT AAAATT GT AG AT AG G CCTTCT G AC ATTTTTTTTCCT AAAATTTTT AAC A GCATTGAAGGTGAAACAGCACAATGTCCCATTCCAAATTTATTTTTGAAACAGATGTAAA TAATTGGC ATTTTAAAGAGAAAGCAAAAACATTTAATGTATTAACAGGCTTATTGCTATGCAGGAAAT AGAAGGGG C ATT AC AAAAATT G AAGCTTGT G AC AT ATTT ATT G CTTCT GTTTTCC AACT AC AT C ACTT C AACT AG AA GTAAAGCTATGATTTTCCTGACTTCACATAGGAGGCAAATTTAGAGAAAGTTGTAAAGAT TTCTATGTT TTGGGTTTTTTTTTTTCCTTTTTTTTTTTAAGAGTATAAGGTTTACACAATCATTCTCAT AATGTGACGC AAGCCAGCAAGGCCAAAAATGCTAGAGAAAATAACGGGATCTCTTCCTTGTAAACTTGTA CAGTATGT GGT G ACTTTTT CAAAAT ACAGCTTTTTGTACAT G ATTT AG AG AC AAATTTT GTACAT G AAACCCC AG AT AG ACT AT AAAT AATT CT AAAC AAAC AAGTAG GT AG AT ATGTATGT AATT G CTTTT AAAT C ATTT AAAT G C CTTTGTTTTTGGACTGTGCAAAGGTTGGAAGTGGGTTTGCATTTCTAAAATGGTGACTTT TATTCTGC AAGAGTTCTTAGTAACTTCTTGAGTGTGGTAGACTTTGGAACATGTAAATTTTTTGCTTG TAATGTTAT CCTGTGGTAGGATTTTGGCAGGTACACACACTGCCCTATTTTATTTTGAGTCTAAGTTAA ATGTTTTCT G AAAAG AGAT ACAT GC ACT G AACTCTTTCC ACT GCGAAT CAAG AT GT GGTAAT AT AAAAGG AT CAAG A C AAAT GAG AT CT AAT ACT ACTGTC AGTTTT AAT GTCC ACTGT GTTTT ATAC AGTAT CTTTTTTT GTTC AC TTTGGAAATTTTTACT AAAAATTGCAAAAAAT AAAGTATT GT GCAAAG AT GT AAGGTTTTTT G AAACTT G AAAT GC ATT AAT AAAT AG ACG ATT AAAT C AACTT G AAG GTTCTATACT CTTT G AACT CT GAG AACT AT C ACAAGAAGCTTCCCACAAGGCAGTGTTTTCTTACAGTTGTCTCTTCCTACAAAAGTATAG ATTATCTTT ATTCTTAATACTTTGGAATCCATGTAGAAAATTTCCAGTTAGATACTCTGCGTACACACA ATAAACCTT TTTAAAACACCCAAAAAAAAAAAAAAAAAA (SEQ ID NO: 3)

The terms “APOC1” and " Apolipoprotein C1" include wild-type forms of the APOC1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type APOC1 . Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type APOC1 nucleic acid sequence (e.g.,

SEQ ID NO: 4, NCBI Reference Sequence: NM_001645). SEQ ID NO: 4 is a wild-type gene sequence encoding APOC1 protein, and is shown below:

AACGCTCACGGGACAGGGGCAGAGGAGAAAAACGTGGGTGGACAGAGGGAGGCAGGC GGTCAGG

GGAAGGCTCAGGAGGAGGGAGATCAACATCAACCTGCCCCGCCCCCTCCCCAGCCTG ATAAAGGT

CCTGCGGGCAGGACAGGACCTCCCAACCAAGCCCTCCAGCAAGGATTCAGAGTGCCC CTCCGGCC

TCGCCATGAGGCTCTTCCTGTCGCTCCCGGTCCTGGTGGTGGTTCTGTCGATCGTCT TGGAAGGCC

CAGCCCCAGCCCAGGGGACCCCAGACGTCTCCAGTGCCTTGGATAAGCTGAAGGAGT TTGGAAACA

CACTGGAGGACAAGGCTCGGGAACTCATCAGCCGCATCAAACAGAGTGAACTTTCTG CCAAGATGC

GGGAGT GGTTTT CAGAGACATTT CAGAAAGTG AAGGAGAAACT CAAG ATT G ACT CAT G AGGACCT G A

AGGGTGACATCCCAGGAGGGGCCTCTGAAATTTCCCACACCCCAGCGCCTGTGCTGA GGACTCCCT

CCATGTGGCCCCAGGTGCCACCAATAAAAATCCTACAGAAAATTCAAAAAAAAAAAA AAAAAA (SEQ ID NO: 4)

As used herein, the term “APOE” refers to the gene encoding Apolipoprotein E. The terms “APOE” and "Apolipoprotein E" include wild-type forms of the APOE gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type APOE. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type APOE nucleic acid sequence (e.g., SEQ ID NO: 5, ENA accession number M12529). SEQ ID NO: 5 is a wild-type gene sequence encoding APOE protein, and is shown below:

CCCCAGCGGAGGTGAAGGACGTCCTTCCCCAGGAGCCGACTGGCCAATCACAGGCAG GAA

GATGAAGGTTCTGTGGGCTGCGTTGCTGGTCACATTCCTGGCAGGATGCCAGGCCAA GGT

GGAGCAAGCGGTGGAGACAGAGCCGGAGCCCGAGCTGCGCCAGCAGACCGAGTGGCA GAG

CGGCCAGCGCTGGGAACTGGCACTGGGTCGCTTTTGGGATTACCTGCGCTGGGTGCA GAC

ACTGTCTGAGCAGGTGCAGGAGGAGCTGCTCAGCTCCCAAGTCACCCAAGAACTGAG GGC

GCTGATGGACGAGACCATGAAGGAGTTGAAGGCCTACAAATCGGAACTGGAGGAACA ACT

GACCCCGGTAGCGGAGGAGACGCGGGCACGGCTGTCCAAGGAGCTGCAGACGGCGCA GGC

CCGGCTGGGCGCGGACATGGAGGACGTGTGCGGCCGCCTGGTGCAGTACCGCGGCGA GGT

GCAGGCCATGCTCGGCCAGAGCACCGAGGAGCTGCGGGTGCGCCTCGCCTCCCACCT GCG

CAAGCTGCGTAAGCGGCTCCTCCGCGATCCCGATGACCTGCAGAAGCGCCTGGCAGT GTA

CCAGGCCGGGGCCCGCGAGGGCGCCGAGCGCGGCCTCAGCGCCATCCGCGAGCGCCT GGG

GCCCCTGGTGGAACAGGGCCGCGTGCGGGCCGCCACTGTGGGCTCCCTGGCCGGCCA GCC

GCTACAGGAGCGGGCCCAGGCCTGGGGCGAGCGGCTGCGCGCGCGGATGGAGGAGAT GGG

CAGTCGGACCCGCGACCGCCTGGACGAGGTGAAGGAGCAGGTGGCGGAGGTGCGCGC CAA

GCTGGAGGAGCAGGCCCAGCAGATACGCCTGCAGGCCGAGGCCTTCCAGGCCCGCCT CAA

GAGCTGGTTCGAGCCCCTGGTGGAAGACATGCAGCGCCAGTGGGCCGGGCTGGTGGA GAA

GGTGCAGGCTGCCGTGGGCACCAGCGCCGCCCCTGTGCCCAGCGACAATCACTGAAC GCC

GAAGCCTGCAGCCATGCGACCCCACGCCACCCCGTGCCTCCTGCCTCCGCGCAGCCT GCA

GCGGGAGACCCTGTCCCCGCCCCAGCCGTCCTCCTGGGGTGGACCCTAGTTTAATAA AGA

TTCACCAAGTTTCACGC

(SEQ ID NO: 5)

As used herein, the term “AXL” refers to the gene encoding Tyrosine-protein kinase receptor UFO. The terms “AXL” and "Tyrosine-protein kinase receptor UFO" include wild-type forms of the AXL gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type AXL. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type AXL nucleic acid sequence (e.g., SEQ ID NO: 6, ENA accession number M76125). SEQ ID NO: 6 is a wild-type gene sequence encoding AXL protein, and is shown below: GCTGGGCAAAGCCGGTGGCAAGGGCCTCCCCTGCCGCTGTGCCAGGCAGGCAGTGCCAAA

TCCGGGGAGCCTGGAGCTGGGGGGAGGGCCGGGGACAGCCCGGCCCTGCCCCCTCCC CCG

CTGGGAGCCCAGCAACTTCTGAGGAAAGTTTGGCACCCATGGCGTGGCGGTGCCCCA GGA

TGGGCAGGGTCCCGCTGGCCTGGTGCTTGGCGCTGTGCGGCTGGGCGTGCATGGCCC CCA

GGGGCACGCAGGCTGAAGAAAGTCCCTTCGTGGGCAACCCAGGGAATATCACAGGTG CCC

GGGGACTCACGGGCACCCTTCGGTGTCAGCTCCAGGTTCAGGGAGAGCCCCCCGAGG TAC

ATTGGCTTCGGGATGGACAGATCCTGGAGCTCGCGGACAGCACCCAGACCCAGGTGC CCC

TGGGTGAGGATGAACAGGATGACTGGATAGTGGTCAGCCAGCTCAGAATCACCTCCC TGC

AGCTTTCCGACACGGGACAGTACCAGTGTTTGGTGTTTCTGGGACATCAGACCTTCG TGT

CCCAGCCTGGCTATGTTGGGCTGGAGGGCTTGCCTTACTTCCTGGAGGAGCCCGAAG ACA

GGACTGTGGCCGCCAACACCCCCTTCAACCTGAGCTGCCAAGCTCAGGGACCCCCAG AGC

CCGTGGACCTACTCTGGCTCCAGGATGCTGTCCCCCTGGCCACGGCTCCAGGTCACG GCC

CCCAGCGCAGCCTGCATGTTCCAGGGCTGAACAAGACATCCTCTTTCTCCTGCGAAG CCC

ATAACGCCAAGGGGGTCACCACATCCCGCACAGCCACCATCACAGTGCTCCCCCAGC AGC

CCCGTAACCTCCACCTGGTCTCCCGCCAACCCACGGAGCTGGAGGTGGCTTGGACTC CAG

GCCT GAGCGGCATCTACCCCCT GACCCACT GCACCCTGCAGGCT GT GCTGTCAGACGAT G

GGATGGGCATCCAGGCGGGAGAACCAGACCCCCCAGAGGAGCCCCTCACCTCGCAAG CAT

CCGTGCCCCCCCATCAGCTTCGGCTAGGCAGCCTCCATCCTCACACCCCTTATCACA TCC

GCGTGGCATGCACCAGCAGCCAGGGCCCCTCATCCTGGACCCACTGGCTTCCTGTGG AGA

CGCCGGAGGGAGTGCCCCTGGGCCCCCCTAAGAACATTAGTGCTACGCGGAATGGGA GCC

AGGCCTTCGTGCATTGGCAAGAGCCCCGGGCGCCCCTGCAGGGTACCCTGTTAGGGT ACC

GGCTGGCGTATCAAGGCCAGGACACCCCAGAGGTGCTAATGGACATAGGGCTAAGGC AAG

AGGTGACCCTGGAGCTGCAGGGGGACGGGTCTGTGTCCAATCTGACAGTGTGTGTGG CAG

CCTACACTGCTGCTGGGGATGGACCCTGGAGCCTCCCAGTACCCCTGGAGGCCTGGC GCC

CAGTGAAGGAACCTTCAACTCCTGCCTTCTCGTGGCCCTGGTGGTATGTACTGCTAG GAG

CAGTCGTGGCCGCTGCCTGTGTCCTCATCTTGGCTCTCTTCCTTGTCCACCGGCGAA AGA

AGG AGACCCGTT AT GG AGAAGTGTTT GAACCAAC AGTGG AAAGAGGTG AACTGGTAGT CA

GGTACCGCGTGCGCAAGTCCTACAGTCGTCGGACCACTGAAGCTACCTTGAACAGCC TGG

GCATCAGT GAAGAGCT GAAGGAGAAGCT GCGGGAT GT GATGGTGGACCGGCACAAGGTGG

CCCTGGGGAAGACTCTGGGAGAGGGAGAGTTTGGAGCTGTGATGGAAGGCCAGCTCA ACC

AGGACGACTCCATCCTCAAGGTGGCTGTGAAGACGATGAAGATTGCCATCTGCACGA GGT

CAGAGCTGGAGGATTTCCTGAGTGAAGCGGTCTGCATGAAGGAATTTGACCATCCCA ACG

TCATGAGGCTCATCGGTGTCTGTTTCCAGGGTTCTGAACGAGAGAGCTTCCCAGCAC CTG

TGGTCATCTTACCTTTCATGAAACATGGAGACCTACACAGCTTCCTCCTCTATTCCC GGC

TCGGGGACCAGCCAGTGTACCTGCCCACTCAGATGCTAGTGAAGTTCATGGCAGACA TCG

CCAGTGGCATGGAGTATCTGAGTACCAAGAGATTCATACACCGGGACCTGGCGGCCA GGA

ACTGCATGCTGAATGAGAACATGTCCGTGTGTGTGGCGGACTTCGGGCTCTCCAAGA AGA

TCTACAATGGGGACTACTACCGCCAGGGACGTATCGCCAAGATGCCAGTCAAGTGGA TTG

CCATTGAGAGTCTAGCTGACCGTGTCTACACCAGCAAGAGCGATGTGTGGTCCTTCG GGG

TGACAATGTGGGAGATTGCCACAAGAGGCCAAACCCCATATCCGGGCGTGGAGAACA GCG

AGATTTATGACTATCTGCGCCAGGGAAATCGCCTGAAGCAGCCTGCGGACTGTCTGG ATG

GACTGTATGCCTTGATGTCGCGGTGCTGGGAGCTAAATCCCCAGGACCGGCCAAGTT TTA CAGAGCTGCGGGAAGATTTGGAGAACACACTGAAGGCCTTGCCTCCTGCCCAGGAGCCTG

ACGAAATCCTCTATGTCAACATGGATGAGGGTGGAGGTTATCCTGAACCCCCTGGAG CTG

CAGGAGGAGCTGACCCCCCAACCCAGCCAGACCCTAAGGATTCCTGTAGCTGCCTCA CTG

CGGCTGAGGTCCATCCTGCTGGACGCTATGTCCTCTGCCCTTCCACAACCCCTAGCC CCG

CTCAGCCTGCTGATAGGGGCTCCCCAGCAGCCCCAGGGCAGGAGGATGGTGCCTGAG ACA

ACCCTCCACCTGGTACTCCCTCTCAGGATCCAAGCTAAGCACTGCCACTGGGGAAAA CTC

CACCTTCCCACTTTTCCACCCCACGCCTTATCCCCACTTGCAGCCCTGTCTTCCTAC CTA

TCCCACCTCCATCCCAGACAGGTCCCTCCCCTTCTCTGTGCAGTAGCATCACCTTGA AAG

CAGTAGCATCACCATCTGTAAAAGGAAGGGGTTGGATTGCAATATCTGAAGCCCTCC CAG

GTGTTAACATTCCAAGACTCTAGAGTCCAAGGTTTAAAGAGTCTAGATTCAAAGGTT CTA

GGTTTCAAAGATGCTGTGAGTCTTTGGTTCTAAGGACCTGAAATTCCAAAGTCTCTA ATT

CT ATT AAAGT GOT AAG GTT CT AAGG C AAAAAAAAAAAAAAAAAAAAA

(SEQ ID NO: 6)

As used herein, the term “BIN refers to the gene encoding Myc box-dependent-interacting protein 1. The terms “BIN and "Myc box-dependent-interacting protein 1" include wild-type forms of the BIN1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type BIN1. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type BIN1 nucleic acid sequence (e.g., SEQ ID NO: 7, ENA accession number AF004015). SEQ ID NO: 7 is a wild-type gene sequence encoding BIN1 protein, and is shown below:

ATGGCAGAGATGGGCAGTAAAGGGGTGACGGCGGGAAAGATCGCCAGCAACGTGCAG AAG

AAGCTCACCCGCGCGCAGGAGAAGGTTCTCCAGAAGCTGGGGAAGGCAGATGAGACC AAG

GATGAGCAGTTTGAGCAGTGCGTCCAGAATTTCAACAAGCAGCTGACGGAGGGCACC CGG

CTGCAGAAGGATCTCCGGACCTACCTGGCCTCCGTCAAAGCCATGCACGAGGCTTCC AAG

AAGCTGAATGAGTGTCTGCAGGAGGTGTATGAGCCCGATTGGCCCGGCAGGGATGAG GCA

AACAAGATCGCAGAGAACAACGACCTGCTGTGGATGGATTACCACCAGAAGCTGGTG GAC

CAGGCGCTGCTGACCATGGACACGTACCTGGGCCAGTTCCCCGACATCAAGTCACGC ATT

GCCAAGCGGGGGCGCAAGCTGGTGGACTACGACAGTGCCCGGCACCACTACGAGTCC CTT

CAAACCGCCAAAAAGAAGGATGAAGCCAAAATTGCCAAGCCTGTCTCGCTGCTTGAG AAA

GCCGCCCCCCAGTGGTGCCAAGGCAAACTGCAGGCTCATCTCGTAGCTCAAACTAAC CTG

CTCCGAAATCAGGCCGAGGAGGAGCTCATCAAAGCCCAGAAGGTGTTTGAGGAGATG AAT

GTGGATCTGCAGGAGGAGCTGCCGTCCCTGTGGAACAGCCGCGTAGGTTTCTACGTC AAC

ACGTTCCAGAGCATCGCGGGCCTGGAGGAAAACTTCCACAAGGAGATGAGCAAGCTC AAC

CAGAACCTCAATGATGTGCTGGTCGGCCTGGAGAAGCAACACGGGAGCAACACCTTC ACG

GTCAAGGCCCAGCCCAGTGACAACGCGCCTGCAAAAGGGAACAAGAGCCCTTCGCCT CCA

GATGGCTCCCCTGCCGCCACCCCCGAGATCAGAGTCAACCACGAGCCAGAGCCGGCC GGC

GGGGCCACGCCCGGGGCCACCCTCCCCAAGTCCCCATCTCAGCTCCGGAAAGGCCCA CCA

GTCCCTCCGCCTCCCAAACACACCCCGTCCAAGGAAGTCAAGCAGGAGCAGATCCTC AGC

CTGTTTGAGGACACGTTTGTCCCTGAGATCAGCGTGACCACCCCCTCCCAGTTTGAG GCC CCGGGGCCTTTCTCGGAGCAGGCCAGTCTGCTGGACCTGGACTTTGACCCCCTCCCGCCC

GTGACGAGCCCTGTGAAGGCACCCACGCCCTCTGGTCAGTCAATTCCATGGGACCTC TGG

GAGCCCACAGAGAGTCCAGCCGGCAGCCTGCCTTCCGGGGAGCCCAGCGCTGCCGAG GGC

ACCTTT GCT GT GTCCTGGCCCAGCCAGACGGCCGAGCCGGGGCCT GCCCAACCAGCAGAG

GCCTCGGAGGTGGCGGGTGGGACCCAACCTGCGGCTGGAGCCCAGGAGCCAGGGGAG ACG

GCGGCAAGTGAAGCAGCCTCCAGCTCTCTTCCTGCTGTCGTGGTGGAGACCTTCCCA GCA

ACTGTGAATGGCACCGTGGAGGGCGGCAGTGGGGCCGGGCGCTTGGACCTGCCCCCA GGT

TTCATGTTCAAGGTACAGGCCCAGCACGACTACACGGCCACTGACACAGACGAGCTG CAG

CTCAAGGCTGGTGATGTGGTGCTGGTGATCCCCTTCCAGAACCCTGAAGAGCAGGAT GAA

GGCTGGCTCATGGGCGTGAAGGAGAGCGACTGGAACCAGCACAAGGAGCTGGAGAAG TGC

CGTGGCGTCTTCCCCGAGAACTTCACTGAGAGGGTCCCATGA

(SEQ ID NO: 7)

As used herein, the term “C1QA” refers to the gene encoding Complement C1q A Chain. The terms “C1QA” and " Complement C1q A Chain " include wild-type forms of the C1 QA gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type C1QA. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type C1QA nucleic acid sequence (e.g., SEQ ID NO: 8, NCBI Reference Sequence: NM_015991 .3). SEQ ID NO: 8 is a wild-type gene sequence encoding C1QA protein, and is shown below:

AGTCTTGCTGAAGTCTGCTTGAAATGTCCCTGGTGAGCTTCTGGCCACTGGGGAAGT TCAGGGGGC

AGGTCTGAAGAAGGGGAAGTAGGAAGGGATGTGAAACTTGGCCACAGCCTGGAGCCA CTCCTGCTG

GGCAGCCCACAGGGTCCCTGGGCGGAGGGCAGGAGCATCCAGTTGGAGTTGACAACA GGAGGCA

GAGGCATCATGGAGGGTCCCCGGGGATGGCTGGTGCTCTGTGTGCTGGCCATATCGC TGGCCTCT

ATGGTGACCGAGGACTTGTGCCGAGCACCAGACGGGAAGAAAGGGGAGGCAGGAAGA CCTGGCAG

ACGGGGGCGGCCAGGCCTCAAGGGGGAGCAAGGGGAGCCGGGGGCCCCTGGCATCCG GACAGG

CATCCAAGGCCTTAAAGGAGACCAGGGGGAACCTGGGCCCTCTGGAAACCCCGGCAA GGTGGGCT

ACCCAGGGCCCAGCGGCCCCCTCGGAGCCCGTGGCATCCCGGGAATTAAAGGCACCA AGGGCAGC

CCAGGAAACATCAAGGACCAGCCGAGGCCAGCCTTCTCCGCCATTCGGCGGAACCCC CCAATGGG

GGGCAACGTGGTCATCTTCGACACGGTCATCACCAACCAGGAAGAACCGTACCAGAA CCACTCCGG

CCGATTCGTCTGCACTGTACCCGGCTACTACTACTTCACCTTCCAGGTGCTGTCCCA GTGGGAAATC

TGCCTGTCCATCGTCTCCTCCTCAAGGGGCCAGGTCCGACGCTCCCTGGGCTTCTGT GACACCACC

AACAAGGGGCTCTTCCAGGTGGTGTCAGGGGGCATGGTGCTTCAGCTGCAGCAGGGT GACCAGGT

CTGGGTTGAAAAAGACCCCAAAAAGGGTCACATTTACCAGGGCTCTGAGGCCGACAG CGTCTTCAG

CGGCTTCCTCATCTTCCCATCTGCCTGAGCCAGGGAAGGACCCCCTCCCCCACCCAC CTCTCTGGC

TTCCATGCTCCGCCTGTAAAATGGGGGCGCTATTGCTTCAGCTGCTGAAGGGAGGGG GCTGGCTCT

GAGAGCCCCAGGACTGGCTGCCCCGTGACACATGCTCTAAGAAGCTCGTTTCTTAGA CCTCTTCCTG

GAATAAACATCTGTGTCTGTGTCTGCTGAACATGAGCTTCAGTTGCTACTCGGAGCA TTGAGAGGGA

GGCCTAAGAATAATAACAATCCAGTGCTTAAGAGTCAAAAAAAAAAAA

(SEQ ID NO: 8) As used herein, the term “C3” refers to the gene encoding Complement C3. The terms “C3” and " Complement C3 " include wild-type forms of the C3 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type C3. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type C3 nucleic acid sequence (e.g., SEQ ID NO: 9, NCBI Reference Sequence: NM_000064.3). SEQ ID NO: 9 is a wild-type gene sequence encoding C3 protein, and is shown below:

AGATAAAAAGCCAGCTCCAGCAGGCGCTGCTCACTCCTCCCCATCCTCTCCCTCTGT CCCTCTGTCC

CTCTGACCCTGCACTGTCCCAGCACCATGGGACCCACCTCAGGTCCCAGCCTGCTGC TCCTGCTAC

TAACCCACCTCCCCCTGGCTCTGGGGAGTCCCATGTACTCTATCATCACCCCCAACA TCTTGCGGCT

GGAGAGCGAGGAGACCATGGTGCTGGAGGCCCACGACGCGCAAGGGGATGTTCCAGT CACTGTTA

CT GTCCACGACTTCCCAGGCAAAAAACTAGT GCT GTCCAGT GAGAAGACT GTGCTGACCCCT GCCA

CCAACCACATGGGCAACGTCACCTTCACGATCCCAGCCAACAGGGAGTTCAAGTCAG AAAAGGGGC

GCAACAAGTTCGTGACCGTGCAGGCCACCTTCGGGACCCAAGTGGTGGAGAAGGTGG TGCTGGTC

AGCCTGCAGAGCGGGTACCTCTTCATCCAGACAGACAAGACCATCTACACCCCTGGC TCCACAGTT

CTCTATCGGATCTTCACCGTCAACCACAAGCTGCTACCCGTGGGCCGGACGGTCATG GTCAACATT

GAGAACCCGGAAGGCATCCCGGTCAAGCAGGACTCCTTGTCTTCTCAGAACCAGCTT GGCGTCTTG

CCCTTGTCTTGGGACATTCCGGAACTCGTCAACATGGGCCAGTGGAAGATCCGAGCC TACTATGAAA

ACTCACCACAGCAGGTCTTCTCCACTGAGTTTGAGGTGAAGGAGTACGTGCTGCCCA GTTTCGAGGT

CATAGTGGAGCCTACAGAGAAATTCTACTACATCTATAACGAGAAGGGCCTGGAGGT CACCATCACC

GCCAGGTTCCTCTACGGGAAGAAAGTGGAGGGAACTGCCTTTGTCATCTTCGGGATC CAGGATGGC

GAACAGAGGATTTCCCTGCCTGAATCCCTCAAGCGCATTCCGATTGAGGATGGCTCG GGGGAGGTT

GTGCTGAGCCGGAAGGTACTGCTGGACGGGGTGCAGAACCCCCGAGCAGAAGACCTG GTGGGGAA

GTCTTTGTACGTGTCTGCCACCGTCATCTTGCACTCAGGCAGTGACATGGTGCAGGC AGAGCGCAG

CGGGATCCCCATCGTGACCTCTCCCTACCAGATCCACTTCACCAAGACACCCAAGTA CTTCAAACCA

GGAATGCCCTTTGACCTCATGGTGTTCGTGACGAACCCTGATGGCTCTCCAGCCTAC CGAGTCCCC

GTGGCAGTCCAGGGCGAGGACACTGTGCAGTCTCTAACCCAGGGAGATGGCGTGGCC AAACTCAG

CATCAACACACACCCCAGCCAGAAGCCCTTGAGCATCACGGTGCGCACGAAGAAGCA GGAGCTCTC

GGAGGCAGAGCAGGCTACCAGGACCATGCAGGCTCTGCCCTACAGCACCGTGGGCAA CTCCAACA

ATTACCTGCATCTCTCAGTGCTACGTACAGAGCTCAGACCCGGGGAGACCCTCAACG TCAACTTCCT

CCTGCGAATGGACCGCGCCCACGAGGCCAAGATCCGCTACTACACCTACCTGATCAT GAACAAGGG

CAGGCTGTTGAAGGCGGGACGCCAGGTGCGAGAGCCCGGCCAGGACCTGGTGGTGCT GCCCCTG

TCCATCACCACCGACTTCATCCCTTCCTTCCGCCTGGTGGCGTACTACACGCTGATC GGTGCCAGC

GGCCAGAGGGAGGTGGTGGCCGACTCCGTGTGGGTGGACGTCAAGGACTCCTGCGTG GGCTCGCT

GGTGGTAAAAAGCGGCCAGTCAGAAGACCGGCAGCCTGTACCTGGGCAGCAGATGAC CCTGAAGA

TAGAGGGTGACCACGGGGCCCGGGTGGTACTGGTGGCCGTGGACAAGGGCGTGTTCG TGCTGAAT

AAGAAGAACAAACTGACGCAGAGTAAGATCTGGGACGTGGTGGAGAAGGCAGACATC GGCTGCACC

CCGGGCAGTGGGAAGGATTACGCCGGTGTCTTCTCCGACGCAGGGCTGACCTTCACG AGCAGCAG

TGGCCAGCAGACCGCCCAGAGGGCAGAACTTCAGTGCCCGCAGCCAGCCGCCCGCCG ACGCCGTT CCGTGCAGCTCACGGAGAAGCGAATGGACAAAGTCGGCAAGTACCCCAAGGAGCTGCGCA AGTGC TGCGAGGACGGCATGCGGGAGAACCCCATGAGGTTCTCGTGCCAGCGCCGGACCCGTTTC ATCTC CCTGGGCGAGGCGTGCAAGAAGGTCTTCCTGGACTGCTGCAACTACATCACAGAGCTGCG GCGGC AGCACGCGCGGGCCAGCCACCTGGGCCTGGCCAGGAGTAACCTGGATGAGGACATCATTG CAGAA G AG AACATCGTTTCCCG AAGT GAGTTCCCAG AG AGCT GGCTGT GG AACGTT GAGG ACTT GAAAG AG CCACCGAAAAATGGAATCTCTACGAAGCTCATGAATATATTTTTGAAAGACTCCATCACC ACGTGGGA GATTCTGGCTGTGAGCATGTCGGACAAGAAAGGGATCTGTGTGGCAGACCCCTTCGAGGT CACAGT AATGCAGGACTTCTTCATCGACCTGCGGCTACCCTACTCTGTTGTTCGAAACGAGCAGGT GGAAATC CGAGCCGTTCTCTACAATTACCGGCAGAACCAAGAGCTCAAGGTGAGGGTGGAACTACTC CACAAT CCAGCCTTCTGCAGCCTGGCCACCACCAAGAGGCGTCACCAGCAGACCGTAACCATCCCC CCCAAG TCCTCGTTGTCCGTTCCATATGTCATCGTGCCGCTAAAGACCGGCCTGCAGGAAGTGGAA GTCAAG GCTGCTGTCTACCATCATTTCATCAGTGACGGTGTCAGGAAGTCCCTGAAGGTCGTGCCG GAAGGA ATCAGAATGAACAAAACTGTGGCTGTTCGCACCCTGGATCCAGAACGCCTGGGCCGTGAA GGAGTG CAGAAAGAGGACATCCCACCTGCAGACCTCAGTGACCAAGTCCCGGACACCGAGTCTGAG ACCAGA ATTCTCCTGCAAGGGACCCCAGTGGCCCAGATGACAGAGGATGCCGTCGACGCGGAACGG CTGAA GCACCTCATTGTGACCCCCTCGGGCTGCGGGGAACAGAACATGATCGGCATGACGCCCAC GGTCAT CGCTGTGCATTACCTGGATGAAACGGAGCAGTGGGAGAAGTTCGGCCTAGAGAAGCGGCA GGGGG CCTTGGAGCTCATCAAGAAGGGGTACACCCAGCAGCTGGCCTTCAGACAACCCAGCTCTG CCTTTG CGGCCTTCGTGAAACGGGCACCCAGCACCTGGCTGACCGCCTACGTGGTCAAGGTCTTCT CTCTGG CTGTCAACCTCATCGCCATCGACTCCCAAGTCCTCTGCGGGGCTGTTAAATGGCTGATCC TGGAGAA GCAGAAGCCCGACGGGGTCTTCCAGGAGGATGCGCCCGTGATACACCAAGAAATGATTGG TGGATT ACGGAACAACAACGAGAAAGACATGGCCCTCACGGCCTTTGTTCTCATCTCGCTGCAGGA GGCTAA AGATATTTGCGAGGAGCAGGTCAACAGCCTGCCAGGCAGCATCACTAAAGCAGGAGACTT CCTTGA AGCCAACTACATGAACCTACAGAGATCCTACACTGTGGCCATTGCTGGCTATGCTCTGGC CCAGATG GGCAGGCTGAAGGGGCCTCTTCTTAACAAATTTCTGACCACAGCCAAAGATAAGAACCGC TGGGAG GACCCTGGTAAGCAGCTCTACAACGTGGAGGCCACATCCTATGCCCTCTTGGCCCTACTG CAGCTA AAAG ACTTT G ACTTTGTGCCTCCCGTCGT GCGTTGGCT CAAT G AAC AG AG AT ACT ACGGTGGTGGCT ATGGCTCTACCCAGGCCACCTTCATGGTGTTCCAAGCCTTGGCTCAATACCAAAAGGACG CCCCTGA CCACCAGGAACTGAACCTTGATGTGTCCCTCCAACTGCCCAGCCGCAGCTCCAAGATCAC CCACCG TATCCACTGGGAATCTGCCAGCCTCCTGCGATCAGAAGAGACCAAGGAAAATGAGGGTTT CACAGTC ACAGCTGAAGGAAAAGGCCAAGGCACCTTGTCGGTGGTGACAATGTACCATGCTAAGGCC AAAGAT CAACTCACCTGTAATAAATTCGACCTCAAGGTCACCATAAAACCAGCACCGGAAACAGAA AAGAGGC CTCAGGATGCCAAGAACACTATGATCCTTGAGATCTGTACCAGGTACCGGGGAGACCAGG ATGCCA CTATGTCTATATTGGACATATCCATGATGACTGGCTTTGCTCCAGACACAGATGACCTGA AGCAGCT GGCCAATGGTGTTGACAGATACATCTCCAAGTATGAGCTGGACAAAGCCTTCTCCGATAG GAACACC CTCATCATCTACCTGGACAAGGTCTCACACTCTGAGGATGACTGTCTAGCTTTCAAAGTT CACCAATA CTTTAATGTAGAGCTTATCCAGCCTGGAGCAGTCAAGGTCTACGCCTATTACAACCTGGA GGAAAGC T GTACCCGGTT CTACCATCCGGAAAAGG AGG AT GG AAAGCT GAACAAGCT CT GCCGTG AT G AACT G TGCCGCTGTGCTGAGGAGAATTGCTTCATACAAAAGTCGGATGACAAGGTCACCCTGGAA GAACGG CTGGACAAGGCCTGTGAGCCAGGAGTGGACTATGTGTACAAGACCCGACTGGTCAAGGTT CAGCTG TCCAATGACTTTGACGAGTACATCATGGCCATTGAGCAGACCATCAAGTCAGGCTCGGAT GAGGTGC AGGTTGGACAGCAGCGCACGTTCATCAGCCCCATCAAGTGCAGAGAAGCCCTGAAGCTGG AGGAGA AGAAACACTACCTCATGTGGGGTCTCTCCTCCGATTTCTGGGGAGAGAAGCCCAACCTCA GCTACAT CATCGGGAAGGACACTTGGGTGGAGCACTGGCCCGAGGAGGACGAATGCCAAGACGAAGA GAACC AGAAACAATGCCAGGACCTCGGCGCCTTCACCGAGAGCATGGTTGTCTTTGGGTGCCCCA ACTGAC CACACCCCCATTCCCCCACTCCAGATAAAGCTTCAGTTATATCTCAAAAAAAAAAAAAAA AA (SEQ ID NO: 9)

As used herein, the term “C9orf72” refers to the gene encoding Guanine nucleotide exchange C9orf72. The terms “C9orf72” and "Guanine nucleotide exchange C9orf72" include wild-type forms of the C9orf72 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type C9orf72. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type C9orf72 nucleic acid sequence (e.g., SEQ ID NO: 10, ENA accession number JN681271). SEQ ID NO: 10 is a wild-type gene sequence encoding C9orf72 protein, and is shown below:

AGG AAAGAG AGGTGCGT CAAACAGCG ACAAGTTCCGCCCACGTAAAAG AT G ACGCTT GGT

GTGTCAGCCGTCCCTGCTGCCCGGTTGCTTCTCTTTTGGGGGCGGGGTCTAGCAAGA GCA

GGTGTGGGTTTAGGAGATATCTCCGGAGCATTTGGATAATGTGACAGTTGGAATGCA GTG

ATGTCGACTCTTTGCCCACCGCCATCTCCAGCTGTTGCCAAGACAGAGATTGCTTTA AGT

GGCAAATCACCTTTATTAGCAGCTACTTTTGCTTACTGGGACAATATTCTTGGTCCT AGA

GTAAGGCACATTTGGGCTCCAAAGACAGAACAGGTACTTCTCAGTGATGGAGAAATA ACT

TTTCTTGCCAACCACACTCTAAATGGAGAAATCCTTCGAAATGCAGAGAGTGGTGCT ATA

GAT GTAAAGTTTTTTGTCTTGTCT GAAAAGGG AGT GATT ATTGTTT CATTAAT CTTT GAT

GGAAACTGGAATGGGGATCGCAGCACATATGGACTATCAATTATACTTCCACAGACA GAA

CTTAGTTTCTACCTCCCACTTCATAGAGTGTGTGTTGATAGATTAACACATATAATC CGG

AAAG G AAG AAT ATGG ATG CAT AAG G AAAG AC AAG AAAAT GTCC AG AAG ATT AT CTT AG AA

GGCACAGAGAGAATGGAAGATCAGGGTCAGAGTATTATTCCAATGCTTACTGGAGAA GTG

ATTCCT GT AAT GG AACT GCTTTCATCT AT G AAATCACACAGTGTTCCT G AAG AAAT AG AT

ATAGCTG ATAC AGTACT C AAT GAT GAT GAT ATT GGT G AC AG CTGT CAT G AAG GCTTT CTT

CTCAATGCCATCAGCTCACACTTGCAAACCTGTGGCTGTTCCGTTGTAGTAGGTAGC AGT

GCAGAGAAAGTAAATAAGATAGTCAGAACATTATGCCTTTTTCTGACTCCAGCAGAG AGA

AAATGCTCCAGGTTATGTGAAGCAGAATCATCATTTAAATATGAGTCAGGGCTCTTT GTA

CAAGGCCTGCTAAAGGATTCAACTGGAAGCTTTGTGCTGCCTTTCCGGCAAGTCATG TAT

GCTCCATATCCCACCACACACATAGATGTGGATGTCAATACTGTGAAGCAGATGCCA CCC

TGTCATGAACATATTTATAATCAGCGTAGATACATGAGATCCGAGCTGACAGCCTTC TGG

AGAGCCACTT CAGAAGAAGACATGGCTCAGG AT ACG AT CAT CT AC ACT GACGAAAGCTTT

ACTCCT G ATTT G AAT ATTTTT C AAG AT GTCTT AC AC AG AG AC ACT CT AGTG AAAG CCTT C

CTGGATCAGGTCTTTCAGCTGAAACCTGGCTTATCTCTCAGAAGTACTTTCCTTGCA CAG

TTTCT ACTTGTCCTTCACAGAAAAGCCTT G AC ACT AAT AAAAT AT ATAGAAGACG AT ACG

CAGAAGGGAAAAAAGCCCTTTAAATCTCTTCGGAACCTGAAGATAGACCTTGATTTA ACA

GCAGAGGGCGATCTTAACATAATAATGGCTCTGGCTGAGAAAATTAAACCAGGCCTA CAC

T CTTTT AT CTTT GG AAG ACCTTT CTAC ACT AGTGT G C AAG AACG AG AT GTTCT AAT G ACT TTTT AAAT GTGT AACTT AAT AAGCCT ATT C CAT C AC AAT CAT G ATCG CT G GT AAAGT AG C TCAGTGGTGTGGGGAAACGTTCCCCTGGATCATACTCCAGAATTCTGCTCTCAGCAATTG CAGTTAAGTAAGTTACACTACAGTTCTCACAAGAGCCTGTGAGGGGATGTCAGGTGCATC ATTACATTGGGTGTCTCTTTTCCTAGATTTATGCTTTTGGGATACAGACCTATGTTTACA AT AT AAT AAAT ATT ATT G CTAT CTTTT AAAG AT AT AAT AAT AGG ATGT AAACTT G ACC AC AACT ACT GTTTTTTT GAAAT AC AT GATTC AT GGTTTACAT GTGTC AAGGTG AAAT CT GAG TTGG CTTTT AC AG AT AGTT G ACTTT CTAT CTTTT GG C ATT CTTT G GTGTGT AG AATT ACT GTAATACTTCTGCAATCAACTGAAAACTAGAGCCTTTAAATGATTTCAATTCCACAGAAA G AAAGT GAG CTT G AAC AT AGG AT GAG CTTT AG AAAG AAAATT GAT C AAGC AG ATGTTT AA TTGGAATTGATTATTAGATCCTACTTTGTGGATTTAGTCCCTGGGATTCAGTCTGTAGAA ATGTCTAATAGTTCTCTATAGTCCTTGTTCCTGGTGAACCACAGTTAGGGTGTTTTGTTT ATTTT ATT GTTCTTGCT ATT GTT GAT ATT CTATGTAGTT GAG CTCTGT AAAAG G AAATT G T ATTTT AT GTTTT AGT AATTGTT GCCAACTTTTTAAATT AATTTTCATT ATTTTT G AGCC AAATTGAAATGTGCACCTCCTGTGCCTTTTTTCTCCTTAGAAAATCTAATTACTTGGAAC AAGTTCAGATTTCACTGGTCAGTCATTTTCATCTTGTTTTCTTCTTGCTAAGTCTTACCA TGTACCTG CTTT G GC AAT C ATT G C AACT CT GAG ATT AT AAAAT G CCTT AG AG AAT AT ACT AACT AAT AAGATCTTTTTTT CAG AAAC AG AAAAT AGTTCCTT G AGTACTTCCTT CTT GCA TTTCTGCCTATGTTTTTGAAGTTGTTGCTGTTTGCCTGCAATAGGCTATAAGGAATAGCA GGAGAAATTTTACTGAAGTGCTGTTTTCCTAGGTGCTACTTTGGCAGAGCTAAGTTATCT TTTGTTTT CTT AATGCGTTTGGACCATTTT GCT GGCTATAAAAT AACT GATT AAT AT AAT TCT AAC AC AAT GTT G AC ATT GTAGTT AC AC AAAC AC AAAT AAAT ATTTT ATTT AAAATT C TGGAAGTAATATAAAAGGGAAAATATATTTATAAGAAAGGGATAAAGGTAATAGAGCCCT TCTGCCCCCCACCCACCAAATTTACACAACAAAATGACATGTTCGAATGTGAAAGGTCAT AAT AGCTTTCCC AT CAT G AATC AG AAAG ATGTGGACAGCTT GAT GTTTT AG ACAACCACT G AACT AGAT G ACTGTT GT ACTGTAGCT CAGT CATTTAAAAAAT AT AT AAAT ACTACCTT G TAGTGTCCCATACTGTGTTTTTTACATGGTAGATTCTT ATTT AAGTGCTAACTGGTT ATT TTCTTTGGCTGGTTTATTGTACTGTTATACAGAATGTAAGTTGTACAGTGAAATAAGTTA TTAAAGCATGTGTAAAC ATTGTT AT AT AT CTTTTCTCCT AAATGGAGAATTTT G AAT AAA AT AT ATTT G AAATTTT (SEQ ID NO: 10)

As used herein, the term “CASS4” refers to the gene encoding Cas scaffolding protein family member 4. The terms “CASS4” and "Cas scaffolding protein family member 4" include wild-type forms of the CASS4 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type CASS4. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type CASS4 nucleic acid sequence (e.g., SEQ ID NO: 11 , ENA accession number AJ276678). SEQ ID NO: 11 is a wild-type gene sequence encoding CASS4 protein, and is shown below:

G AAG AGT G GT GTTTTTTT CTTCTTCTTCTT CTTTT GTG GTTT C AC AT AGC AAAT G AGT G A CAGTCTCTACTTACAGACAAAGTGAGACGTCAGGCATTGAGACATAGCTCCATAGAATTC AGTTTCTGAGAACCAGCCAGAAGCATGCAGTGACATTGCACAATCTGCCTCTGAAGCTGG

AGATACTAGCTGCAGAGCTCAGGGGAGCTGCTCCACATCACCGACATGAAGGGAACA GGC

ATCATGGACTGTGCGCCCAAGGCACTCCTGGCCAGGGCACTTTATGACAACTGCCCT GAC

TGCTCTGACGAGCTGGCTTTCAGCAGAGGGGACATCCTGACCATTCTGGAGCAACAC GTG

CCAGAAAGCGAGGGTTGGTGGAAGTGTTTGCTCCATGGGAGGCAAGGCCTGGCCCCT GCC

AACCGCCTCCAAATCCTCACGGAGGTCGCTGCAGACAGGCCGTGCCCCCCATTCCTG AGA

GGCCTGGAAGAAGCTCCTGCCAGCTCAGAGGAGACCTATCAGGTGCCCACTCTACCC CGC

CCTCCCACTCCAGGCCCCGTTTATGAGCAGATGAGGAGTTGGGCGGAGGGGCCCCAG CCC

CCTACTGCCCAAGTCTATGAATTCCCCGACCCTCCCACCAGTGCCAGAATCATCTGT GAA

AAGACTCTCAGCTTTCCAAAACAGGCCATCCTCACGCTTCCCAGACCTGTCCGGGCC TCA

CTGCCGACTCTGCCTTCCCAGGTGTATGACGTGCCTACCCAGCACCGGGGCCCCGTG GTC

CTGAAGGAGCCAGAGAAGCAGCAGTTATATGACATACCAGCCAGCCCCAAGAAGGCA GGA

CTCCATCCCCCAGACAGCCAAGCAAGTGGGCAGGGTGTTCCCCTGATATCAGTGACT ACC

TTAAGAAGAGGCGGTTACAGCACATTACCAAATCCTCAGAAATCGGAATGGATTTAT GAC

ACTCCAGTGTCTCCAGGAAAGGCCAGCGTCAGAAACACGCCTCTCACCAGCTTTGCG GAA

GAATCAAGGCCCCACGCTCTCCCCAGTTCCAGCTCCACTTTCTACAATCCTCCAAGT GGC

AGATCCAGGTCCCT CACTCCAC AACT G AAT AACAAT GT GCCCATGCAG AAAAAACT CAGC

CTTCCAGAAATTCCTTCTTATGGCTTTCTTGTACCCAGAGGCACATTTCCTTTGGAT GAA

GAT GTCAGCAACAAGGTTCCTT CAAGCTT CT CT G ATTCCCCGAGTGGACAGC AG AACACC

AAGCCCAATATAGACATCCCTAAAGCAACGTCGAGTGTTTCTCAGGCTGGGAAGGAG CTG

GAGAAAGCCAAGGAGGTGTCAGAGAATTCCGCGGGCCATAATTCCTCATGGTTCTCC AGA

CGGACAACTTCCCCATCTCCTGAACCGGACAGATTATCAGGTTCCAGTTCTGACAGC AGA

GCTAGCATCGTTTCCTCGTGCTCCACCACATCCACCGACGACTCCTCCAGCTCTTCC TCG

GAGGAGTCAGCAAAGGAGCTCTCCTTGGACCTGGATGTGGCCAAGGAGACAGTGATG GCT

CTGCAGCACAAGGTGGTCAGCTCTGTCGCTGGCCTGATGCTCTTTGTCAGCAGGAAG TGG

AGATTCCGAGACTATCTGGAGGCCAACATTGATGCAATCCACAGGTCCACTGATCAC ATA

GAAGCCTCTGTAAGAGAATTTCTGGATTTTGCCCGAGGAGTCCATGGGACTGCCTGT AAC

CTCACTGACAGTAACCTTCAGAACAGAATTCGGGACCAGATGCAGACCATCTCCAAC TCC

TACCGCATCCTGCTTGAAACAAAGGAAAGCTTGGATAATCGCAATTGGCCTCTGGAA GTT

CTT GT GACT G ACAGT GTCCAGAACAGCCCAGAT G ACCTT GAG AGGTTTGTCATGGT GGCA

CGGATGCTTCCAGAAGACATCAAGAGGTTTGCCTCCATTGTCATTGCCAATGGAAGG CTC

CTTTTTAAGCGGAACTGTGAAAAGGAAGAGACTGTGCAGTTGACCCCAAATGCAGAA TTT

AAGTGTGAAAAATACATCCAGCCTCCCCAAAGAGAAACTGAATCACACCAAAAGAGT ACC

CCTTCC ACT AAG C AAAG G G AAG AT GAACACTCTTCT G AACT ATT AAAG AAAAAT AG AGC A

AATATCTGTGGACAGAATCCTGGCCCTCTTATACCTCAGCCTTCGAGTCAACAGACT CCT

GAGAGGAAACCCCGCTTATCTGAACACTGCCGGCTGTACTTTGGGGCGCTCTTCAAA GCC

ATCAGCGCATTTCACGGCAGCCTCAGCAGCAGCCAGCCCGCGGAGATCATCACTCAG AGC

AAGCTGGTCATCATGGTGGGACAGAAGCTGGTGGACACGCTGTGCATGGAGACCCAG GAG

AGGGACGTGCGCAATGAGATCCTCCGCGGCAGCAGTCACCTCTGCAGCCTGCTCAAG GAC

GTAGCGCTGGCCACTAAGAATGCCGTGCTCACATACCCCAGCCCTGCCGCGCTGGGG CAC

CTCCAGGCGGAGGCTGAGAAGCTGGAGCAACACACGCGGCAGTTCAGAGGGACACTG GGA

TGAGGACTGTCTACCTCCCTTCCTCCTCTGCTCACC (SEQ ID NO: 11)

As used herein, the term “CCL5” refers to the gene encoding C-C motif chemokine 5. The terms “CCL5” and "C-C motif chemokine 5" include wild-type forms of the CCL5 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type CCL5. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type CCL5 nucleic acid sequence (e.g., SEQ ID NO: 12, ENA accession number M21121). SEQ ID NO: 12 is a wild-type gene sequence encoding CCL5 protein, and is shown below:

CCTCCGACAGCCTCTCCACAGGTACCATGAAGGTCTCCGCGGCACGCCTCGCTGTCA TCC

TCATTGCTACTGCCCTCTGCGCTCCTGCATCTGCCTCCCCATATTCCTCGGACACCA CAC

CCTGCTGCTTTGCCTACATTGCCCGCCCACTGCCCCGTGCCCACATCAAGGAGTATT TCT

ACACCAGTGGCAAGTGCTCCAACCCAGCAGTCGTCTTTGTCACCCGAAAGAACCGCC AAG

TGTGTGCCAACCCAGAGAAGAAATGGGTTCGGGAGTACATCAACTCTTTGGAGATGA GCT

AGG ATGGAGAGTCCTT G AACCT G AACTTACACAAATTTGCCT GTTT CTGCTTGCT CTT GT

CCTAGCTTGGGAGGCTTCCCCTCACTATCCTACCCCACCCGCTCCTTGAAGGGCCCA GAT

TCTGACCACGACGAGCAGCAGTTACAAAAACCTTCCCCAGGCTGGACGTGGTGGCTC AGC

CTTGTAATCCCAGCACTTTGGGAGGCCAAGGTGGGTGGATCACTTGAGGTCAGGAGT TCG

AGACAGCCTGGCCAACATGATGAAACCCCATGTGTACTAAAAATACAAAAAATTAGC CGG

GCGTGGTAGCGGGCGCCTGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATGG CGT

GAACCCGGGAGCGGAGCTTGCAGTGAGCCGAGATCGCGCCACTGCACTCCAGCCTGG GCG

ACAG AGCGAG ACTCCGT CT CAAAAAAAAAAAAAAAAAAAAAAAAAAT ACAAAAATT AGCC

GCGTGGTGGCCCACGCCTGTAATCCCAGCTACTCGGGAGGCTAAGGCAGGAAAATTG TTT

GAACCCAGGAGGTGGAGGCTGCAGTGAGCTGAGATTGTGCCACTTCACTCCAGCCTG GGT

GACAAAGTGAGACTCCGTCACAACAACAACAACAAAAAGCTTCCCCAACTAAAGCCT AGA

AGAGCTTCTGAGGCGCTGCTTTGTCAAAAGGAAGTCTCTAGGTTCTGAGCTCTGGCT TTG

CCTTGGCTTTGCAAGGGCTCTGTGACAAGGAAGGAAGTCAGCATGCCTCTAGAGGCA AGG

AAGGGAGGAACACTGCACTCTTAAGCTTCCGCCGTCTCAACCCCTCACAGGAGCTTA CTG

GCAAACATGAAAAATCGGGG

(SEQ ID NO: 12)

As used herein, the term “CD2AP” refers to the gene encoding CD2-associated protein. The terms “CD2AP” and "CD2-associated protein" include wild-type forms of the CD2AP gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type CD2AP. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type CD2AP nucleic acid sequence (e.g., SEQ ID NO: 13, ENA accession number AF146277). SEQ ID NO: 13 is a wild-type gene sequence encoding CD2AP protein, and is shown below: GGAATTCCGGGAGGAGCGGACGTCGGCTTCTCCCCGCGGGAGCCCCCAGCATGGTTGACT

AT ATTGTG G AGT ATG ACT AT GAT G CTGTAC AT GAT GAT G AATT AACT ATTCG AGTT G GAG

AAATCATCAGGAATGTGAAAAAGCTACAGGAGGAAGGGTGGCTGGAAGGAGAACTAA ATG

G G AG AAG AG G AAT GTTC CCT G AC AATTTCGTT AAG G AAATT AAAAG AG AG AC GG AATT C A

AGGATGACAGTTTGCCCATCAAACGGGAAAGGCATGGGAATGTAGCAAGTCTTGTAC AAC

GAATAAGCACCTATGGACTTCCAGCTGGAGGAATTCAGCCACATCCACAAACCAAAA ACA

TTAAGAAGAAGACCAAG AAGCGTC AGT GT AAAGTT CTTTTT GAGT ACATTCCACAAAAT G

AGG AT G AACT GG AGCT G AAAGTGGGAGATATT ATT GAT ATT AAT GAAGAGGTAG AAGAAG

GCTGGTGGAGT GG AACCCT G AAT AACAAGTTGGG ACT GTTTCCCT CAAATTTT GT GAAAG

AATT AG AGGTAACAG AT GAT GGTGAAACT CAT G AAGCCCAGG ACG ATT CAG AAACTGTTT

TGGCTGGGCCTACTTCACCTATACCTTCTCTGGGAAATGTGAGTGAAACTGCATCTG GAT

CAGTTACACAGCCAAAGAAAATTCGAGGAATTGGATTTGGAGACATTTTTAAAGAAG GTT

CT GT G AAACTTCGG AC AAG AACATCCAGT AGT GAAAC AG AAG AG AAAAAACCAGAAAAGC

CCTTAATCCTACAGTCACTGGGACCCAAAACTCAGAGTGTGGAGATAACAAAAACAG ATA

CCG AAGGT AAAATT AAAGCT AAAGAATATTGTAG AACATT ATTTGCCT AT GAAGGT ACT A

AT G AAG AT G AACTT ACTTTT AAAG AGG GG G AG AT AATCCATTT G ATAAGT AAG GAG ACT G

GAGAAGCTGGCTGGTGGAGGGGCGAACTTAATGGTAAAGAAGGAGTATTTCCAGACA ATT

TTGCT GTCCAG AT AAAT GAACTT GAT AAAG ACTTTCCAAAACC AAAGAAACCACCACCTC

CTGCTAAGGCTCCAGCTCCAAAGCCTGAACTGATAGCTGCAGAGAAGAAATATTTTT CTT

T AAAGCCT G AAG AAAAGGAT G AAAAAT CAACACT GG AACAGAAACCTT CTAAACCAGC AG

CTCCACAAGTCCCACCCAAGAAACCTACTCCACCTACCAAAGCCAGTAATTTATTGA GAT

CTTCTGGAACAGTGTACCCAAAGCGACCTGAAAAACCAGTTCCTCCACCACCTCCTA TAG

CC AAG ATT AAT G GG G AAGTTT CT AG C ATTT CAT C AAAATTT G AAACT G AGCC AGTAT C AA

AACT AAAG CT AG ATT CT G AAC AG CTGCCCCTT AG ACC AAAAT C AGT AG ACTTT GATT C AC

TTACAGTAAGGACCTCCAAAGAAACAGATGTTGTAAATTTTGATGACATAGCTTCCT CAG

AAAACTTGCTTCATCTCACTGCAAATAGACCAAAGATGCCTGGAAGAAGGTTGCCGG GCC

GTTTCAATGGTGGACATTCTCCAACTCACAGCCCCGAAAAAATCTTGAAGTTACCAA AAG

AAGAAGACAGTGCCAACCTGAAGCCATCTGAATTAAAAAAAGATACATGCTACTCTC CAA

AGCCATCTGTGTACCTTTCAACACCTTCCAGTGCTTCTAAAGCAAATACAACTGCTT TCC

TGACTCCATTAGAAATCAAAGCTAAAGTGGAAACAGATGATGTGAAAAAAAATTCCC TGG

AT GAACTT AG AGCCCAG ATTATT GAATTGTT GT GCATTGTAGAAGCACT GAAAAAGGATC

ACGGGAAAGAACTGGAAAAACTGCGAAAAGATTTGGAAGAAGAGAAGACAATGAGAA GTA

ATCTAGAGATGGAAATAGAGAAGCTGAAAAAAGCTGTCCTGTCTTCTTGAGTGGTGT GGA

CCTGGTGTTCATAATGTTCCAGGGATTCAGAAGCAACGCTATGAACTTCAGCTGACT TGT

T ACTT AAAAATTGTG AATT CTGTTGTTGT GAT AAAT AT GAG C AAAT G AAGT GT AAT ATCT

AT AG AAAAGT AG AGT G AG GGTG AATTT AT AT AT AT ATTTT GTTTT G CC AAT AT G AAG AAA

AAGAGGCCTTATTTCTTAACTGTGCTGGGATTGCAAACACTTTTTAAAAAATTGTTT GCT

T G AAAAT ACTACT G AAT AT AAAT AAG AAT GTGCTCAGT AGTTTTTTT ATT G AAACTT GTA

TT ATTTTT AAAG AG AT CTATACTAT AAAT ATGGTG ATAT ATTT AC AAGTAAT CTGT AAG A

TATACT ATTT GAG AGG G AC AG ATT AG CCTTTT AGTAACT ATAGT C ACT ACTTTTTCCAT A

ATGCATAAGGGATATAAACTCTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTG TGT

ATATATATATATATATTTTTACTTTTATCCTCTTACCGAAGGTTACACTGTTGTGCC TGT TTGTCTG C AAT G CTGTTT AT ATTTT G GGT GAT G AAAT AG G AGTTTCCT AG CTATAT AAAC C AG ATT ACT C ACCC AT G CAT ATAGT AAG AACT AAT G AAT AAT C AAAAT AATTT CAT C AAC TTTT AG AAT ATTTT ATGTTG CTTGC ACTAT AG G AGT CAT AAAAGG AACTT AGTT AAAAT A TGTT GG ATTGTT AAAC ATTT G GG G AAAT AT G AACT GT ATTTT AAATTTGTT AG GTCTG AA AAAT CT AAAACTGTT AATTTAACCCTTAACTT GTGCCT AG AAACT ACAGCACAT AT AAAA TATGTAAACACCAGCCTGTTGCTGTACTTTTCTGCTTATTTTACAGCCTCAAATATTTCT C ATT ATCTTGTC ACTTAGTTCTT C ATGTTT CTCCTTCT G ACTTTT AAT AAT GGT AAT AG G AAAACAAAACCCAAAGCTTTTCAAACTTCAGTGTGAGGTTTCCTATTTTGACAAGTTAAC TTGT AAAT ACT C AG GTTTT ACG ATGTAT AATTT ACCT AAT AG ACC AAACT AACT CAT G G A GAT ATTTT G AACT ATT ATTT AGGTAC AAACTTT AT AAAG AAT GTTAGT ATGTC AT AAAAT AT AACATT AC AG CTT ATTT AAAAC C AAAT AT ATT G AACAT ATTTT AAAAT AC ATTT C AC A G AATGG AT GAATT AGTT GTTT CTT CAAAAGTT ACTTAT G AACAGTT G AAT GCCTTT AAAA TGTTCTGTCTGTAGGTACATCTAAAAACACAAGTGGGTTTATTTAAATTTTTAAAATTTG AAATTTTTT ATTT GCCAAAAATT GTTTTATGCTTT ATT AT ATCGCAAAT GAGT GTCAGAT TTTT GAGT ACCAAT GAT CAT GCTTCCATTTTTTTTAGTTTTAAACCACCAAACCAAT ATT TTTCCTTT AAATTTT AAT CTT AT AAT AT AG AAAT CTT ATGTT AAT G AAATTTT GT CAT GT TT C AAAT AAAG AAAACT G AAGT AG AAAAT AG AAAT G CC AGTAAAC AAC AT AAT GTTT AAT TT AC AACTT AC ATT AG GG GTTT G GG GG AAT G CT AATT AT AT ATT GAG AAT AT AC ATT AG A ACTCTTCAAAATGGGCTCTTCTAATGAGGTCACTACTGAACAAAATTGTTCCCTCTTCTG TT AAAT AG AAT AG GTTT AAAT G ACT AGTC AAAT GAATT ATTTT CTCCTTGTT AAAT AAAT TAAATCTTACTTTCTTTTAATGACCAACCTTAGGTAAAACAAAAATATTGTAATCCTAGA AATTATCCTCCAGCTTTCTCACCTGAAAATCTATTGAAGTGATCCCTGGTCATCCTAATA ATGGGATGAGGGAAGTTTCCAGCAGATTTCAGGCTGTTCTTAAAGTTTTTGTTGGTCATT TTCT C AAT AGTAC AT G AAAT C AAG ATGCTT AT GAG CAT GG AAAT GT ATTT AAAGTTTTT G CTT GT GTCCTCCT CAGTCAG AATAG AAAAGTAACT GAAAT ACT CTT ACCTTT CT GTCCTT GAT AAAAT AGTAAAGAAAACCAAACAAACCCAGGCCTGATGGGAAAAATGATTCCTTTAT T CT AG C AATT ACTTT CTGTTG GTAT GG GAAAT GTT ATT AATTT CT ATT ACT AAAGTT CAT AT C AC AAAAT GAT ATTT AAT AAT AACCTTGGGGT AAAT CAT G AATTTTTTTTT CTACGTG T GAGT AT AAAAG AC AAAAGTT G AAC AG CAT G G AAT CTT C ATTGCC AAATT ATT AGTG AAT GTATAGTTCAGGTATTCTTTGAGACACACAGTATCATTAATTTCCGAATTGTATTTCAGT GTTATTTTTTGTTTGTGACCACTAAGCTTCTGTCTTAATACAAAGCTGTTACCTTCTACA G AATTT AAGTCTGAAGAT GT AAAG AGAG AACAGGCCTT GT GT AACAG AAG ATACT CTTTT TTAT GCTCCTT ACT GT GATCACAG AAAAATT AAAAATCCAAGT GCTCT CT AG ATTTGTT G AT AAAC ATTTT ATGCTTG C ATTT AAACTT G AAATGTAT G AGC AG AAT GAG AC AAT C AGTT AAATCAGAAATGAGAAGTATTATAATGTAAAGGCCTTGTTTTGCTGTAGCAATAAAATGA CCAAGTGCAAT G ACTT G ATTTAATAAAATCCGG AATT C (SEQ ID NO: 13)

As used herein, the term “CD33” refers to the gene encoding Myeloid cell surface antigen CD33. The terms “CD33” and "Myeloid cell surface antigen CD33" include wild-type forms of the CD33 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type CD33. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type CD33 nucleic acid sequence (e.g., SEQ ID NO: 14, ENA accession number M23197). SEQ ID NO: 14 is a wild-type gene sequence encoding CD33 protein, and is shown below:

GCTTCCTCAGACATGCCGCTGCTGCTACTGCTGCCCCTGCTGTGGGCAGGGGCCCTG GCT

ATGGATCCAAATTTCTGGCTGCAAGTGCAGGAGTCAGTGACGGTACAGGAGGGTTTG TGC

GTCCTCGTGCCCTGCACTTTCTTCCATCCCATACCCTACTACGACAAGAACTCCCCA GTT

CATGGTTACTGGTTCCGGGAAGGAGCCATTATATCCGGGGACTCTCCAGTGGCCACA AAC

AAGCTAGATCAAGAAGTACAGGAGGAGACTCAGGGCAGATTCCGCCTCCTTGGGGAT CCC

AGTAGGAACAACTGCTCCCTGAGCATCGTAGACGCCAGGAGGAGGGATAATGGTTCA TAC

TTCTTTCGGATGGAGAGAGGAAGTACCAAATACAGTTACAAATCTCCCCAGCTCTCT GTG

CATGTGACAGACTTGACCCACAGGCCCAAAATCCTCATCCCTGGCACTCTAGAACCC GGC

CACTCCAAAAACCTTACCTGCTCTGTGTCCTGGGCCTGTGAGCAGGGAACACCCCCG ATC

TTCTCCTGGTTGTCAGCTGCCCCCACCTCCCTGGGCCCCAGGACTACTCACTCCTCG GTG

CTCATAATCACCCCACGGCCCCAGGACCACGGCACCAACCTGACCTGTCAGGTGAAG TTC

GCTGGAGCTGGTGTGACTACGGAGAGAACCATCCAGCTCAACGTCACCTATGTTCCA CAG

AACCCAACAACTGGTATCTTTCCAGGAGATGGCTCAGGGAAACAAGAGACCAGAGCA GGA

CTGGTTCATGGGGCCATTGGAGGAGCTGGTGTTACAGCCCTGCTCGCTCTTTGTCTC TGC

CTCATCTTCTTCATAGTGAAGACCCACAGGAGGAAAGCAGCCAGGACAGCAGTGGGC AGC

AATGACACCCACCCTACCACAGGGTCAGCCTCCCCGAAACACCAGAAGAACTCCAAG TTA

CATGGCCCCACTGAAACCTCAAGCTGTTCAGGTGCCGCCCCTACTGTGGAGATGGAT GAG

GAGCTGCATTATGCTTCCCTCAACTTTCATGGGATGAATCCTTCCAAGGACACCTCC ACC

GAATACTCAGAGGTCAGGACCCAGTGAGGAACCCTCAAGAGCATCAGGCTCAGCTAG AAG

ATCCACATCCTCTACAGGTCGGGGACCAAAGGCTGATTCTTGGAGATTTAACTCCCC ACA

GGCAATGGGTTTATAGACATTATGTGAGTTTCCTGCTATATTAACATCATCTTGAGA CTT

TGCAAGCAGAGAGTCGTGGAATCAAATCTGTGCTCTTTCATTTGCTAAGTGTATGAT GTC

AC AC AAG CTCCTT AACCTTCC AT GT CTCC ATTTT CTTCTCTGTGAAGT AG GTAT AAG AAG

TCCTATCTCATAGGGATGCTGTGAGCATTAAATAAAGGTACACATGGAAAACACCAG

(SEQ ID NO: 14)

As used herein, the term “CD68” refers to the gene encoding CD68 Molecule. The terms “CD68” and " CD68 molecule" include wild-type forms of the CD68 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type CD68. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type CD68 nucleic acid sequence (e.g., SEQ ID NO: 15, NCBI Reference Sequence: NM_001251 .2). SEQ ID NO: 15 is a wild-type gene sequence encoding CD68 protein, and is shown below:

TTAATTACAAAAACTAATGACTAAGAGAGAGGTGGCTAGAGCTGAGGCCCCTGAGTC AGGCTGTGG

GTGGGATCATCTCCAGTACAGGAAGTGAGACTTTCATTTCCTCCTTTCCAAGAGAGG GCTGAGGGAG CAGGGTTGAGCAACTGGTGCAGACAGCCTAGCTGGACTTTGGGTGAGGCGGTTCAGCCAT GAGGCT

GGCTGTGCTTTTCTCGGGGGCCCTGCTGGGGCTACTGGCAGCCCAGGGGACAGGGAA TGACTGTC

CTCACAAAAAATCAGCTACTTTGCTGCCATCCTTCACGGTGACACCCACGGTTACAG AGAGCACTGG

AACAACCAGCCACAGGACTACCAAGAGCCACAAAACCACCACTCACAGGACAACCAC CACAGGCAC

CACCAGCCACGGACCCACGACTGCCACTCACAACCCCACCACCACCAGCCATGGAAA CGTCACAGT

TCATCCAACAAGCAATAGCACTGCCACCAGCCAGGGACCCTCAACTGCCACTCACAG TCCTGCCAC

CACTAGTCATGGAAATGCCACGGTTCATCCAACAAGCAACAGCACTGCCACCAGCCC AGGATTCACC

AGTTCTGCCCACCCAGAACCACCTCCACCCTCTCCGAGTCCTAGCCCAACCTCCAAG GAGACCATT

GGAGACTACACGTGGACCAATGGTTCCCAGCCCTGTGTCCACCTCCAAGCCCAGATT CAGATTCGA

GTCATGTACACAACCCAGGGTGGAGGAGAGGCCTGGGGCATCTCTGTACTGAACCCC AACAAAACC

AAGGTCCAGGGAAGCTGTGAGGGTGCCCATCCCCACCTGCTTCTCTCATTCCCCTAT GGACACCTC

AGCTTTGGATTCATGCAGGACCTCCAGCAGAAGGTTGTCTACCTGAGCTACATGGCG GTGGAGTAC

AATGTGTCCTTCCCCCACGCAGCACAGTGGACATTCTCGGCTCAGAATGCATCCCTT CGAGATCTCC

AAGCACCCCTGGGGCAGAGCTTCAGTTGCAGCAACTCGAGCATCATTCTTTCACCAG CTGTCCACCT

CGACCTGCTCTCCCTGAGGCTCCAGGCTGCTCAGCTGCCCCACACAGGGGTCTTTGG GCAAAGTTT

CTCCTGCCCCAGTGACCGGTCCATCTTGCTGCCTCTCATCATCGGCCTGATCCTTCT TGGCCTCCTC

GCCCTGGTGCTTATTGCTTTCTGCATCATCCGGAGACGCCCATCCGCCTACCAGGCC CTCTGAGCAT

TTGCTTCAAACCCCAGGGCACTGAGGGGGTTGGGGTGTGGTGGGGGGGTACCCTTAT TTCCTCGAC

ACGCAACTGGCTCAAAGACAATGTTATTTTCCTTCCCTTTCTTGAAGAACAAAAAGA AAGCCGGGCAT

GACGGCTCATGCCTGTAATCCCAGCACTTTGGGAGGCTGAGGCAGGTGGATCACTGG AGGTCAGGA

GTTTGAGACCAGCCTGGCCAACATGGTGAAACCCTGTCTCTACTAAAAATACAATTA GCCAGGTGTG

GCGGCGTAATCCCAGCTGGCCTGTAATCCCAGCTACTTGGGAGGCTGAGGCAGAACT GCTTGAACC

CAGGAGGTGGAGGTTGCAGTGAGCCGTCATCGCGCCACTAAGCCAAGATCGCGCCAC TGCACTCC

AGCCTGGGCGACAGAGCCAGACTGTCTCAAATAAATAAATATGAGATAATGCAGTCG GGAGAAGGG

AGGGAGAGAATTTTATTAAATGTGACGAACTGCCCCCCCCCCCCCCCCAGCAGGAGA GCAGCAAAA

TTTATGCAAATCTTTGACGGGGTTTTCCTTGTCCTGCCAGGATTAAAAGCCATGAGT TTCTTGTCAAA

AAAAAAAAAAAAAA

(SEQ ID NO: 15)

As used herein, the term “CLPTM1” refers to the gene encoding CLPTM1 Regulator of GABA Type A Receptor Forward Trafficking. The terms “CLPTM1” and " CLPTM1 Regulator of GABA Type A Receptor Forward Trafficking " include wild-type forms of the CLPTM1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type CLPTM1. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type CLPTM1 nucleic acid sequence (e.g., SEQ ID NO: 16, NCBI Reference Sequence: NM_001294.3). SEQ ID NO: 16 is a wild-type gene sequence encoding CLPTM1 protein, and is shown below:

AGGTTGGTCCTTCCATAGCCGGAAGTGGCCTTCCTGAGAGGCGTGGCTGCGGCACTC TTGCCGGAT

AGGGTGGCCCGGCGGGGCTAGGAAAGCGTGAAATCTCGCGCGATTGCGCTGCGAAGT CGGGGAC

GGGGCGGGGCTGGCGGCGGGGGCGGGGACCCGGAGCGGGAAGATGGCGGCGGCGCAG GAGGC GGACGGGGCCCGCAGCGCCGTGGTGGCGGCCGGGGGAGGCAGCTCCGGTCAGGTGACCAG CAAT

GGCAGCATCGGGAGGGACCCGCCAGCGGAGACCCAGCCTCAGAACCCACCGGCCCAG CCGGCAC

CCAATGCCTGGCAGGTCATCAAAGGTGTGCTGTTTAGGATCTTCATCATCTGGGCCA TCAGCAGTTG

GTTCCGCCGAGGGCCGGCCCCTCAGGACCAGGCGGGCCCCGGAGGAGCTCCACGCGT CGCCAGC

CGCAACCTGTTCCCCAAAG AC ACTTT AAT G AACCTGCAT GT GT ACATCT CAG AGCACG AGC ACTTT A

CAGACTTCAACGCCACGTCGGCACTCTTCTGGGAACAGCACGATCTTGTGTATGGCG ACTGGACTA

GCGGCGAGAACTCAGACGGCTGCTACGAGCACTTTGCTGAGCTCGATATCCCACAGA GCGTCCAGC

AGAACGGCTCCATCTACATCCACGTTTACTTCACCAAGAGTGGCTTCCACCCAGACC CCCGGCAGAA

GGCCCTGTACCGCCGGCTTGCCACAGTCCACATGTCCCGGATGATCAACAAATACAA GCGCAGACG

ATTTCAGAAAACCAAGAACCTGCTGACAGGAGAGACAGAAGCGGACCCAGAAATGAT CAAGAGGGC

TGAGGACTATGGGCCTGTGGAGGTGATCTCCCATTGGCACCCCAACATCACCATCAA CATCGTGGA

CGACCACACGCCGTGGGTGAAGGGCAGTGTGCCCCCTCCCCTGGATCAATATGTGAA GTTCGACGC

CGTGAGCGGTGACTACTATCCCATCATCTACTTCAATGACTACTGGAACCTGCAGAA GGACTACTAC

CCCATCAACGAGAGCCTGGCCAGCCTGCCGCTCCGCGTCTCCTTCTGCCCACTCTCG CTTTGGCGC

TGGCAGCTCTATGCTGCCCAGAGCACCAAGTCGCCCTGGAACTTCCTGGGTGATGAG TTGTACGAG

CAGTCAGATGAGGAGCAGGACTCGGTGAAGGTGGCCCTGCTGGAGACCAACCCCTAC CTGCTGGC

GCTCACCATCATCGTGTCTATCGTTCACAGTGTCTTCGAGTTCCTGGCCTTCAAGAA TGATATCCAGT

TCTGGAACAGCCGGCAGTCCCTGGAGGGCCTGTCCGTGCGCTCCGTCTTCTTCGGCG TTTTCCAGT

CATTCGTGGTCCTCCTCTACATCCTGGACAACGAGACCAACTTCGTGGTCCAGGTCA GCGTCTTCAT

TGGGGTCCTCATCGACCTCTGGAAGATCACCAAGGTCATGGACGTCCGGCTGGACCG AGAGCACAG

GGTGGCAGGAATCTTCCCCCGCCTATCCTTCAAGGACAAGTCCACGTATATCGAGTC CTCGACCAAA

GTGTATGATGATATGGCATTCCGGTACCTGTCCTGGATCCTCTTCCCGCTCCTGGGC TGCTATGCCG

TCTACAGTCTTCTGTACCTGGAGCACAAGGGCTGGTACTCCTGGGTGCTCAGCATGC TCTACGGCTT

CCTGCTGACCTTCGGCTTCATCACCATGACGCCCCAGCTCTTCATCAACTACAAGCT CAAGTCTGTG

GCCCACCTTCCCTGGCGCATGCTCACCTACAAGGCCCTCAACACATTCATCGACGAC CTGTTCGCCT

TTGTCATCAAGATGCCCGTTATGTACCGGATCGGCTGCCTGCGGGACGATGTGGTTT TCTTCATCTA

CCTCTACCAACGGTGGATCTACCGCGTCGACCCCACCCGAGTCAACGAGTTTGGCAT GAGTGGAGA

AGACCCCACAGCTGCCGCCCCCGTGGCCGAGGTTCCCACAGCAGCAGGGGCCCTCAC GCCCACAC

CTGCACCCACCACGACCACCGCCACCAGGGAGGAGGCCTCCACGTCCCTGCCCACCA AGCCCACC

CAGGGGGCCAGCTCTGCCAGCGAGCCCCAGGAAGCCCCTCCAAAGCCAGCAGAGGAC AAGAAAAA

GGATTAGTCGAGACTGGTCCTCACCTGCTCCGGCTCCTGGCGACCACTACCCCTGCG TCCCGGCCC

CCTCGCCTCCCCTCCCTGTCGCCCTTTCCCTGGACAGATCAGGCCGGGGCGGTGGGA GGCCCGCC

TCAGGTCAGGGCCCAGCGTGTGATGTAGGGGCCGGGGCAGGCCAGGGTTTGTTTGTG GAGGCGCT

GTCTGTCCCTCTGTCCCTCTGTGTTTCCAGCCATCTCGCCCTGCCAGCCCAGCACCA CTGGGAATCA

TGGTGAAGCTGATGCAGCGTTGCCGAGGGGGTGGGTTGGGCGGGGGTGGGGCCGGGC CCCCCTA

CGGGATGCCCACGGCCGTTCATCATCTTGTCCCTCGTCCCCCTACCACACTCCCCCT CCTAGACCG

CCGCCCTTTAACACAGTCTGGATTTAATAAATTCATATGGGTGTTTAACTTAAACTC AGCACTAAAAAA

AAAAAAAAAAAA

(SEQ ID NO: 16)

As used herein, the term “CLU” refers to the gene encoding Clusterin. The terms “CLU” and "Clusterin' ¹ include wild-type forms of the CLU gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type CLU. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type CLU nucleic acid sequence (e.g., SEQ ID NO: 17, ENA accession number M25915). SEQ ID NO: 17 is a wild-type gene sequence encoding CLU protein, and is shown below:

CTGCGAACCCTCTCTACTCTCCGAAGGGAATTGTCCTTCCTGGCTTCCACTACTTCC ACC

CCTGAATGCACAGGCAGCCCGGCCCAAGTCTCCCACTAGGGATGCAGATGGATTCGG TGT

GAAGGGCTGGCTGCTGTTGCCTCCGGCTCTTGAAAGTCAAGTTCAGAGGCGTGCAAA GAC

TCCAGAATTGGAGGCATGATGAAGACTCTGCTGCTGTTTGTGGGGCTGCTGCTGACC TGG

GAGAGTGGGCAGGTCCTGGGGGACCAGACGGTCTCAGACAATGAGCTCCAGGAAATG TCC

AATCAGGGAAGTAAGTACGTCAATAAGGAAATTCAAAATGCTGTCAACGGGGTGAAA CAG

AT AAAG ACT CTC AT AG AAAAAAC AAACG AAG AG CG C AAG AC ACT G CT C AGC AACCT AG AA

GAAGCCAAGAAGAAGAAAGAGGATGCCCTAAATGAGACCAGGGAATCAGAGACAAAG CTG

AAGGAGCTCCCAGGAGTGTGCAATGAGACCATGATGGCCCTCTGGGAAGAGTGTAAG CCC

TGCCTGAAACAGACCTGCATGAAGTTCTACGCACGCGTCTGCAGAAGTGGCTCAGGC CTG

GTTGGCCGCCAGCTTGAGGAGTTCCTGAACCAGAGCTCGCCCTTCTACTTCTGGATG AAT

GGTGACCGCATCGACTCCCTGCTGGAGAACGACCGGCAGCAGACGCACATGCTGGAT GTC

ATGCAGGACCACTTCAGCCGCGCGTCCAGCATCATAGACGAGCTCTTCCAGGACAGG TTC

TTCACCCGGGAGCCCCAGGATACCTACCACTACCTGCCCTTCAGCCTGCCCCACCGG AGG

CCTCACTTCTTCTTTCCCAAGTCCCGCATCGTCCGCAGCTTGATGCCCTTCTCTCCG TAC

GAGCCCCTGAACTTCCACGCCATGTTCCAGCCCTTCCTTGAGATGATACACGAGGCT CAG

CAGGCCATGGACATCCACTTCCACAGCCCGGCCTTCCAGCACCCGCCAACAGAATTC ATA

CGAGAAGGCGACGATGACCGGACTGTGTGCCGGGAGATCCGCCACAACTCCACGGGC TGC

CTGCGGATGAAGGACCAGTGTGACAAGTGCCGGGAGATCTTGTCTGTGGACTGTTCC ACC

AACAACCCCTCCCAGGCTAAGCTGCGGCGGGAGCTCGACGAATCCCTCCAGGTCGCT GAG

AGGTTGACCAGGAAATATAACGAGCTGCTAAAGTCCTACCAGTGGAAGATGCTCAAC ACC

TCCTCCTTGCTGGAGCAGCTGAACGAGCAGTTTAACTGGGTGTCCCGGCTGGCAAAC CTC

ACGCAAGGCGAAGACCAGTACTATCTGCGGGTCACCACGGTGGCTTCCCACACTTCT GAC

TCGGACGTTCCTTCCGGTGTCACTGAGGTGGTCGTGAAGCTCTTTGACTCTGATCCC ATC

ACTGTGACGGTCCCTGTAGAAGTCTCCAGGAAGAACCCTAAATTTATGGAGACCGTG GCG

GAGAAAGCGCTGCAGGAATACCGCAAAAAGCACCGGGAGGAGTGAGATGTGGATGTT GCT

TTTGCACCTACGGGGGCATCTGAGTCCAGCTCCCCCCAAGATGAGCTGCAGCCCCCC AGA

GAGAGCTCTGCACGTCACCAAGTAACCAGGC

(SEQ ID NO: 17)

As used herein, the term “CR1 ” refers to the gene encoding Complement receptor type 1 . The terms “CR1” and "Complement receptor type 1" include wild-type forms of the CR1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type CR1 . Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type CR1 nucleic acid sequence (e.g., SEQ ID NO: 18, ENA accession number Y00816). SEQ ID NO: 18 is a wild-type gene sequence encoding CR1 protein, and is shown below:

CGTGGTTTGTAGATGTGCTTGGGGAGAATGGGGGCCTCTTCTCCAAGAAGCCCGGAG CCT

GTCGGGCCGCCGGCGCCCGGTCTCCCCTTCTGCTGCGGAGGATCCCTGCTGGCGGTT GTG

GTGCTGCTTGCGCTGCCGGTGGCCTGGGGTCAATGCAATGCCCCAGAATGGCTTCCA TTT

GCCAGGCCTACCAACCTAACTGATGAGTTTGAGTTTCCCATTGGGACATATCTGAAC TAT

GAATGCCGCCCTGGTTATTCCGGAAGACCGTTTTCTATCATCTGCCTAAAAAACTCA GTC

TGGACTGGTGCTAAGGACAGGTGCAGACGTAAATCATGTCGTAATCCTCCAGATCCT GTG

AATGGCATGGTGCATGTGATCAAAGGCATCCAGTTCGGATCCCAAATTAAATATTCT TGT

ACTAAAGGATACCGACTCATTGGTTCCTCGTCTGCCACATGCATCATCTCAGGTGAT ACT

GTCATTTGGGATAATGAAACACCTATTTGTGACAGAATTCCTTGTGGGCTACCCCCC ACC

ATCACCAATGGAGATTTCATTAGCACCAACAGAGAGAATTTTCACTATGGATCAGTG GTG

ACCTACCGCTGCAATCCTGGAAGCGGAGGGAGAAAGGTGTTTGAGCTTGTGGGTGAG CCC

TCCATATACTGCACCAGCAATGACGATCAAGTGGGCATCTGGAGCGGCCCCGCCCCT CAG

TGCATTATACCTAACAAATGCACGCCTCCAAATGTGGAAAATGGAATATTGGTATCT GAC

AACAGAAGCTTATTTTCCTTAAATGAAGTTGTGGAGTTTAGGTGTCAGCCTGGCTTT GTC

ATGAAAGGACCCCGCCGTGTGAAGTGCCAGGCCCTGAACAAATGGGAGCCGGAGCTA CCA

AGCT GCTCCAGGGTAT GTCAGCCACCTCCAGAT GTCCT GCATGCT GAGCGTACCCAAAGG

GACAAGGACAACTTTTCACCTGGGCAGGAAGTGTTCTACAGCTGTGAGCCCGGCTAC GAC

CTCAGAGGGGCTGCGTCTATGCGCTGCACACCCCAGGGAGACTGGAGCCCTGCAGCC CCC

ACATGTGAAGTGAAATCCTGTGATGACTTCATGGGCCAACTTCTTAATGGCCGTGTG CTA

TTTCCAGTAAATCTCCAGCTTGGAGCAAAAGTGGATTTTGTTTGTGATGAAGGATTT CAA

TTAAAAGGCAGCTCTGCTAGTTACTGTGTCTTGGCTGGAATGGAAAGCCTTTGGAAT AGC

AGT GTTCCAGTGTGTG AACAAAT CTTTT GT CCAAGTCCTCCAGTTATTCCTAAT GGGAGA

CACACAGGAAAACCTCTGGAAGTCTTTCCCTTTGGAAAAGCAGTAAATTACACATGC GAC

CCCCACCCAGACAGAGGGACGAGCTTCGACCTCATTGGAGAGAGCACCATCCGCTGC ACA

AGTGACCCTCAAGGGAATGGGGTTTGGAGCAGCCCTGCCCCTCGCTGTGGAATTCTG GGT

CACTGTCAAGCCCCAGATCATTTTCTGTTTGCCAAGTTGAAAACCCAAACCAATGCA TCT

GACTTTCCCATTGGGACATCTTTAAAGTACGAATGCCGTCCTGAGTACTACGGGAGG CCA

TTCTCTATCACATGTCTAGATAACCTGGTCTGGTCAAGTCCCAAAGATGTCTGTAAA CGT

AAATCATGTAAAACTCCTCCAGATCCAGTGAATGGCATGGTGCATGTGATCACAGAC ATC

CAGGTTGGATCCAGAATCAACTATTCTTGTACTACAGGGCACCGACTCATTGGTCAC TCA

TCTGCTGAATGTATCCTCTCGGGCAATGCTGCCCATTGGAGCACGAAGCCGCCAATT TGT

CAACGAATTCCTTGTGGGCTACCCCCCACCATCGCCAATGGAGATTTCATTAGCACC AAC

AGAGAGAATTTTCACTATGGATCAGTGGTGACCTACCGCTGCAATCCTGGAAGCGGA GGG

AGAAAGGTGTTTGAGCTTGTGGGTGAGCCCTCCATATACTGCACCAGCAATGACGAT CAA

GTGGGCATCTGGAGCGGCCCGGCCCCTCAGTGCATTATACCTAACAAATGCACGCCT CCA

AATGTGGAAAATGGAATATTGGTATCTGACAACAGAAGCTTATTTTCCTTAAATGAA GTT

GTGGAGTTTAGGTGTCAGCCTGGCTTTGTCATGAAAGGACCCCGCCGTGTGAAGTGC CAG

GCCCTGAACAAATGGGAGCCGGAGCTACCAAGCTGCTCCAGGGTATGTCAGCCACCT CCA

GATGTCCTGCATGCTGAGCGTACCCAAAGGGACAAGGACAACTTTTCACCCGGGCAG GAA GTGTTCTACAGCT GT GAGCCCGGCTAT GACCTCAGAGGGGCT GCGTCTAT GCGCT GCACA

CCCCAGGG AG ACT GG AGCCCTGCAGCCCCCACAT GT GAAGT GAAATCCTGT GAT GACTT C

ATGGGCCAACTTCTTAATGGCCGTGTGCTATTTCCAGTAAATCTCCAGCTTGGAGCA AAA

GTGGATTTTGTTTGTGATGAAGGATTTCAATTAAAAGGCAGCTCTGCTAGTTATTGT GTC

TTGGCTGGAATGGAAAGCCTTTGGAATAGCAGTGTTCCAGTGTGTGAACAAATCTTT TGT

CCAAGTCCTCCAGTTATTCCTAATGGGAGACACACAGGAAAACCTCTGGAAGTCTTT CCC

TTTGGAAAAGCAGT AAATT ACACATGCG ACCCCCACCCAG ACAG AGGG ACG AGCTTCGAC

CTCATTGGAGAGAGCACCATCCGCTGCACAAGTGACCCTCAAGGGAATGGGGTTTGG AGC

AGCCCT GCCCCTCGCT GT GGAATTCT GGGTCACT GTCAAGCCCCAGATCATTTTCT GTTT

GCCAAGTTGAAAACCCAAACCAATGCATCTGACTTTCCCATTGGGACATCTTTAAAG TAC

GAATGCCGTCCTGAGTACTACGGGAGGCCATTCTCTATCACATGTCTAGATAACCTG GTC

TGGTCAAGTCCCAAAGATGTCTGTAAACGTAAATCATGTAAAACTCCTCCAGATCCA GTG

AATGGCATGGTGCATGTGATCACAGACATCCAGGTTGGATCCAGAATCAACTATTCT TGT

ACT AC AGGG C AC CG ACT C ATT GGTCACTCATCTGCT G AAT GTATCCTCT C AG GC AAT ACT

GCCCATTGGAGCACGAAGCCGCCAATTTGTCAACGAATTCCTTGTGGGCTACCCCCA ACC

ATCGCCAATGGAGATTTCATTAGCACCAACAGAGAGAATTTTCACTATGGATCAGTG GTG

ACCTACCGCTGCAATCTTGGAAGCAGAGGGAGAAAGGTGTTTGAGCTTGTGGGTGAG CCC

TCCATATACTGCACCAGCAATGACGATCAAGTGGGCATCTGGAGCGGCCCCGCCCCT CAG

TGCATTATACCTAACAAATGCACGCCTCCAAATGTGGAAAATGGAATATTGGTATCT GAC

AACAGAAGCTTATTTTCCTTAAATGAAGTTGTGGAGTTTAGGTGTCAGCCTGGCTTT GTC

ATGAAAGGACCCCGCCGTGTGAAGTGCCAGGCCCTGAACAAATGGGAGCCAGAGTTA CCA

AGCTGCTCCAGGGTGTGTCAGCCGCCTCCAGAAATCCTGCATGGTGAGCATACCCCA AGC

CATCAGGACAACTTTTCACCTGGGCAGGAAGTGTTCTACAGCTGTGAGCCTGGCTAT GAC

CTCAGAGGGGCTGCGTCTCTGCACTGCACACCCCAGGGAGACTGGAGCCCTGAAGCC CCG

AGATGTGCAGTGAAATCCTGTGATGACTTCTTGGGTCAACTCCCTCATGGCCGTGTG CTA

TTTCCACTTAATCTCCAGCTTGGGGCAAAGGTGTCCTTTGTCTGTGATGAAGGGTTT CGC

TTAAAGGGCAGTTCCGTTAGTCATTGTGTCTTGGTTGGAATGAGAAGCCTTTGGAAT AAC

AGTGTTCCTGTGTGTGAACATATCTTTTGTCCAAATCCTCCAGCTATCCTTAATGGG AGA

CACACAGGAACTCCCTCTGGAGATATTCCCTATGGAAAAGAAATATCTTACACATGT GAC

CCCCACCCAGACAGAGGGATGACCTTCAACCTCATTGGGGAGAGCACCATCCGCTGC ACA

AGTGACCCTCATGGGAATGGGGTTTGGAGCAGCCCTGCCCCTCGCTGTGAACTTTCT GTT

CGTGCTGGTCACTGTAAAACCCCAGAGCAGTTTCCATTTGCCAGTCCTACGATCCCA ATT

AATGACTTTGAGTTTCCAGTCGGGACATCTTTGAATTATGAATGCCGTCCTGGGTAT TTT

GGGAAAATGTTCTCTATCTCCTGCCTAGAAAACTTGGTCTGGTCAAGTGTTGAAGAC AAC

TGTAGACGAAAATCATGTGGACCTCCACCAGAACCCTTCAATGGAATGGTGCATATA AAC

ACAGATACACAGTTTGGATCAACAGTTAATTATTCTTGTAATGAAGGGTTTCGACTC ATT

GGTTCCCCATCTACTACTTGTCTCGTCTCAGGCAATAATGTCACATGGGATAAGAAG GCA

CCTATTTGTGAGATCATATCTTGTGAGCCACCTCCAACCATATCCAATGGAGACTTC TAC

AGCAACAATAGAACATCTTTTCACAATGGAACGGTGGTAACTTACCAGTGCCACACT GGA

CCAGATGGAGAACAGCTGTTTGAGCTTGTGGGAGAACGGTCAATATATTGCACCAGC AAA

GATGATCAAGTTGGTGTTTGGAGCAGCCCTCCCCCTCGGTGTATTTCTACTAATAAA TGC

ACAG CTCC AG AAGTT G AAAAT G C AATT AG AGT ACC AG G AAAC AG G AGTTT CTTTTCCCT C ACTGAGATCATCAGATTTAGATGTCAGCCCGGGTTTGTCATGGTAGGGTCCCACACTGTG

CAGTGCCAGACCAATGGCAGATGGGGGCCCAAGCTGCCACACTGCTCCAGGGTGTGT CAG

CCGCCTCCAGAAATCCT GCATGGT GAGCAT ACCCT AAGCC AT CAGG AC AACTTTT CACCT

GGGCAGGAAGT GTTCTACAGCT GT GAGCCCAGCTAT GACCTCAGAGGGGCT GCGTCTCT G

CACTGCACGCCCCAGGGAGACTGGAGCCCTGAAGCCCCTAGATGTACAGTGAAATCC TGT

GATGACTTCCTGGGCCAACTCCCTCATGGCCGTGTGCTACTTCCACTTAATCTCCAG CTT

GGGGCAAAGGTGTCCTTTGTTTGCGATGAAGGGTTCCGATTAAAAGGCAGGTCTGCT AGT

CATTGTGTCTTGGCTGGAATGAAAGCCCTTTGGAATAGCAGTGTTCCAGTGTGTGAA CAA

ATCTTTTGTCCAAATCCTCCAGCTATCCTTAATGGGAGACACACAGGAACTCCCTTT GGA

GAT ATTCCCT AT GG AAAAG AAATATCTT ACGCATGCG ACACCCACCCAG AC AGAGGGAT G

ACCTTCAACCTCATTGGGGAGAGCTCCATCCGCTGCACAAGTGACCCTCAAGGGAAT GGG

GTTTGGAGCAGCCCTGCCCCTCGCTGTGAACTTTCTGTTCCTGCTGCCTGCCCACAT CCA

CCCAAGATCCAAAACGGGCATTACATTGGAGGACACGTATCTCTATATCTTCCTGGG ATG

ACAATCAGCTACACTTGTGACCCCGGCTACCTGTTAGTGGGAAAGGGCTTCATTTTC TGT

ACAGACCAGGGAATCTGGAGCCAATTGGATCATTATTGCAAAGAAGTAAATTGTAGC TTC

CCACTGTTTATGAATGGAATCTCGAAGGAGTTAGAAATGAAAAAAGTATATCACTAT GGA

GATTATGTGACTTTGAAGTGTGAAGATGGGTATACTCTGGAAGGCAGTCCCTGGAGC CAG

TGCCAGGCGGATGACAGATGGGACCCTCCTCTGGCCAAATGTACCTCTCGTGCACAT GAT

G CTCT CAT AGTT G GC ACTTT ATCTG GTACG AT CTT CTTT ATTTT ACTC AT C ATTTTCCT C

TCTTGGATAATTCTAAAGCACAGAAAAGGCAATAATGCACATGAAAACCCTAAAGAA GTG

GCTATCCATTTACATTCTCAAGGAGGCAGCAGCGTTCATCCCCGAACTCTGCAAACA AAT

GAAGAAAATAGCAGGGTCCTTCCTTGACAAAGTACTATACAGCTGAAGAACATCTCG AAT

ACAATTTTGGTGGGAAAGGAGCCAATTGATTTCAACAGAATCAGATCTGAGCTTCAT AAA

GTCTTT G AAGT GACTT CACAG AG ACGCAG AC AT GTGCACTT GAAGATGCT GCCCCTTCCC

TGGTACCTAGCAAAGCTCCTGCCTCTTTGTGTGCGTCACTGTGAAACCCCCACCCTT CTG

CCTCGTGCTAAACGCACACAGTATCTAGTCAGGGGAAAAGACTGCATTTAGGAGATA GAA

AATAGTTTGGATTACTTAAAGGAATAAGGTGTTGCCTGGAATTTCTGGTTTGTAAGG TGG

TCACTGTTCTTTTTTAAAATATTTGTAATATGGAATGGGCTCAGTAAGAAGAGCTTG GAA

AAT GCAGAAAGTT AT G AAAAAT AAGTCACTT AT AATT AT GCT ACCT ACT GAT AACCACTC

CT AAT ATTTT GATT C ATTTT CTGCCTATCTT CTTT C AC AT ATGT GTTTTTTT AC AT ACGT

ACTTTTCCCCCCTTAGTTTGTTTCCTTTTATTTTATAGAGCAGAACCCTAGTCTTTT AAA

C AGTTT AG AGT G AAAT ATATGCTAT AT C AGTTTTT ACTTT CTCT AGG G AG AAAAATT AAT

TT ACT AG AAAG GC AT G AAAT GAT C ATGG G AAG AGTG GTT AAG ACT ACT G AAG AG AAAT AT

TTGGAAAATAAGATTTCGATATCTTCTTTTTTTTTGAGATGGAGTCTGGCTCTGTCT CCC

AGGCTGGAGTGCAGTGGCGTAATCTCGGCTCACTGCAACGTCCGCCTCCCG

(SEQ ID NO: 18)

As used herein, the term “CSF1” refers to the gene encoding Macrophage colony-stimulating factor 1 . The terms “CSF1” and "Macrophage colony-stimulating factor 1" include wild-type forms of the CSF1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type CSF1 . Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type CSF1 nucleic acid sequence (e.g., SEQ ID NO: 19, ENA accession number M37435). SEQ ID NO: 19 is a wild-type gene sequence encoding CSF1 protein, and is shown below:

CCTGGGTCCTCTCGGCGCCAGAGCCGCTCTCCGCATCCCAGGACAGCGGTGCGGCCC TCG

GCCGGGGCGCCCACTCCGCAGCAGCCAGCGAGCCAGCTGCCCCGTATGACCGCGCCG GGC

GCCGCCGGGCGCTGCCCTCCCACGACATGGCTGGGCTCCCTGCTGTTGTTGGTCTGT CTC

CTGGCGAGCAGGAGTATCACCGAGGAGGTGTCGGAGTACTGTAGCCACATGATTGGG AGT

GGACACCTGCAGTCTCTGCAGCGGCTGATTGACAGTCAGATGGAGACCTCGTGCCAA ATT

ACATTTGAGTTTGTAGACCAGGAACAGTTGAAAGATCCAGTGTGCTACCTTAAGAAG GCA

TTTCTCCTGGTACAAGACATAATGGAGGACACCATGCGCTTCAGAGATAACACCGCC AAT

CCCATCGCCATTGTGCAGCTGCAGGAACTCTCTTTGAGGCTGAAGAGCTGCTTCACC AAG

G ATTAT GAAGAGC AT GACAAGGCCTGCGTCCG AACTTT CTAT GAGACACCT CTCCAGTT G

CT GG AG AAG GT C AAG AATGTCTTT AAT G AAAC AAAG AAT CTCCTT G AC AAG G ACT GG AAT

ATTTTCAGCAAGAACTGCAACAACAGCTTTGCTGAATGCTCCAGCCAAGATGTGGTG ACC

AAGCCTGATTGCAACTGCCTGTACCCCAAAGCCATCCCTAGCAGTGACCCGGCCTCT GTC

TCCCCTCATCAGCCCCTCGCCCCCTCCATGGCCCCTGTGGCTGGCTTGACCTGGGAG GAC

TCTGAGGGAACTGAGGGCAGCTCCCTCTTGCCTGGTGAGCAGCCCCTGCACACAGTG GAT

CCAGGCAGTGCCAAGCAGCGGCCACCCAGGAGCACCTGCCAGAGCTTTGAGCCGCCA GAG

ACCCCAGTTGTCAAGGACAGCACCATCGGTGGCTCACCACAGCCTCGCCCCTCTGTC GGG

GCCTTCAACCCCGGGATGGAGGATATTCTTGACTCTGCAATGGGCACTAATTGGGTC CCA

GAAGAAGCCTCTGGAGAGGCCAGTGAGATTCCCGTACCCCAAGGGACAGAGCTTTCC CCC

TCCAGGCCAGGAGGGGGCAGCATGCAGACAGAGCCCGCCAGACCCAGCAACTTCCTC TCA

GCATCTTCTCCACTCCCTGCATCAGCAAAGGGCCAACAGCCGGCAGATGTAACTGCT ACA

GCCTTGCCCAGGGTGGGCCCCGTGATGCCCACTGGCCAGGACTGGAATCACACCCCC CAG

AAGACAGACCATCCATCTGCCCTGCTCAGAGACCCCCCGGAGCCAGGCTCTCCCAGG ATC

TCATCACTGCGCCCCCAGGCCCTCAGCAACCCCTCCACCCTCTCTGCTCAGCCACAG CTT

TCCAGAAGCCACTCCTCGGGCAGCGTGCTGCCCCTTGGGGAGCTGGAGGGCAGGAGG AGC

ACCAGGGATCGGACGAGCCCCGCAGAGCCAGAAGCAGCACCAGCAAGTGAAGGGGCA GCC

AGGCCCCTGCCCCGTTTTAACTCCGTTCCTTTGACTGACACAGGCCATGAGAGGCAG TCC

GAGGGATCCTCCAGCCCGCAGCTCCAGGAGTCTGTCTTCCACCTGCTGGTGCCCAGT GTC

ATCCTGGTCTTGCTGGCTGTCGGAGGCCTCTTGTTCTACAGGTGGAGGCGGCGGAGC CAT

CAAGAGCCTCAGAGAGCGGATTCTCCCTTGGAGCAACCAGAGGGCAGCCCCCTGACT CAG

GATGACAGACAGGTGGAACTGCCAGTGTAGAGGGAATTCTAAGCTGGACGCACAGAA CAG

TCTCTTCGTGGGAGGAGACATTATGGGGCGTCCACCACCACCCCTCCCTGGCCATCC TCC

T GGAAT GT GGTCT GCCCTCCACCAGAGCTCCT GCCT GCCAGGACTGGACCAGAGCAGCCA

GGCTGGGGCCCCTCTGTCTCAACCCGCAGACCCTTGACTGAATGAGAGAGGCCAGAG GAT

GCTCCCCATGCTGCCACTATTTATTGTGAGCCCTGGAGGCTCCCATGTGCTTGAGGA AGG

CTGGTGAGCCCGGCTCAGGACCCTCTTCCCTCAGGGGCTGCAGCCTCCTCTCACTCC CTT

CCATGCCGGAACCCAGGCCAGGGACCCACCGGCCTGTGGTTTGTGGGAAAGCAGGGT GCA

CGCTGAGGAGTGAAACAACCCTGCACCCAGAGGGCCTGCCTGGTGCCAAGGTATCCC AGC

CTGGACAGGCATGGACCTGTCTCCAGACAGAGGAGCCTGAAGTTCGTGGGGCGGGAC AGC CTCGGCCT GATTTCCCGTAAAGGT GT GCAGCCT GAGAGACGGGAAGAGGAGGCCTCT GCA

CCTGCTGGTCTGCACTGACAGCCTGAAGGGTCTACACCCTCGGCTCACCTAAGTCCC TGT

GCTGGTTGCCAGGCCCAGAGGGGAGGCCAGCCCTGCCCTCAGGACCTGCCTGACCTG CCA

GTGATGCCAAGAGGGGGATCAAGCACTGGCCTCTGCCCCTCCTCCTTCCAGCACCTG CCA

GAGCTTCTCCAGCAGGCCAAGCAGAGGCTCCCCTCATGAAGGAAGCCATTGCACTGT GAA

CACTGTACCTGCCTGCTGAACAGCCTCCCCCCGTCCATCCATGAGCCAGCATCCGTC CGT

CCTCCACTCTCCAGCCTCTCCCCAGCCTCCTGCACTGAGCTGGCCTCACCAGTCGAC TGA

GGGAGCCCCTCAGCCCTGACCTTCTCCTGACCTGGCCTTTGACTCCCCGGAGTGGAG TGG

GGTGGGAGAACCTCCTGGGCCGCCAGCCAGAGCCGCTCTTTAGGCTGTGTTCTTCGC CCA

GGTTTCTGCATCTTCCACTTTGACATTCCCAAGAGGGAAGGGACTAGTGGGAGAGAG CAA

GGGAGGGGAGGGCACAGACAGAGAGCCTACAGGGCGAGCTCTGACTGAAGATGGGCC TTT

GAAATATAGGTATGCACCTGAGGTTGGGGGAGGGTCTGCACTCCCAAACCCCAGCGC AGT

GTCCTTTCCCTGCTGCCGACAGGAACCTGGGGCTGAGCAGGTTATCCCTGTCAGGAG CCC

TGGACTGGGCTGCATCTCAGCCCCACCTGCATGGTATCCAGCTCCCATCCACTTCTC ACC

CTTCTTTCCTCCTGACCTTGGTCAGCAGTGATGACCTCCAACTCTCACCCACCCCCT CTA

CCATCACCTCTAACCAGGCAAGCCAGGGTGGGAGAGCAATCAGGAGAGCCAGGCCTC AGC

TTCCAATGCCTGGAGGGCCTCCACTTTGTGGCCAGCCTGTGGTGCTGGCTCTGAGGC CTA

GGCAACGAGCGACAGGGCTGCCAGTTGCCCCTGGGTTCCTTTGTGCTGCTGTGTGCC TCC

TCTCCTGCCGCCCTTTGTCCTCCGCTAAGAGACCCTGCCCTACCTGGCCGCTGGGCC CCG

TGACTTTCCCTTCCTGCCCAGGAAAGTGAGGGTCGGCTGGCCCCACCTTCCCTGTCC TGA

TGCCGACAGCTTAGGGAAGGGCACTGAACTTGCATATGGGGCTTAGCCTTCTAGTCA CAG

CCTCTAT ATTT G ATGCT AG AAAAC AC AT ATTTTT AAAT G G AAG AAAAAT AAAAAGG C ATT

CCCCCTTCATCCCCCTACCTTAAACATATAATATTTTAAAGGTCAAAAAAGCAATCC AAC

CCACTGCAGAAGCTCTTTTTGAGCACTTGGTGGCATCAGAGCAGGAGGAGCCCCAGA GCC

ACCTCTGGTGTCCCCCAGGCTACCTGCTCAGGAACCCCTTCTGTTCTCTGAGAACTC AAC

AG AGG AC ATT GGCTCACGCACTGT G AG ATTTT GTTTTT AT ACTT G C AACT GGT G AATT AT

TTTTT AT AAAGTC ATTT AAAT ATCT ATTT AAAAG AT AGG AAG CTG CTTATAT ATTT AAT A

ATAAAAGAAGTGCACAAGCTGCCGTTGACGTAGCTCGAG

(SEQ ID NO: 19)

As used herein, the term “CST7” refers to the gene encoding Cystatin-F. The terms “CST7” and "Cystatin-F" include wild-type forms of the CST7 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type CST7. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type CST7 nucleic acid sequence (e.g., SEQ ID NO: 20, ENA accession number AF031824). SEQ ID NO: 20 is a wild-type gene sequence encoding CST7 protein, and is shown below:

GGCTCAGCACAGGCACAAACCATT GCCCGGCACT GGCCCGT GOT GCCTGAGAAGGATTGG CACGGGCACAGACCACTGCCCCCACCTGCCCTGCGCCATCTACCCAAGAAGGCTCGGCAC GGGCACCAACCACTGCCTCCAACTGCCCCATGCTGCCTGAGAAGGCACTGCACGGCCACC CCCAACTGCCCCGCACTGTCCCTACCCGGGCAGCCATGCGAGCGGCTGGAACTCTGCTGG

CCTTCTGCTGCCTGGTCTTGAGCACCACTGGGGGCCCTTCCCCAGATACTTGTTCCC AGG

ACCTTAACTCACGTGTGAAGCCAGGATTTCCTAAAACAATAAAGACCAATGACCCAG GAG

TCCTCCAAGCAGCCAGATACAGTGTTGAAAAGTTCAACAACTGCACGAACGACATGT TCT

TGTTCAAGGAGTCCCGCATCACAAGGGCCCTAGTTCAGATAGTGAAAGGCCTGAAAT ATA

TGCTGGAGGTGGAAATTGGCAGAACTACCTGCAAGAAAAACCAGCACCTGCGTCTGG ATG

ACTGTGACTTCCAAACC AACCACACCTT G AAGCAG ACT CT G AGCTGCTACT CT GAAGTCT

GGGTCGTGCCCTGGCTCCAGCACTTCGAGGTGCCTGTTCTCCGTTGTCACTGACCCC CGC

CTCTTCAGCAAGACCACAGCCATGACAAACACCAGGATGCATGCTCCTTGTCCCCTC CCA

CCCGCCTCATGACCCAGCCTCACAGACCCTCTCAGGCCTCTGACGAGTGAGCGGGTG AAG

TGCCACTGGGTCACCGCAGGGCAGCTGGAATGGCAGCATGGTAGCACCTCCTAACAG ATT

AAAT AG AT C AC ATTT GCTTCT AAAATT

(SEQ ID NO: 20)

As used herein, the term “CTSB” refers to the gene encoding Cathepsin B. The terms “CTSB” and "Cathepsin B" include wild-type forms of the CTSB gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type CTSB. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type CTSB nucleic acid sequence (e.g., SEQ ID NO: 21 , ENA accession number M14221). SEQ ID NO: 21 is a wild-type gene sequence encoding CTSB protein, and is shown below:

AATTCCGCGGCAACCGCTCCGGCAACGCCAACCGCTCCGCTGCGCGCAGGCTGGGCT GCA

GGCTCTCGGCTGCAGCGCTGGGCTGGTGTGCAGTGGTGCGACCACGGCTCACGGCAG CCT

CAGCCACCCAGATGTAAGCGATCTGGTTCCCACCTCAGCCTTCCGAGTAGTGGATCT AGG

ATCTGGCTTCCAACATGTGGCAGCTCTGGGCCTCCCTCTGCTGCCTGCTGGTGTTGG CCA

ATGCCCGGAGCAGGCCCTCTTTCCATCCCGTGTCGGATGAGCTGGTCAACTATGTCA ACA

AACGGAATACCACGTGGCAGGCCGGGCACAACTTCTACAACGTGGACATGAGCTACT TGA

AGAGGCTATGTGGTACCTTCCTGGGTGGGCCCAAGCCACCCCAGAGAGTTATGTTTA CCG

AGGACCTGAAGCTGCCTGCAAGCTTCGATGCACGGGAACAATGGCCACAGTGTCCCA CCA

TCAAAGAGATCAGAGACCAGGGCTCCTGTGGCTCCTGCTGGGCCTTCGGGGCTGTGG AAG

CCATCTCTGACCGCATCTGCATCCACACCAATGCGCACGTCAGCGTGGAGGTGTCGG CGG

AGGACCTGCTCACCTGCTGTGGCAGCATGTGTGGGGACGGCTGTAATGGTGGCTATC CTG

CTGAAGCTTGGAACTTCTGGACAAGAAAAGGCCTGGTTTCTGGTGGCCTCTATGAAT CCC

ATGTAGGGTGCAGACCGTACTCCATCCCTCCCTGTGAGCACCACGTCAACGGCTCCC GGC

CCCCATGCACGGGGGAGGGAGATACCCCCAAGTGTAGCAAGATCTGTGAGCCTGGCT ACA

GCCCGACCTACAAACAGGACAAGCACTACGGATACAATTCCTACAGCGTCTCCAATA GCG

AGAAGGACATCATGGCCGAGATCTACAAAAACGGCCCCGTGGAGGGAGCTTTCTCTG TGT

ATTCGGACTTCCTGCTCTACAAGTCAGGAGTGTACCAACACGTCACCGGAGAGATGA TGG

GTGGCCATGCCATCCGCATCCTGGGCTGGGGAGTGGAGAATGGCACACCCTACTGGC TGG

TTGCCAACTCCT GG AAC ACT GACT GGGGTG AC AAT GGCTTCTTT AAAAT ACT CAGAGGAC AGGATCACTGCGGAATCGAATCAGAAGTGGTGGCTGGAATTCCACGCACCGATCAGTACT

GGGAAAAGATCTAATCTGCCGTGGGCCTGTCGTGCCAGTCCTGGGGGCGAGATCGGG GTA

G AAAGT C ATTTT ATT CTTT AAGTT C ACGTAAG AT AC AAGTTT CAGGCAGGGTCT G AAG G A

CTGGATTGGCCAAAGTCCTCCAAGGAGACCAAGTCCTGGCTACATCCCAGCCTGTGG TTA

CAGTGCAGACAGGCCATGTGAGCCACCGCTGCCAGCACAGAGCGTCCTTCCCCCTGT AGA

CTAGTGCCGTGGGAGTACCTGCTGCCCAGCTGCTGTGGCCCCCTCCGTGATCCATCC ATC

TCCAGGGAGCAAGACAGAGACGCAGGATGGAAAGCGGAGTTCCTAACAGGATGAAAG TTC

CCCCATCAGTTCCCCCAGTACCTCCAAGCAAGTAGCTTTCCACATTTGTCACAGAAA TCA

GAGGAGAGATGGTGTTGGGAGCCCTTTGGAGAACGCCAGTCTCCAGGTCCCCCTGCA TCT

ATCGAGTTTGCAATGTCACAACCTCTCTGATCTTGTGCTCAGCATGATTCTTTAATA GAA

GTTTTATTTTTCGTGCACTCTGCTAATCATGTGGGTGAGCCAGTGGAACAGCGGGAG CCT

GTGCTGGTTTGCAGATTGCCTCCTAATGACGCGGCTCAAAAGGAAACCAAGTGGTCA GGA

GTTGTTTCTGACCCACTGATCTCTACTACCACAAGGAAAATAGTTTAGGAGAAACCA GCT

TTTACTGTTTTTGAAAAATTACAGCTTCACCCTGTCAAGTTAACAAGGAATGCCTGT GCC

AATAAAAGGTTTCTCCAACTTG

(SEQ ID NO: 21)

As used herein, the term “CTSD” refers to the gene encoding Cathepsin D. The terms “CTSD” and "Cathepsin D" include wild-type forms of the CTSD gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type CTSD. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type CTSD nucleic acid sequence (e.g., SEQ ID NO: 22, ENA accession number M11233). SEQ ID NO: 22 is a wild-type gene sequence encoding CTSD protein, and is shown below:

GGCTATAAGCGCACGGCCTCGGCGACCCTCTCCGACCCGGCCGCCGCCGCCATGCAG CCC

TCCAGCCTTCTGCCGCTCGCCCTCTGCCTGCTGGCTGCACCCGCCTCCGCGCTCGTC AGG

ATCCCGCTGCACAAGTTCACGTCCATCCGCCGGACCATGTCGGAGGTTGGGGGCTCT GTG

GAGGACCTGATTGCCAAAGGCCCCGTCTCAAAGTACTCCCAGGCGGTGCCAGCCGTG ACC

GAGGGGCCCATTCCCGAGGTGCTCAAGAACTACATGGACGCCCAGTACTACGGGGAG ATT

GGCATCGGGACGCCCCCCCAGTGCTTCACAGTCGTCTTCGACACGGGCTCCTCCAAC CTG

TGGGTCCCCTCCATCCACTGCAAACTGCTGGACATCGCTTGCTGGATCCACCACAAG TAC

AACAGCGACAAGTCCAGCACCTACGTGAAGAATGGTACCTCGTTTGACATCCACTAT GGC

TCGGGCAGCCTCTCCGGGTACCTGAGCCAGGACACTGTGTCGGTGCCCTGCCAGTCA GCG

TCGTCAGCCTCTGCCCTGGGCGGTGTCAAAGTGGAGAGGCAGGTCTTTGGGGAGGCC ACC

AAGCAGCCAGGCATCACCTTCATCGCAGCCAAGTTCGATGGCATCCTGGGCATGGCC TAC

CCCCGCATCTCCGTCAACAACGT GCTGCCCGT CTTCGACAACCT GAT GCAGCAGAAGCT G

GTGGACCAGAACATCTTCTCCTTCTACCTGAGCAGGGACCCAGATGCGCAGCCTGGG GGT

GAGCTGATGCTGGGTGGCACAGACTCCAAGTATTACAAGGGTTCTCTGTCCTACCTG AAT

GTCACCCGCAAGGCCTACTGGCAGGTCCACCTGGACCAGGTGGAGGTGGCCAGCGGG CTG

ACCCTGTGCAAGGAGGGCTGTGAGGCCATTGTGGACACAGGCACTTCCCTCATGGTG GGC CCGGTGGATGAGGTGCGCGAGCTGCAGAAGGCCATCGGGGCCGTGCCGCTGATTCAGGGC GAGTACATGATCCCCTGTGAGAAGGTGTCCACCCTGCCCGCGATCACACTGAAGCTGGGA GGCAAAGGCTACAAGCTGTCCCCAGAGGACTACACGCTCAAGGTGTCGCAGGCCGGGAAG ACCCTCTGCCTGAGCGGCTTCATGGGCATGGACATCCCGCCACCCAGCGGGCCACTCTGG ATCCTGGGCGACGTCTTCATCGGCCGCTACTACACTGTGTTTGACCGTGACAACAACAGG GTGGGCTTCGCCGAGGCTGCCCGCCTCTAGTTCCCAAGGCGTCCGCGCGCCAGCACAGAA ACAGAGGAGAGTCCCAGAGCAGGAGGCCCCTGGCCCAGCGGCCCCTCCCACACACACCCA CACACTCGCCCGCCCACTGTCCTGGGCGCCCTGGAAGCCGGCGGCCCAAGCCCGACTTGC TGTTTTGTTCTGTGGTTTTCCCCTCCCTGGGTTCAGAAATGCTGCCTGCCTGTCTGTCTC TCCATCTGTTTGGTGGGGGTAGAGCTGATCCAGAGCACAGATCTGTTTCGTGCATTGGAA GACCCCACCCAAGCTTGGCAGCCGAGCTCGTGTATCCTGGGGCTCCCTTCATCTCCAGGG AGTCCCCTCCCCGGCCCTACCAGCGCCCGCTGGGCTGAGCCCCTACCCCACACCAGGCCG TCCTCCCGGGCCCTCCCTTGGAAACCTGCCCTGCCTGAGGGCCCCTCTGCCCAGCTTGGG CCCAGCTGGGCTCTGCCACCCTACCTGTTCAGTGTCCCGGGCCCGTTGAGGATGAGGCCG CTAGAGGCCTGAGGATGAGCTGGAAGGAGTGAGAGGGGACAAAACCCACCTTGTTGGAGC CTGCAGGGTGGTGCTGGGACTGAGCCAGTCCCAGGGGCATGTATTGGCCTGGAGGTGGGG TTGGGATTGGGGGCTGGTGCCAGCCTTCCTCTGCAGCTGACCTCTGTTGTCCTCCCCTTG GGCGGCTGAGAGCCCCAGCTGACATGGAAATACAGTTGTTGGCCTCCGGCCTCCCCTC (SEQ ID NO: 22)

As used herein, the term “CTSL” refers to the gene encoding Cathepsin L1 . The terms “CTSL” and "Cathepsin L1" include wild-type forms of the CTSL gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type CTSL. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type CTSL nucleic acid sequence (e.g., SEQ ID NO: 23, ENA accession number X12451). SEQ ID NO: 23 is a wild-type gene sequence encoding CTSL protein, and is shown below:

AGAACCGCGACCTCCGCAACCTTGAGCGGCATCCGTGGAGTGCGCCTGCAGCTACGA CCG

CAGCAGGAAAGCGCCGCCGGCCAGGCCCAGCTGTGGCCGGACAGGGACTGGAAGAGA GGA

CGCGGTCGAGTAGGTGTGCACCAGCCCTGGCAACGAGAGCGTCTACCCCGAACTCTG CTG

GCCTTGAGGTGGGGAAGCCGGGGAGGGCAGTTGAGGACCCCGCGGAGGCGCGTGACT GGT

TGAGCGGGCAGGCCAGCCTCCGAGCCGGGTGGACACAGGTTTTAAAACATGAATCCT ACA

CTCATCCTTGCTGCCTTTTGCCTGGGAATTGCCTCAGCTACTCTAACATTTGATCAC AGT

TTAGAGGCACAGTGGACCAAGTGGAAGGCGATGCACAACAGATTATACGGCATGAAT GAA

G AAGGATGGAGG AGAGCAGTGTGGGAGAAG AAC AT GAAG AT GATT GAACT GCACAAT CAG

GAATACAGGGAAGGGAAACACAGCTTCACAATGGCCATGAACGCCTTTGGAGACATG ACC

AGTGAAGAATTCAGGCAGGTGATGAATGGCTTTCAAAACCGTAAGCCCAGGAAGGGG AAA

GTGTTCCAGGAACCTCTGTTTTATGAGGCCCCCAGATCTGTGGATTGGAGAGAGAAA GGC

TACGTGACTCCTGTGAAGAATCAGGGTCAGTGTGGTTCTTGTTGGGCTTTTAGTGCT ACT

GGTGCTCTTGAAGGACAGATGTTCCGGAAAACTGGGAGGCTTATCTCACTGAGTGAG CAG AATCTGGTAGACTGCTCTGGGCCTCAAGGCAATGAAGGCTGCAATGGTGGCCTAATGGAT

TATGCTTTCCAGTATGTTCAGGATAATGGAGGCCTGGACTCTGAGGAATCCTATCCA TAT

GAGGCAACAGAAGAATCCTGTAAGTACAATCCCAAGTATTCTGTTGCTAATGACACC GGC

TTTGTGGACATCCCTAAGCAGGAGAAGGCCCTGATGAAGGCAGTTGCAACTGTGGGG CCC

ATTTCTGTTGCTATTGATGCAGGTCATGAGTCCTTCCTGTTCTATAAAGAAGGCATT TAT

TTTGAGCCAGACTGTAGCAGTGAAGACATGGATCATGGTGTGCTGGTGGTTGGCTAC GGA

TTT G AAAG C AC AG AAT C AG AT AAC AAT AAAT ATT G GCTGGT G AAG AAC AGCT G GG GT G AA

GAATGGGGCATGGGTGGCTACGTAAAGATGGCCAAAGACCGGAGAAACCATTGTGGA ATT

GCCTCAGCAGCCAGCTACCCCACTGTGTGAGCTGGTGGACGGTGATGAGGAAGGACT TGA

CTGGGGATGGCGCATGCATGGGAGGAATTCATCTTCAGTCTACCAGCCCCCGCTGTG TCG

GAT ACACACTCG AAT CATT GAAG ATCCG AGT GT GATTT GAATT CTGTG AT ATTTTCACAC

TGGT AAAT GTTACCTCT ATTTT AATT ACTGCTAT AAAT AG GTTT AT ATT ATT GATT C ACT

TACT G ACTTT GC ATTTTCGTTTTT AAAAG GAT GTAT AAATTTTT ACCTGTTT AAAT AAAA

TTT AATTT C AAAT GT

(SEQ ID NO: 23)

As used herein, the term “CXCL10” refers to the gene encoding C-X-C motif chemokine 10. The terms “CXCL10” and "C-X-C motif chemokine 10" include wild-type forms of the CXCL10 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type CXCL10. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type CXCL10 nucleic acid sequence (e.g., SEQ ID NO: 24, ENA accession number X02530). SEQ ID NO: 24 is a wild-type gene sequence encoding CXCL10 protein, and is shown below:

G AG AC ATTCCT C AATT G CTT AG AC AT ATT CTGAGCCT AC AG C AG AG GAACCTCCAGTCTC

AGCACCATGAATCAAACTGCGATTCTGATTTGCTGCCTTATCTTTCTGACTCTAAGT GGC

ATTCAAGGAGTACCTCTCTCTAGAACCGTACGCTGTACCTGCATCAGCATTAGTAAT CAA

CCTGTT AATCC AAG GT CTTT AG AAAAACTT G AAATT ATTCCT G C AAG CC AATTTT GTCC A

CGTGTTGAGATCATTGCTACAATGAAAAAGAAGGGTGAGAAGAGATGTCTGAATCCA GAA

TCGAAGGCCATCAAGAATTTACTGAAAGCAGTTAGCAAGGAAATGTCTAAAAGATCT CCT

TAAAACCAGAGGGGAGCAAAATCGATGCAGTGCTTCCAAGGATGGACCACACAGAGG CTG

CCTCTCCCATCACTTCCCTACATGGAGTATATGTCAAGCCATAATTGTTCTTAGTTT GCA

GTTACACTAAAAGGTGACCAATGATGGTCACCAAATCAGCTGCTACTACTCCTGTAG GAA

GGTTAATGTTCATCATCCTAAGCTATTCAGTAATAACTCTACCCTGGCACTATAATG TAA

GCTCTACTGAGGTGCTATGTTCTTAGTGGATGTTCTGACCCTGCTTCAAATATTTCC CTC

ACCTTTCCCATCTTCCAAGGGTACTAAGGAATCTTTCTGCTTTGGGGTTTATCAGAA TTC

T C AG AAT CT C AAAT AACT AAAAGGTATGC AAT C AAAT CTG CTTTTT AAAG AAT G CT CTTT

ACTTCATGGACTTCCACTGCCATCCTCCCAAGGGGCCCAAATTCTTTCAGTGGCTAC CTA

CATACAATTCCAAACACATACAGGAAGGTAGAAATATCTGAAAATGTATGTGTAAGT ATT

CTT ATTT AAT G AAAG ACTGTAC AAAGTAT AAGTCTT AG AT GTATAT ATTTCCT AT ATT GT

TTT C AGTGT AC AT G G AAT AAC AT GT AATT AAGTACTATGTAT C AAT G AGT AAC AGG AAAA TTTT AAAAAT AC AG AT AG ATATATG CTCTG CAT GTT AC AT AAG AT AAATGTG CT G AAT G G TTTT C AAAT AAAAAT GAGGTACTCTCCTG G AAAT ATT AAG AAAG ACT ATCT AAAT GTTG A AAG AT C AAAAGGTT AAT AAAGT AATT AT AACT (SEQ ID NO: 24)

As used herein, the term “CXCL13” refers to the gene encoding C-X-C motif chemokine 13. The terms “CXCL13” and "C-X-C motif chemokine 13" include wild-type forms of the CXCL13 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type CXCL13. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type CXCL13 nucleic acid sequence (e.g., SEQ ID NO: 25, ENA accession number AF044197). SEQ ID NO: 25 is a wild-type gene sequence encoding CXCL13 protein, and is shown below:

TTCGGCACTTGGGAGAAGATGTTTGAAAAAACTGACTCTGCTAATGAGCCTGGACTC AGA

GCTCAAGTCTGAACTCTACCTCCAGACAGAATGAAGTTCATCTCGACATCTCTGCTT CTC

ATGCTGCTGGTCAGCAGCCTCTCTCCAGTCCAAGGTGTTCTGGAGGTCTATTACACA AGC

TTGAGGTGTAGATGTGTCCAAGAGAGCTCAGTCTTTATCCCTAGACGCTTCATTGAT CGA

ATTCAAATCTTGCCCCGTGGGAATGGTTGTCCAAGAAAAGAAATCATAGTCTGGAAG AAG

AACAAGTCAATTGTGTGTGTGGACCCTCAAGCTGAATGGATACAAAGAATGATGGAA GTA

TT GAGAAAAAGAAGTTCTT CAACTCT ACC AGTTCCAGTGTTT AAGAGAAAG ATTCCCT GA

TGCTGATATTTCCACTAAGAACACCTGCATTCTTCCCTTATCCCTGCTCTGGATTTT AGT

TTTGTGCTTAGTTAAATCTTTTCCAGGGAGAAAGAACTTCCCCATACAAATAAGGCA TGA

GGACTATGTGAAAAATAACCTTGCAGGAGCTGATGGGGCAAACTCAAGCTTCTTCAC TCA

CAGCACCCTAT AT ACACTT GG AGTTTGCATT CTT ATT CAT CAGGGAGG AAAGTTT CTTT G

AAAAT AGTT ATT C AGTTATAAGT AAT AC AGG ATT ATTTT GATT AT AT ACTTGTT GTTT AA

T GTTT AAAATTT CTT AG AAAAC AAT G G AAT G AG AATTT AAGCC T C AAATTT G AAC AT GTG

G CTT G AATT AAG AAG AAAATT AT G GC AT AT ATT AAAAGC AGG CTT CTAT G AAAG ACT C AA

AAAGCTGCCTGGGAGGCAGATGGAACTTGAGCCTGTCAAGAGGCAAAGGAATCCATG TAG

T AG AT ATCCTCTGCTT AAAAACT C ACT ACG G AG GAG AATT AAGTCCT ACTTTT AAAG AAT

TT CTTT AT AAAATTT ACTGTCT AAG ATT AAT AG C ATTCG AAG ATCCCC AG ACTT CAT AG A

ATACTCAGGGAAAGCATTTAAAGGGTGATGTACACATGTATCCTTTCACACATTTGC CTT

GACAAACTTCTTTCACTCACATCTTTTTCACTGACTTTTTTTGTGGGGGCGGGGCCG GGG

G G ACT CTGGTATCT AATT CTTT AAT G ATTCCT AT AAAT CT AAT G AC ATT C AAT AAAGTT G

AGCAAACATTTT ACTT

(SEQ ID NO: 25)

As used herein, the term “DSG2” refers to the gene encoding Desmoglein 2. The terms “DSG2” and "Desmoglein 2 " include wild-type forms of the DSG2 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type DSG2. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type DSG2 nucleic acid sequence (e.g., SEQ ID NO: 26, NCBI Reference Sequence: NM_001943.4). SEQ ID NO: 26 is a wild-type gene sequence encoding DSG2 protein, and is shown below:

CCACCTCTGTAAAAGCGGCCCGGGCCGGCCCCCGGCTCCATTTTCTCGCGGCGGCCA CACCTGGA

GCCGCGCCTTTGGGTTGGGCTGGGCTGGGCCGCGCAACCGCCACGGGAAGACAGCCC TCGGGGC

GGGGAGGGAGAGGGTGGCCGGGCCGGGGGGAGGCCGGGGCCAGGGAGGAGCCGAGTG CGCGC

TCGGGGCAGGCGGCGGCGCGGAGCGGTGCGGCGGCGGGAGGCGGAGGCGAGGGTGCG ATGGC

GCGGAGCCCGGGACGCGCGTACGCCCTGCTGCTTCTCCTGATCTGCTTTAACGTTGG AAGTGGACT

T C ACTT AC AG GTCTT AAG C AC AAG AAAT G AAAAT AAGCTGCTTCCT AAAC AT C CT C ATTT AGTGCGGC

AAAAGCGCGCCTGGATCACCGCCCCCGTGGCTCTTCGGGAGGGAGAGGATCTGTCCA AGAAGAAT

CC AATT G CC AAG AT AC ATT CTG ATCTTG C AG AAG AAAG AG G ACT C AAAATT ACTT AC AAAT AC ACTGG

AAAAGGGATTACAGAGCCACCTTTTGGTATATTTGTCTTTAACAAAGATACTGGAGA ACTGAATGTTA

CCAGCATTCTTGATCGAGAAGAAACACCATTTTTTCTGCTAACAGGTTACGCTTTGG ATGCAAGAGGA

AACAATGTAGAGAAACCCTTAGAGCTACGCATTAAGGTTCTTGATATCAATGACAAC GAACCAGTGTT

CACACAGGATGTCTTTGTTGGGTCTGTTGAAGAGTTGAGTGCAGCACATACTCTTGT GATGAAAATCA

ATGCAACAGATGCAGATGAGCCCAATACCCTGAATTCGAAAATTTCCTATAGAATCG TATCTCTGGAG

CCTGCTTATCCTCCAGTGTTCTACCTAAATAAAGATACAGGAGAGATTTATACAACC AGTGTTACCTT

G G ACAG AG AG G AAC AC AGC AGCT AC ACTTT G AC AGT AG AAGC AAG AG AT G G C AAT G GAG AAG TT AC

AGACAAACCTGTAAAAC AAGCT CAAGTT CAGATTCGT ATTTTGG AT GT CAAT G ACAAT AT ACCTGTAG

TAGAAAATAAAGTGCTTGAAGGGATGGTTGAAGAAAATCAAGTCAACGTAGAAGTTA CGCGCATAAA

AGT GTTCG AT G C AG AT G AAAT AGGTTCT GAT AATT G GCT G GC AAATTTT AC ATTT G CAT C AG G AAAT G

AAGGAGGTTATTTCCACATAGAAACAGATGCTCAAACTAACGAAGGAATTGTGACCC TTATTAAGGAA

GTAGATTATGAAGAAATGAAGAATCTTGACTTCAGTGTTATTGTCGCTAATAAAGCA GCTTTTCACAA

GTCGATTAGGAGTAAATACAAGCCTACACCCATTCCCATCAAGGTCAAAGTGAAAAA TGTGAAAGAA

GGCATTCATTTTAAAAGCAGCGTCATCTCAATTTATGTTAGCGAGAGCATGGATAGA TCAAGCAAAGG

CCAAATAATTGGAAATTTTCAAGCTTTTGATGAGGACACTGGACTACCAGCCCATGC AAGATATGTAA

AATT AG AAG AT AG AG AT AATT GGATCTCTGTG GATT CTGT C AC AT CT G AAATT AAACTT GC AAAACTT C

CT G ATTTT G AAT CT AG AT AT GTT C AAAAT G GC AC AT AC ACT GT AAAG ATTGTG G CC AT AT C AG AAG ATT

ATCCT AG AAAAACC AT CACT GGCACAGTCCTT AT CAAT GTT G AAG AC ATC AACG ACAACTGTCCC AC A

CTGATAGAGCCTGTGCAGACAATCTGTCACGATGCAGAGTATGTGAATGTTACTGCA GAGGACCTGG

ATGGACACCCAAACAGTGGCCCTTTCAGTTTCTCCGTCATTGACAAACCACCTGGCA TGGCAGAAAA

ATGGAAAATAGCACGCCAAGAAAGTACCAGTGTGCTGCTGCAACAAAGTGAGAAAAA GCTTGGGAG

AAGTGAAATTC AGTTCCT GATTT CAG ACAAT CAGGGTTTT AGTT GTCCT GAAAAGCAGGTCCTT ACAC

TCACAGTTTGTGAGTGTCTGCATGGCAGCGGCTGCAGGGAAGCACAGCATGACTCCT ATGTGGGCC

TGGGACCCGCAGCAATTGCGCTCATGATTTTGGCCTTTCTGCTCCTGCTATTGGTAC CACTTTTACTG

CTGATGTGCCATTGCGGAAAGGGCGCCAAAGGCTTTACCCCCATACCTGGCACCATA GAGATGCTG

CATCCTTGGAATAATGAAGGAGCACCACCTGAAGACAAGGTGGTGCCATCATTTCTG CCAGTGGATC

AAGGGGGCAGTCTAGTAGGAAGAAATGGAGTAGGAGGTATGGCCAAGGAAGCCACGA TGAAAGGA

AGTAGCTCTGCTTCCATTGTCAAAGGGCAACATGAGATGTCCGAGATGGATGGAAGG TGGGAAGAA

CACAGAAGCCTGCTTTCTGGTAGAGCTACCCAGTTTACAGGGGCCACAGGCGCTATC ATGACCACT

GAAACCACGAAGACCGCAAGGGCCACAGGGGCTTCCAGAGACATGGCCGGAGCTCAG GCAGCTGC TGTTGCACTGAACGAAGAATTCTTAAGAAATTATTTCACTGATAAAGCGGCCTCTTACAC TGAGGAAG

ATGAAAATCACACAGCCAAAGATTGCCTTCTGGTTTATTCTCAGGAAGAAACTGAAT CGCTGAATGCT

TCTATTGGTTGTTGCAGTTTTATTGAAGGAGAGCTAGATGACCGCTTCTTAGATGAT TTGGGACTTAA

ATT C AAG AC ACT AG CT G AAGTTT GCCT G GGTC AAAAAAT AG AT AT AAAT AAG G AAATT GAG C AG AG AC

AAAAACCTGCC AC AG AAACAAGT AT G AACACAGCTTCACATTC ACT CTGTGAGCAA ACT ATGGTT AAT

TCAGAGAATACCTACTCCTCTGGCAGTAGCTTCCCAGTTCCAAAATCTTTGCAAGAA GCCAATGCAG

AGAAAGTAACTCAGGAAATAGTCACTGAAAGATCTGTGTCTTCTAGGCAGGCGCAAA AGGTAGCTAC

ACCTCTTCCTGACCCAATGGCTTCTAGAAATGTGATAGCAACAGAAACTTCCTATGT CACAGGGTCCA

CTATGCCACCAACCACTGTGATCCTGGGTCCTAGCCAGCCACAGAGCCTTATTGTGA CAGAGAGGG

TGTATGCTCCAGCTTCTACCTTGGTAGATCAGCCTTATGCTAATGAAGGTACAGTTG TGGTCACTGAA

AGAGTAATACAGCCTCATGGGGGTGGATCGAATCCTCTGGAAGGCACTCAGCATCTT CAAGATGTAC

CTTACGTCATGGT GAGGGAAAGAGAGAGCTTCCTT GCCCCCAGCTCAGGT GT GCAGCCTACTCT GG

CCATGCCTAATATAGCAGTAGGACAGAATGTGACAGTGACAGAAAGAGTTCTAGCAC CTGCTTCCAC

TCTGCAATCCAGTTACCAGATTCCCACTGAAAATTCTATGACGGCTAGGAACACCAC GGTGTCTGGA

GCTGGAGTCCCTGGCCCTCTGCCAGATTTTGGTTTAGAGGAATCTGGTCATTCTAAT TCTACCATAAC

CACATCTTCCACCAGAGTTACCAAGCATAGCACTGTACAGCATTCTTACTCCTAAAC AGCAGTCAGCC

AC AAACT G ACC C AG AGTTT AATT AG C AGT G ACT AATTT C ATGTTTCC AAT GTACCT G ATTTTT CAT GAG

CCTT AC AG AC AC AC AG AG AC AC AT AC AC ATT G ATCTT AAAATTTTT CTC AGT C ACT GAT AT GC AAAG G

ACCACACTGTCTCTGCTTCCAGGAGTATTTTAGAAATGTTCCACAATTTACTGAAGA CATAGAGATGA

TGCTGCTGCTTAGGTGCCTTTTAGCAAGCTATGCAAACAATCCTGATAAAACAAGAT ACATAGAGAGT

CAATCTGGCTTCTGAGAATTTACCAAGTGAACAGAGTACCTAGTTCATCAGCCGTCC AGTAAAGCAA

CCCAGGAAACTGACTGGGTCTCTTTGCCTACCGTATTAACATTAAACATTGATGTTC TGTATTCTGTA

CTTT ACTG C AC CC AG C AG ACTTT CAAC AACT C ATT G ATCC AAAG AT AC AT GC AC AGTCT GAG C AC C AG

CT ATGGT GCT CAT AACTT CTTT AAGACTT G AACCCTTTCAATCT GT GT GATTC ATT AAATT GG ACC ATT

GAT GAT AAG AAT AC AC ATT GT ATGTTTCT GT GCACAT GACAGTGTGTGTGT GTGCACGTACATACT GT

ATAGTCTTAAAAATAGCATTATACTGGCCAGGGGTGGTGGCTAACGCCTGTAATCCC AGCACTTTGG

GAGGCCGAGGCGGGTGGATCAACTGTGGTCAGGAGTTTGAGATCAGCCAGGCCAACC TGGTGAAA

CCCCGTCTCTACTAAAAATACAAAAATTAGCTGGGCGTGATGGTGGGCGCCTGTAAT CCCAGCTACT

TGGGAGGCTGAGGCAGGAGAATCACTTGAACCCGGGAGGCGGAGGTTGCAGTGAGCC GAGATCGC

ACCATTGCACTCCAGTCTGGGCAACAGAGTGAGATTCCGTCTCAAAAAAAAAAAGAA AAGGAAAAAA

AAATAGCATTATACCTCTTCCTTGTCTCAACCGCCATGAAAATTCTGAACACTCCAA ATTCAGTTGAAT

AATCCAAAACAAAATTT ATAAGTAT AAAATAATTTTACTTCTTAT AGTAATAGTAT ACTTT AAAAAGCCT

C AGG GTAT ATT ATCTTCT AAAC AGCT AC AATT C AGTG C AG CT AC ATT AACC AACT ATGTTCTCT AGTT G

AGAACAACTAGGCCTATTTCACTGCTGTGTAGCCTCAGTGCCTAACATGGGTGCCAA ATAAATATTCG

T AG AATT AC ACT GAATT GT AAAAACC ATTCGTTTTT GTTTACAATT GCCAAAAATCT CAAAAGGCCCT G

T ATTT ATGTAATT CTTT G AAATT ATT ATTTT ATTTT G ATTT CT C AGTT ATT GACTGGCTGGGTGTGACTT

AGT AC AT AAGTACT C AAT ATT AT AAAAACCT C AAAT AATT G ACTT G ATTTT AC AC AAC ATCCTTCCCTTT

TCT AC AAGTT AATTTTTTT AC AAAT C ATTT GGGTTATCTCCT AAAT AG GTT AT ATTTT ATT G CTTCT AG A

AAC AAT GTTT C AAAAT AT ATGTGC ATT ATC AGT AAT AATTTGTAT AAAT ATTT C CC AC AAC AATTTT CAT

AATTTTCAAAGACTAATTTCTTGACTGAAGATATTTTGCTAGGGAAGTGAAACTTTA AAATTTTGTAGA

TTTT AAAAAAT ATTGTT GAATGGT GT CAT GC AAAGGATTT AT AT AGT GT GCTCCCACT AACTGTACAG A

TCAGGACACATATTTTTAGACATCTAAGTCTGTAGCTTAAATGGAGGTTACTCTTCC ATCATCTAGAAT TGTTTACTTAGTAATTGTTGTTTCTTTTATTATTATAGACTTACTATCAGTTTTATTTTG CCAAGTATGCA

ACAGGTATATCACTAGTATATGAAAATGTAAATATCACTTGTGTACTCAAACAAAAG TTGGTCTTAAGC

TTCCACCTTGAGCAGCCTTGGAAACCTAACCTGCCTCTTTTAGCATAATCACATTTT CTAAATGATTTT

CTTTGTTCCT G AAAAAGTGATTTGTATT AGTTTTACATTTGTTTTTTGGAAG ATT AT ATTTGTAT AT GT A

TCATCATAAAATATTTAAATAAAAAGTATCTTTAGAGTGACCCTTTCCCCATAGATT TTTATTTCTCTAT

TATATTTTACAAGGAATATAACTCAGTTTGTTAGGGAGAGTGCCTTAAAGGCAGGTG TTTCTTGGACT

TTGTTATTTAATTAGATCTGCTTGCAATAAAAAAAGTTGTCGGTTATCTAAAATTCA AAAAAAAAAAAAA

AAAA

(SEQ ID NO: 26)

As used herein, the term “ECHDC3” refers to the gene encoding Enoyl-CoA Hydratase Domain Containing 3. The terms “ECHDC” and " Enoyl-CoA Hydratase Domain Containing 3" include wild-type forms of the ECHDC gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type ECHDC. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type ECHDC nucleic acid sequence (e.g., SEQ ID NO: 27, NCBI Reference Sequence: NM_024693.4). SEQ ID NO: 27 is a wild-type gene sequence encoding ECHDC protein, and is shown below:

GGGGCGGGGCGTGCCGGGGCGGGGCGTAGTACGGACTGGGCCTGGCCTGGGGCGTCC CCGCGA

AGCCTGGGCCTGTCAGGCGGTTCCGTCCGGGTCTCGGCCACCGTCGAGTTCCGTCGA GTTCCGTC

CCGGCCCTGCTCACAGCAGCGCCCTCGGAGCGCCCAGCACCTGCGGCCGGCCAGGCA GCGCGAT

CCTGCGGCGTCTGGCCATCCCGAATGCTATGGCCGCCGTCGCCGTCTTGCGGGCCTT CGGGGCAA

GTGGGCCCATGTGTCTCCGGCGCGGCCCCTGGGCCCAGCTCCCCGCCCGCTTCTGCA GCCGGGA

CCCGGCCGGGGCGGGGCGGCGGGAGTCGGAGCCGCGGCCCACCAGCGCGCGGCAGCT GGACGG

CATAAGGAACATCGTCTTGAGCAATCCCAAGAAGAGGAACACGTTGTCACTTGCAAT GCTGAAATCT

CTCCAAAGTGACATTCTTCATGACGCTGACAGCAACGATCTGAAAGTCATTATCATC TCGGCTGAGG

GGCCTGTGTTTTCTTCTGGGCATGACTTAAAGGAGCTGACAGAGGAGCAAGGCCGTG ATTACCATG

CCGAAGTATTTCAGACCTGTTCCAAGGTCATGATGCACATCCGGAACCACCCCGTCC CCGTCATTGC

CATGGTCAATGGCCTGGCCACGGCTGCCGGCTGTCAACTGGTTGCCAGCTGCGACAT TGCCGTGG

CGAGCGACAAGTCCTCTTTTGCCACTCCTGGGGTGAACGTCGGGCTCTTCTGTTCTA CCCCTGGGG

TTGCCTTGGCAAGAGCAGTGCCTAGAAAGGTGGCCTTGGAGATGCTCTTTACTGGTG AGCCCATTTC

TGCCCAGGAGGCCCTGCTCCACGGGCTGCTTAGCAAGGTGGTGCCAGAGGCGGAGCT GCAGGAG

GAGACCATGCGGATCGCTAGGAAGATCGCATCGCTGAGCCGTCCGGTGGTGTCCCTG GGCAAAGC

CACCTTCTACAAGCAGCTGCCCCAGGACCTGGGGACGGCTTACTACCTCACCTCCCA GGCCATGGT

GGACAACCTGGCCCTGCGGGACGGGCAGGAGGGCATCACGGCCTTCCTCCAGAAGAG AAAACCTG

TCTGGTCACACGAGCCAGTGTGAGTGGAGGCAGAGGAGTGAGGCCCACGGGCAGCGC CCAGGAG

CCCACCTTCCCCTCTGGCCCAGCCACCACTGCCTCTCAGCTTCAACAGGTGACAGGC TGCTTTCGT

GACTTGATATTGGTGTCATAGCATTTGGCCTACATTAAAAGCCACAATTTCATGGGG AAAGGACAAAA

T GGAGAGT GACTGAGGTGCT GACCTCAGT GCAAGGCT GGT GAACCCT GCAGCGGGCCAGCTATGG

TGGGAAGCCTGGCATTTGGGGTGCTCCTTGCAACGTCTTAAGCAAGCGACCCCCCTG ACATAGCAA

AAGGTGGCAACCCATGGAGGCAGAAAGAAGGACGCCAGCCTGACCCTTATCTGAAAC GTCCTAAGC AGAGTTAATCCTGGCTGCTCAGGAGAGGCGACACATTTCAAATCTCCACGAGATATTCTC CACACAG AAAATCTTCTTGATTCTATAGAGACTTAATCATGCCTATGGCTTTGAATAATCTTATGTG ATTTAAATAA ATT AAAT CTTT AT AAAAAAAAAAAAAAAAAAAA (SEQ ID NO: 27)

As used herein, the term ΈRHA1” refers to the gene encoding Ephrin type-A receptor 1 . The terms ΈRHA1” and "Ephrin type-A receptor 1" include wild-type forms of the EPHA1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type EPHA1 . Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type EPHA1 nucleic acid sequence (e.g.,

SEQ ID NO: 28, ENA accession number M18391). SEQ ID NO: 28 is a wild-type gene sequence encoding EPHA1 protein, and is shown below:

GCCCCCGCCCGGCCCGCCCCGCTCTCCTAGTCCCTTGCAACCTGGCGCTGCATCCGG GCC

ACTGTCCCAGGTCCCAGGTCCCGGCCCGGAGCTATGGAGCGGCGCTGGCCCCTGGGG CTA

GGGCTGGTGCTGCTGCTCTGCGCCCCGCTGCCCCCGGGGGCGCGCGCCAAGGAAGTT ACT

CTGATGGACACAAGCAAGGCACAGGGAGAGCTGGGCTGGCTGCTGGATCCCCCAAAA GAT

GGGTGGAGTGAACAGCAACAGATACTGAATGGGACACCCCTCTACATGTACCAGGAC TGC

CCAATGCAAGGACGCAGAGACACTGACCACTGGCTTCGCTCCAATTGGATCTACCGC GGG

GAGGAGGCTTCCCGCGTCCACGTGGAGCTGCAGTTCACCGTGCGGGACTGCAAGAGT TTC

CCTGGGGGAGCCGGGCCTCTGGGCTGCAAGGAGACCTTCAACCTTCTGTACATGGAG AGT

GACCAGGATGTGGGCATTCAGCTCCGACGGCCCTTGTTCCAGAAGGTAACCACGGTG GCT

GCAGACCAGAGCTTCACCATTCGAGACCTTGCGTCTGGCTCCGTGAAGCTGAATGTG GAG

CGCTGCTCTCTGGGCCGCCTGACCCGCCGTGGCCTCTACCTCGCTTTCCACAACCCG GGT

GCCTGTGTGGCCCTGGTGTCTGTCCGGGTCTTCTACCAGCGCTGTCCTGAGACCCTG AAT

GGCTTGGCCCAATTCCCAGACACTCTGCCTGGCCCCGCTGGGTTGGTGGAAGTGGCG GGC

ACCTGCTTGCCCCACGCGCGGGCCAGCCCCAGGCCCTCAGGTGCACCCCGCATGCAC TGC

AGCCCT GAT GGCGAGTGGCT GGT GCCT GTAGGACGGT GCCACTGTGAGCCT GGCTAT GAG

GAAGGTGGCAGTGGCGAAGCATGTGTTGCCTGCCCTAGCGGCTCCTACCGGATGGAC ATG

GACACACCCCATTGTCTCACGTGCCCCCAGCAGAGCACTGCTGAGTCTGAGGGGGCC ACC

ATCTGTACCTGTGAGAGCGGCCATTACAGAGCTCCCGGGGAGGGCCCCCAGGTGGCA TGC

ACAGGTCCCCCCTCGGCCCCCCGAAACCTGAGCTTCTCTGCCTCAGGGACTCAGCTC TCC

CTGCGTTGGGAACCCCCAGCAGATACGGGGGGACGCCAGGATGTCAGATACAGTGTG AGG

TGTTCCCAGTGTCAGGGCACAGCACAGGACGGGGGGCCCTGCCAGCCCTGTGGGGTG GGC

GTGCACTTCTCGCCGGGGGCCCGGGCGCTCACCACACCTGCAGTGCATGTCAATGGC CTT

GAACCTTATGCCAACTACACCTTTAATGTGGAAGCCCAAAATGGAGTGTCAGGGCTG GGC

AGCTCTGGCCATGCCAGCACCTCAGTCAGCATCAGCATGGGGCATGCAGAGTCACTG TCA

GGCCTGTCTCTGAGACTGGTGAAGAAAGAACCGAGGCAACTAGAGCTGACCTGGGCG GGG

TCCCGGCCCCGAAGCCCTGGGGCGAACCTGACCTATGAGCTGCACGTGCTGAACCAG GAT

GAAGAACGGTACCAGATGGTTCTAGAACCCAGGGTCTTGCTGACAGAGCTGCAGCCT GAC

ACCACATACATCGTCAGAGTCCGAATGCTGACCCCACTGGGTCCTGGCCCTTTCTCC CCT GATCATGAGTTTCGGACCAGCCCACCAGTGTCCAGGGGCCTGACTGGAGGAGAGATTGTA

GCCGTCATCTTTGGGCTGCTGCTTGGTGCAGCCTTGCTGCTTGGGATTCTCGTTTTC CGG

TCCAGGAGAGCCCAGCGGCAGAGGCAGCAGAGGCACGTGACCGCGCCACCGATGTGG ATC

GAGAGGACAAGCTGTGCTGAAGCCTTATGTGGTACCTCCAGGCATACGAGGACCCTG CAC

AGGGAGCCTTGGACTTTACCCGGAGGCTGGTCTAATTTTCCTTCCCGGGAGCTTGAT CCA

GCGTGGCT GATGGT GGACACT GTCATAGGAGAAGGAGAGTTT GGGGAAGT GTATCGAGGG

ACCCTCAGGCTCCCCAGCCAGGACTGCAAGACTGTGGCCATTAAGACCTTAAAAGAC ACA

TCCCCAGGTGGCCAGTGGTGGAACTTCCTTCGAGAGGCAACTATCATGGGCCAGTTT AGC

CACCCGCATATTCTGCATCTGGAAGGCGTCGTCACAAAGCGAAAGCCGATCATGATC ATC

ACAGAATTTATGGAGAATGCAGCCCTGGATGCCTTCCTGAGGGAGCGGGAGGACCAG CTG

GTCCCTGGGCAGCTAGTGGCCATGCTGCAGGGCATAGCATCTGGCATGAACTACCTC AGT

AATCACAATTATGTCCACCGGGACCTGGCTGCCAGAAACATCTTGGTGAATCAAAAC CTG

TGCTGCAAGGTGTCTGACTTTGGCCTGACTCGCCTCCTGGATGACTTTGATGGCACA TAC

GAAACCCAGGGAGGAAAGATCCCTATCCGTTGGACAGCCCCTGAAGCCATTGCCCAT CGG

ATCTTCACCACAGCCAGCGATGTGTGGAGCTTTGGGATTGTGATGTGGGAGGTGCTG AGC

TTTGGGGACAAGCCTTATGGGGAGATGAGCAATCAGGAGGTTATGAAGAGCATTGAG GAT

GGGTACCGGTTGCCCCCTCCTGTGGACTGCCCTGCCCCTCTGTATGAGCTCATGAAG AAC

TGCTGGGCATATGACCGTGCCCGCCGGCCACACTTCCAGAAGCTTCAGGCACATCTG GAG

CAACTGCTTGCCAACCCCCACTCCCTGCGGACCATTGCCAACTTTGACCCCAGGGTG ACT

CTTCGCCTGCCCAGCCTGAGTGGCTCAGATGGGATCCCGTATCGAACCGTCTCTGAG TGG

CTCGAGTCCATACGCATGAAACGCTACATCCTGCACTTCCACTCGGCTGGGCTGGAC ACC

ATGGAGTGTGTGCTGGAGCTGACCGCTGAGGACCTGACGCAGATGGGAATCACACTG CCC

GGGCACCAGAAGCGCATTCTTTGCAGTATTCAGGGATTCAAGGACTGATCCCTCCTC TCA

CCCCATGCCCAATCAGGGTGCAAGGAGCAAGGACGGGGCCAAGGTCGCTCATGGTCA CTC

CCTGCGCCCCTTCCCACAACCTGCCAGACTAGGCTATCGGTGCTGCTTCTGCCCGCT TTA

AGGAGAACCCTGCTCTGCACCCCAGAAAACCTCTTTGTTTTAAAAGGGAGGTGGGGG TAG

AAGTAAAAGGATGATCATGGGAGGGAGCTCAGGGGTTAATATATATACATACATACA CAT

ATATATATTGTTGTAAATAAACAGGAAATGATTTTCTGCCTCCATCCCACCCATCAG GGC

TGCAGGCACT

(SEQ ID NO: 28)

As used herein, the term “FABP5” refers to the gene encoding Fatty acid-binding protein 5. The terms “FABP5” and "Fatty acid-binding protein 5" include wild-type forms of the FABP5 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type FABP5. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type FABP5 nucleic acid sequence (e.g., SEQ ID NO: 29, ENA accession number M94856). SEQ ID NO: 29 is a wild-type gene sequence encoding FABP5 protein, and is shown below:

ACCGCCGACGCAGACCCCTCTCTGCACGCCAGCCCGCCCGCACCCACCATGGCCACA GTT

CAGCAGCTGGAAGGAAGATGGCGCCTGGTGGACAGCAAAGGCTTTGATGAATACATG AAG GAGCTAGGAGTGGGAATAGCTTTGCGAAAAATGGGCGCAATGGCCAAGCCAGATTGTATC ATCACTTGTG AT GGTAAAAACCT CACCAT AAAAACT GAGAGCACTTT G AAAACAAC AC AG TTTTCTTGTACCCTGGGAGAGAAGTTTGAAGAAACCACAGCTGATGGCAGAAAAACTCAG ACTGTCTGCAACTTTACAGATGGTGCATTGGTTCAGCATCAGGAGTGGGATGGGAAGGAA AGCACAATAACAAGAAAATTGAAAGATGGGAAATTAGTGGTGGAGTGTGTCATGAACAAT GTCACCT GT ACTCGG AT CTAT G AAAAAGT AGAATAAAAATTCCATC AT CACTTT GG ACAG G AGTT AATT AAG AG AAT G ACC AAG CT C AGTT C AAT G AGO AAAT CTC CAT ACT GTTT CTTT CTTTTTTTTTT C ATT ACTGTGTT C AATT AT CTTT AT CAT AAAC ATTTT AC ATGC AGCTAT TTCAAAGTGTGTTGGATTAATTAGGATCATCCCTTTGGTTAATAAATAAATGTGTTTGTG CT (SEQ ID NO: 29)

As used herein, the term “FERMT2” refers to the gene encoding Fermitin family homolog 2. The terms “FERMT2” and "Fermitin family homolog 2" include wild-type forms of the FERMT2 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type FERMT2. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type FERMT2 nucleic acid sequence (e.g., SEQ ID NO: 30, ENA accession number Z24725). SEQ ID NO: 30 is a wild-type gene sequence encoding FERMT2 protein, and is shown below:

CAAAAAGTGTGTGGAAAGGTGGATTGAGGGAGCGGGACCCCCGCGGGACCCGAGGGG GCG

GCAGGCGGGGAACGGGGAGTCAGCCCGCGCTGTGTCTCGGGGCCGGCCGGCAGGAAG GAG

CCATGGCTCTGGACGGGATAAGGATGCCAGATGGCTGCTACGCGGACGGGACGTGGG AAC

TGAGTGTCCATGTGACGGACCTGAACCGCGATATCACCCTGAGAGTGACCGGCGAGG TGC

ACATTGGAGGCGTGATGCTTAAGCTGGTGGAGAAACTCGATGTAAAAAAAGATTGGT CTG

ACCATGCTCTCTGGTGGGAAAAGAAGAGAACTTGGCTTCTGAAGACACATTGGACCT TAG

ATAAGTATGGTATTCAGGCAGATGCTAAGCTTCAGTTCACCCCTCAGCACAAACTGC TCC

GCCTGCAGCTTCCCAACATGAAGTATGTGAAGGTGAAAGTGAATTTCTCTGATAGAG TCT

TCAAAGCTGTTTCTGACATCTGTAAGACTTTTAATATCAGACACCCCGAAGAACTTT CTC

T CTTAAAG AAACCCAG AGATCCAACAAAG AAAAAAAAGAAGAAGCT AG AT G ACC AGT CT G

AAGATGAGGCACTTGAATTAGAGGGGCCTCTTATCACTCCTGGATCAGGAAGTATAT ATT

CAAGCCCAGGACTGTATAGTAAAACAATGACCCCCACTTATGATGCTCATGATGGAA GCC

CCTT GT CACC AACTT CTGCTTGGTTTGGT GACAGTGCTTT GT CAG AAGGCAATCCTGGT A

TACTTGCTGTCAGTCAACCAATCACGTCACCAGAAATCTTGGCAAAAATGTTCAAGC CTC

AAG CTCTTCTTG AT AAAG C AAAAAT C AACC AAGG AT G GCTT G ATTCCT C AAG AT CTCTC A

T GGAAC AAG AT GT GAAGG AAAAT GAGGCCTT GOT GCTCCG ATTCAAGT ATT ACAGCTTTT

TTGATTTGAATCCAAAGTATGATGCAATCAGAATCAATCAGCTTTATGAGCAGGCCA AAT

GGGCCATTCTCCTGGAAGAGATTGAATGCACAGAAGAAGAAATGATGATGTTTGCAG CCC

TGC AGTATC ATAT C AAT AAGCTGT C AAT CAT G AC AT C AG AG AAT C ATTT G AAC AAC AGT G

ACAAAGAAGTTGATGAAGTTGATGCTGCCCTTTCAGACCTGGAGATTACTCTGGAAG GGG

GTAAAACGTCAACAATTTTGGGTGACATTACTTCCATTCCTGAACTTGCTGACTACA TTA

AAGTTTTCAAGCCAAAAAAGCTGACTCTGAAAGGTTACAAACAATATTGGTGCACCT TCA AAG ACACAT CC ATTT CTT GTT AT AAG AGCAAAG AAGAATCC AGTGGCACACCAGCT CAT C

AGATGAACCTCAGGGGATGTGAAGTTACCCCAGATGTAAACATTTCAGGCCAAAAAT TTA

ACATT AAACTCCT G ATTCCAGTTGCAGAAGGCAT G AAT G AAAT CTGGCTTCGTTGTGACA

ATGAAAAACAGTATGCACACTGGATGGCAGCCTGCAGATTAGCCTCCAAAGGCAAGA CCA

TGGCGGACAGTTCTTACAACTTAGAAGTTCAGAATATTCTTTCCTTTCTGAAGATGC AGC

ATTT AAACCCAG ATCCTC AGTT AAT ACC AGAGC AG ATCACG ACT GAT AT AACTCCT GAAT

GTTTGGTGTCTCCCCGCTATCTAAAAAAGTATAAGAACAAGCAGATAACAGCGAGAA TCT

TGGAGGCCCATCAGAATGTAGCTCAGATGAGTCTAATTGAAGCCAAGATGAGATTTA TTC

AAGCTTGGCAGTCACTACCTGAATTTGGCATCACTCACTTCATTGCAAGGTTCCAAG GGG

G C AAAAAAG AAG AACTT ATT GG AATT G CAT AC AAC AG ACT GATT CG GAT G GAT GCC AGC A

CTGGAGATGCAATTAAAACATGGCGTTTCAGCAACATGAAACAGTGGAATGTCAACT GGG

AAATCAAAATGGTCACCGTAGAGTTTGCAGATGAAGTACGATTGTCCTTCATTTGTA CTG

AAGTAGATTGCAAAGTGGTTCATGAATTCATTGGTGGCTACATATTTCTCTCAACAC GTG

CAAAAG ACCAAAACG AG AGTTT AG AT GAAGAG AT GTTCT ACAAACTT ACC AGTGGTTGGG

TGTGAATAGAAATACTGTTTAATGAAACTCCACGGCCATAACAATATTTAACTTTAA AAG

CT GTTTGTT ATATGCTG CTT AAT AAAGT AAG CTT G AAATTT AT C ATTTT AT CAT G AAAAC

TTCTTTGCCTTACCAGACCAGTTAATATGTGCACTAAACAAGCACGACTATTAATCT ATC

ATGTTATGATATAATAAACTTGAATTTGGCACACATTCCTTAGGGCCATGAATTGAA AAC

T GAAAT AGT GGGCAAAT CAGG AACAAACCAT CACT G ATTT ACT GATTTAAGCT AGCCAAA

CTGTAAGAAACAAGCCATCTATTTTAAAGCTATCCAGGGCTTAACCTATATGAACTC TAT

TT AT CAT GTCT AAT G CAT GTG ATTT AAT GTAT GTTT AATTT GAT AT C ATGTTTT AAAAT A

TCCTACTTCTGGTAGCCATTTAATTCCTCCCCCTACCCCCAAATAAATCAGGCATGC AGG

AGGCCTGATATTTAGTAATGTCATTGTGTTTGACCTTGAAGGAAAATGCTATTAGTC CGT

CGTGCTTNATTTGTTTTTGTCCTTGAATAAGCATGTTATGTATATNGTCTCGTGTTT TTA

TTTTTACACCATATTGTATTACACTTTTAGTATTCACCAGCATAANCACTGTCTGCC TAA

AAT AT G CAACT CTTT GC ATT AC AAT AT G AAGTAAAGTT CTATGAAGTATG C ATTTT GTGT

AACT AAT GT AAAAAC AC AAATTTT AT AAAATT GT AC AGTTTTTT AAAAACT ACT C AC AAC

T AG CAG ATGG CTT AAAT GT AG CA AT CTCTGCGTT AATT AAATGCCTTT AAG AG AT AT AAT

TAACGTG C AGTTTT AAT AT CT ACT AAATT AAG AAT G ACTT C ATT AT GAT CAT G ATTT GCC

ACAATGTCCTTAACTCTAATGCCTGGACTGGCCATGTTCTAGTCTGTTGCGCTGTTA CAA

TCTGTATTGGTGCTAGTCAGAAAATTCCTAGCTCACATAGCCCAAAAGGGTGCGAGG GAG

AGGTGGATTACCAGTATTGTTCAATAATCCATGGTTCAAAGACTGTATAAATGCATT TTA

TTTT AAAT AAAAG C AAAACTTTT ATTT AAA

(SEQ ID NO: 30)

As used herein, the term “FTH1 ” refers to the gene encoding Ferritin heavy chain. The terms “FTH1 ” and "Ferritin heavy chain" include wild-type forms of the FTH1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type FTH1 . Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type FTH1 nucleic acid sequence (e.g., SEQ ID NO: 31 , ENA accession number X00318). SEQ ID NO: 31 is a wild-type gene sequence encoding FTH1 protein, and is shown below:

CACCGCACCCTCGGACTGCCCCAAGGCCCCCGCCGCCGCTCCAGCGCCGCGCAGCCA CCGCCGC

CGCCGCCGCCTCTCCTTAGTCGCCGCCATGACGACCGCGTCCACCTCGCAGGTGCGC CAGAACTA

CCACCAGGACTCAGAGGCCGCCATCAACCGCCAGATCAACCTGGAGCTCTACGCCTC CTACGTTTA

CCT GTCCATGTCTTACT ACTTT GACCGCG AT GATGT GGCTTT GAAG AACTTT GCCAAAT ACTTT CTT C

ACCAATCTCATGAGGAGAGGGAACATGCTGAGAAACTGATGAAGCTGCAGAACCAAC GAGGTGGCC

GAATCTTCCTTCAGGATATCAAGAAACCAGACTGTGATGACTGGGAGAGCGGGCTGA ATGCAATGGA

GTGT GCATT ACATTTGGAAAAAAAT GT GAAT CAGTC ACT ACT GG AACTGCACAAACT GGCC ACT GACA

AAAATGACCCCCATTTGTGTGACTTCATTGAGACACATTACCTGAATGAGCAGGTGA AAGCCATCAAA

GAATTGGGTGACCACGTGACCAACTTGCGCAAGATGGGAGCGCCCGAATCTGGCTTG GCGGAATAT

CTCTTTGACAAGCACACCTGGGAGACAGTGATAATGAAAGCTAAGCCTCGGGCTAAT TTCCCATAGC

CGTGGGGTGACTTCCTGGTCACCAAGGCAGTGCATGCATGTTGGGGTTTCCTTTACC TTTTCTATAA

GTTGTACCAAAACATCCACTTAAGTTCTTTGATTTGTACCATTCCTTCAAATAAAGA AATTTGGTACCC

(SEQ ID NO: 31)

As used herein, the term “GNAS” refers to the gene encoding Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas. The terms “GNAS” and "Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas" include wild-type forms of the GNAS gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type GNAS. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type GNAS nucleic acid sequence (e.g., SEQ ID NO: 32, ENA accession number X04408). SEQ ID NO: 32 is a wild-type gene sequence encoding GNAS protein, and is shown below:

GCGGGCGTGCTGCCGCCGCTGCCGCCGCCGCCGCAGCCCGGCCGCGCCCCGCCGCCG CCG

CCGCCGCCATGGGCTGCCTCGGGAACAGTAAGACCGAGGACCAGCGCAACGAGGAGA AGG

CGCAGCGTGAGGCCAACAAAAAGATCGAGAAGCAGCTGCAGAAGGACAAGCAGGTCT ACC

GGGCCACGCACCGCCT GCT GCT GCTGGGTGCTGGAGAATCT GGTAAAAGCACCATT GT GA

AGCAGATGAGGATCCTGCATGTTAATGGGTTTAATGGAGAGGGCGGCGAAGAGGACC CGC

AGGCTGCAAGGAGCAACAGCGATGGTGAGAAGGCAACCAAAGTGCAGGACATCAAAA ACA

ACCTGAAAGAGGCGATTGAAACCATTGTGGCCGCCATGAGCAACCTGGTGCCCCCCG TGG

AGCT GGCCAACCCCG AG AACCAGTT CAGAGTGGACT ACATCCT G AGTGT GAT GAACGTG C

CTGACTTTGACTTCCCTCCCGAATTCTATGAGCATGCCAAGGCTCTGTGGGAGGATG AAG

GAGTGCGTGCCTGCTACGAACGCTCCAACGAGTACCAGCTGATTGACTGTGCCCAGT ACT

TCCTGGACAAGATCGACGTGATCAAGCAGGCTGACTATGTGCCGAGCGATCAGGACC TGC

TTCGCTGCCGTGTCCTGACTTCTGGAATCTTTGAGACCAAGTTCCAGGTGGACAAAG TCA

ACTTCCACATGTTTGACGTGGGTGGCCAGCGCGATGAACGCCGCAAGTGGATCCAGT GCT

TCAACGATGTGACTGCCATCATCTTCGTGGTGGCCAGCAGCAGCTACAACATGGTCA TCC

GGGAGGACAACCAGACCAACCGCCTGCAGGAGGCTCTGAACCTCTTCAAGAGCATCT GGA ACAACAGATGGCTGCGCACCATCTCTGTGATCCTGTTCCTCAACAAGCAAGATCTGCTCG

CTGAGAAAGTCCTTGCTGGGAAATCGAAGATTGAGGACTACTTTCCAGAATTTGCTC GCT

ACACTACTCCTGAGGATGCTACTCCCGAGCCCGGAGAGGACCCACGCGTGACCCGGG CCA

AGT ACTT CATTCGAG AT GAGTTTCT GAGG AT CAGCACTGCCAGTGGAG AT GGGCGT CACT

ACTGCTACCCTCATTTCACCTGCGCTGTGGACACTGAGAACATCCGCCGTGTGTTCA ACG

ACTGCCGTGACATCATTCAGCGCATGCACCTTCGTCAGTACGAGCTGCTCTAAGAAG GGA

ACCCCCAAATTTAATTAAAGCCTTAAGCACAATTAATTAAAAGTGAAACGTAATTGT ACA

AGCAGTTAATCACCCACCATAGGGCATGATTAACAAAGCAACCTTTCCCTTCCCCCG AGT

GATTTTGCGAAACCCCCTTTTCCCTTCAGCTTGCTTAGATGTTCCAAATTTAGAAAG CTT

AAGGCGGCCTACAGAAAAAGGAAAAAAGGCCACAAAAGTTCCCTCTCACTTTCAGTA AAA

AT AAAT AAAAC AGO AGO AG C AAAC AAAT AAAAT G AAAT AAAAG AAAC AAAT G AAAT AAAT

ATTGTGTT GT GCAGCATT AAAAAAAATCAAAAT AAAAATT AAAT GT G AGCAAAG

(SEQ ID NO: 32)

As used herein, the term “GRN” refers to the gene encoding Progranulin. The terms “GRN” and "Progranulin" include wild-type forms of the GRN gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type GRN. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type GRN nucleic acid sequence (e.g., SEQ ID NO: 33, ENA accession number X62320). SEQ ID NO: 33 is a wild-type gene sequence encoding GRN protein, and is shown below:

GCTGCTGCCCAAGGACCGCGGAGTCGGACGCAGGCAGACCATGTGGACCCTGGTGAG CTG

GGTGGCCTTAACAGCAGGGCTGGTGGCTGGAACGCGGTGCCCAGATGGTCAGTTCTG CCC

TGTGGCCTGCTGCCTGGACCCCGGAGGAGCCAGCTACAGCTGCTGCCGTCCCCTTCT GGA

CAAATGGCCCACAACACTGAGCAGGCATCTGGGTGGCCCCTGCCAGGTTGATGCCCA CTG

CTCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGACTTCCAGTTGCTGCCCCTT CCC

AGAGGCCGTGGCATGCGGGGATGGCCATCACTGCTGCCCACGGGGCTTCCACTGCAG TGC

AGACGGGCGATCCTGCTTCCAAAGATCAGGTAACAACTCCGTGGGTGCCATCCAGTG CCC

TGATAGTCAGTTCGAATGCCCGGACTTCTCCACGTGCTGTGTTATGGTCGATGGCTC CTG

GGGGTGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGCACTGCTGTCC GCA

CGGTGCCTTCTGCGACCTGGTTCACACCCGCTGCATCACACCCACGGGCACCCACCC CCT

GGCAAAGAAGCTCCCTGCCCAGAGGACTAACAGGGCAGTGGCCTTGTCCAGCTCGGT CAT

GTGTCCGGACGCACGGTCCCGGTGCCCTGATGGTTCTACCTGCTGTGAGCTGCCCAG TGG

GAAGTATGGCT GOT GCCCAATGCCCAACGCCACCT GOT GCTCCGATCACCTGCACT GOT G

CCCCCAAGACACTGTGTGTGACCTGATCCAGAGTAAGTGCCTCTCCAAGGAGAACGC TAC

CACGGACCTCCTCACTAAGCTGCCTGCGCACACAGTGGGGGATGTGAAATGTGACAT GGA

GGTGAGCTGCCCAGATGGCTATACCTGCTGCCGTCTACAGTCGGGGGCCTGGGGCTG CTG

CCCTTTTACCCAGGCTGTGTGCTGTGAGGACCACATACACTGCTGTCCCGCGGGGTT TAC

GTGTGACACGCAGAAGGGTACCTGTGAACAGGGGCCCCACCAGGTGCCCTGGATGGA GAA

GGCCCCAGCTCACCTCAGCCTGCCAGACCCACAAGCCTTGAAGAGAGATGTCCCCTG TGA TAATGTCAGCAGCTGTCCCTCCTCCGATACCTGCTGCCAACTCACGTCTGGGGAGTGGGG

CTGCTGTCCAATCCCAGAGGCTGTCTGCTGCTCGGACCACCAGCACTGCTGCCCCCA GGG

CTACACGTGTGTAGCTGAGGGGCAGTGTCAGCGAGGAAGCGAGATCGTGGCTGGACT GGA

GAAGATGCCTGCCCGCCGGGCTTCCTTATCCCACCCCAGAGACATCGGCTGTGACCA GCA

CACCAGCTGCCCGGTGGGGCAGACCTGCTGCCCGAGCCTGGGTGGGAGCTGGGCCTG CTG

CCAGTTGCCCCATGCTGTGTGCTGCGAGGATCGCCAGCACTGCTGCCCGGCTGGCTA CAC

CT GCAACGT GAAGGCTCGATCCT GCGAGAAGGAAGT GGTCTCT GCCCAGCCTGCCACCTT

CCT GGCCCGTAGCCCTCACGT GGGTGTGAAGGACGT GGAGT GT GGGGAAGGACACTTCT G

CCATGATAACCAGACCTGCTGCCGAGACAACCGACAGGGCTGGGCCTGCTGTCCCTA CCG

CCAGGGCGTCTGTTGTGCTGATCGGCGCCACTGCTGTCCTGCTGGCTTCCGCTGCGC AGC

CAGGGGTACCAAGT GTTT GCGCAGGGAGGCCCCGCGCT GGGACGCCCCTTT GAGGGACCC

AGCCTTGAGACAGCTGCTGTGAGGGACAGTACTGAAGACTCTGCAGCCCTCGGGACC CCA

CTCGGAGGGTGCCCTCTGCTCAGGCCTCCCTAGCACCTCCCCCTAACCAAATTCTCC CTG

GACCCCATTCTGAGCTCCCCATCACCATGGGAGGTGGGGCCTCAATCTAAGGCCTTC CCT

GTCAGAAGGGGGTTGTGGCAAAAGCCACATTACAAGCTGCCATCCCCTCCCCGTTTC AGT

GGACCCTGTGGCCAGGTGCTTTTCCCTATCCACAGGGGTGTTTGTGTGTGTGCGCGT GTG

CGTTT CAAT AAAGTTT GT ACACTTTCAAAAAAAAAAAAAAAAAAAAAAAAAA

(SEQ ID NO: 33)

As used herein, the term “HBEGF” refers to the gene encoding Heparin Binding EGF Like Growth Factor. The terms “HBEGF” and "Heparin Binding EGF Like Growth Factor" include wild-type forms of the HBEGF gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type HBEGF. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type HBEGF nucleic acid sequence (e.g., SEQ ID NO: 34, NCBI Reference Sequence: NM_001945.2). SEQ ID NO:

34 is a wild-type gene sequence encoding HBEGF protein, and is shown below:

ATTCGGCCGAAGGAGCTACGCGGGCCACGCTGCTGGCTGGCCTGACCTAGGCGCGCG GGGTCGG

GCGGCCGCGCGGGCGGGCTGAGTGAGCAAGACAAGACACTCAAGAAGAGCGAGCTGC GCCTGGG

TCCCGGCCAGGCTTGCACGCAGAGGCGGGCGGCAGACGGTGCCCGGCGGAATCTCCT GAGCTCC

GCCGCCCAGCTCTGGTGCCAGCGCCCAGTGGCCGCCGCTTCGAAAGTGACTGGTGCC TCGCCGCC

TCCTCTCGGTGCGGGACCATGAAGCTGCTGCCGTCGGTGGTGCTGAAGCTCTTTCTG GCTGCAGTT

CTCTCGGCACTGGTGACTGGCGAGAGCCTGGAGCGGCTTCGGAGAGGGCTAGCTGCT GGAACCAG

CAACCCGGACCCTCCCACTGTATCCACGGACCAGCTGCTACCCCTAGGAGGCGGCCG GGACCGGA

AAGTCCGTGACTTGCAAGAGGCAGATCTGGACCTTTTGAGAGTCACTTTATCCTCCA AGCCACAAGC

ACTGGCCACACCAAACAAGGAGGAGCACGGGAAAAGAAAGAAGAAAGGCAAGGGGCT AGGGAAGA

AGAGGGACCCATGTCTTCGGAAATACAAGGACTTCTGCATCCATGGAGAATGCAAAT ATGTGAAGGA

GCTCCGGGCTCCCTCCTGCATCTGCCACCCGGGTTACCATGGAGAGAGGTGTCATGG GCTGAGCCT

CCCAGTGGAAAATCGCTTATATACCTATGACCACACAACCATCCTGGCCGTGGTGGC TGTGGTGCTG

TCATCTGTCTGTCTGCTGGTCATCGTGGGGCTTCTCATGTTTAGGTACCATAGGAGA GGAGGTTATG

ATGTGG AAAAT G AAG AG AAAGT GAAGTTGGGCAT G ACT AATTCCCACT G AG AGAGACTTGTGCT CAA GGAATCGGCTGGGGACTGCTACCTCTGAGAAGACACAAGGTGATTTCAGACTGCAGAGGG GAAAGA

CTTCCATCTAGTCACAAAGACTCCTTCGTCCCCAGTTGCCGTCTAGGATTGGGCCTC CCATAATTGC

TTTGCCAAAATACCAGAGCCTTCAAGTGCCAAACAGAGTATGTCCGATGGTATCTGG GTAAGAAGAA

AGCAAAAGCAAGGGACCTTCATGCCCTTCTGATTCCCCTCCACCAAACCCCACTTCC CCTCATAAGT

TT GTTT AAAC ACTT AT CTT CT GG ATT AG AAT G CCG GTT AAATT C CAT ATG CTC CAG GAT CTTT G ACTG A

AAAAAAAAAAGAAGAAGAAGAAGGAGAGCAAGAAGGAAAGATTT GT GAACTGGAAGAAAGCAACAAA

GATTGAGAAGCCATGTACTCAAGTACCACCAAGGGATCTGCCATTGGGACCCTCCAG TGCTGGATTT

GATGAGTTAACTGTGAAATACCACAAGCCTGAGAACTGAATTTTGGGACTTCTACCC AGATGGAAAAA

TAACAACTATTTTTGTTGTTGTTGTTTGTAAATGCCTCTTAAATTATATATTTATTT TATTCTATGTATGT

T AATTT ATTT AGTTTTT AAC AAT CT AAC AAT AAT ATTT C AAGT GCCT AG ACTGTT ACTTTGG C AATTT C C

TGGCCCTCCACTCCTCATCCCCACAATCTGGCTTAGTGCCACCCACCTTTGCCACAA AGCTAGGATG

GTTCTGTGACCCATCTGTAGTAATTTATTGTCTGTCTACATTTCTGCAGATCTTCCG TGGTCAGAGTG

CCACTGCGGGAGCTCTGTATGGTCAGGATGTAGGGGTTAACTTGGTCAGAGCCACTC TATGAGTTG

GACTTCAGTCTTGCCTAGGCGATTTTGTCTACCATTTGTGTTTTGAAAGCCCAAGGT GCTGATGTCAA

AGTGTAACAGATATCAGTGTCTCCCCGTGTCCTCTCCCTGCCAAGTCTCAGAAGAGG TTGGGCTTCC

ATGCCTGTAGCTTTCCTGGTCCCTCACCCCCATGGCCCCAGGCCCACAGCGTGGGAA CTCACTTTC

CCTTGTGTCAAGACATTTCTCTAACTCCTGCCATTCTTCTGGTGCTACTCCATGCAG GGGTCAGTGCA

GCAGAGGACAGTCTGGAGAAGGTATTAGCAAAGCAAAAGGCTGAGAAGGAACAGGGA ACATTGGAG

CTGACTGTTCTTGGTAACTGATTACCTGCCAATTGCTACCGAGAAGGTTGGAGGTGG GGAAGGCTTT

GTATAATCCCACCCACCTCACCAAAACGATGAAGTTATGCTGTCATGGTCCTTTCTG GAAGTTTCTGG

T GCCATTT CT G AACT GTTACAACTT GT ATTTCCAAACCTGGTT CAT ATTT AT ACTTTGCAATCC AAATAA

AG AT AACC CTT ATTCC AT AAAAAAAAAAAAAAAAAAAAAAAA

(SEQ ID NO: 34)

As used herein, the term “HLA-DRB1” refers to the gene encoding HLA class II histocompatibility antigen, DRB1 beta chain. The terms “HLA-DRB1” and "HLA class II histocompatibility antigen, DRB1 beta chain" include wild-type forms of the HLA-DRB1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type HLA-DRB1 . Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type HLA-DRB1 nucleic acid sequence (e.g., SEQ ID NO: 35, ENA accession number X00699). SEQ ID NO: 35 is a wild-type gene sequence encoding HLA-DRB1 protein, and is shown below:

CTGCTCTGGCCCCTGGTCCTGTCCTGTTCTCCAGCATGGTGTGTCTGAGGCTCCCTG GAG

GCTCCTGCATGGCAGTTCTGACAGTGACACTGATGGTGCTGAGCTCCCCACTGGCTT TGG

CT GGGGACACC AG ACC ACGTTT CTTGGAGT ACT CTACGT CT GAGT GT CATTT CTT CAAT G

GGACGGAGCGGGTGCGGTACCTGGACAGATACTTCCATAACCAGGAGGAGAACGTGC GCT

TCGACAGCGACGTGGGGGAGTTCCGGGCGGTGACGGAGCTGGGGCGGCCTGATGCCG AGT

ACTGGAACAGCCAGAAGGACCTCCTGGAGCAGAAGCGGGGCCGGGTGGACAACTACT GCA

GACACAACTACGGGGTTGTGGAGAGCTTCACAGTGCAGCGGCGAGTCCATCCTAAGG TGA

CTGTGTATCCTTCAAAGACCCAGCCCCTGCAGCACCATAACCTCCTGGTCTGTTCTG TGA

GTGGTTTCTATCCAGGCAGCATTGAAGTCAGGTGGTTCCGGAATGGCCAGGAAGAGA AGA CTGGGGTGGTGTCCACAGGCCTGATCCACAATGGAGACTGGACCTTCCAGACCCTGGTGA

TGCTGGAAACAGTTCCTCGGAGTGGAGAGGTTTACACCTGCCAAGTGGAGCACCCAA GCG

TGACAAGCCCTCTCACAGTGGAATGGAGAGCACGGTCTGAATCTGCACAGAGCAAGA TGC

TGAGTGGAGTCGGGGGCTTTGTGCTGGGCCTGCTCTTCCTTGGGGCCGGGCTGTTCA TCT

ACTTCAGGAATCAGAAAGGACACTCTGGACTTCAGCCAAGAGGATTCCTGAGCTGAA GTG

CAGATGACACATTCAAAGAAGAACTTTCTGCCCCAGCTTTGCAGGATGAAAAGCTTT CCC

TCCTGGCTGTTATTCTTCCACAAGAGAGGGCTTTCTCAGGACCTGGTTGCTACTGGT TCA

GCAACTGCAGAAAATGTCCTCCCTTGTGGCTTCCTCAGCTCCTGTTCTTGGCCTGAA GCC

CCACAGCTTTGATGGCAGTGCCTCATCTTCAACTTTTGTGCTCCCCTTTGCCTAAAC CCT

ATGGCCTCCTGTGCATCTGTACTCACCCTGTACCA

(SEQ ID NO: 35)

As used herein, the term “HLA-DRB5” refers to the gene encoding HLA class II histocompatibility antigen, DR beta 5 chain. The terms “HLA-DRB5” and "HLA class II histocompatibility antigen, DR beta 5 chain" include wild-type forms of the HLA-DRB5 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type HLA-DRB5. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type HLA-DRB5 nucleic acid sequence (e.g., SEQ ID NO: 36, ENA accession number M20429). SEQ ID NO: 36 is a wild-type gene sequence encoding HLA-DRB5 protein, and is shown below:

CCAGCATGGTGTGTCTGAAGCTCCCTGGAGGTTCCTACATGGCAAAGCTGACAGTGA CAC

TGATGGTGCTGAGCTCCCCACTGGCTTTGGCTGGGGACACCCGACCACGTTTCTTGC AGC

AGGATAAGTATGAGTGTCATTTCTTCAACGGGACGGAGCGGGTGCGGTTCCTGCACA GAG

ACATCTATAACCAAGAGGAGGACTTGCGCTTCGACAGCGACGTGGGGGAGTACCGGG CGG

T GACGGAGCT GGGGCGGCCT GACGCT GAGTACTGGAACAGCCAGAAGGACTTCCT GGAAG

ACAGGCGCGCCGCGGTGGACACCTACTGCAGACACAACTACGGGGTTGGTGAGAGCT TCA

CAGTGCAGCGGCGAGTTGAGCCTAAGGTGACTGTGTATCCTGCAAGGACCCAGACCC TGC

AGCACCACAACCTCCTGGTCTGCTCTGTGAATGGTTTCTATCCAGGCAGCATTGAAG TCA

GGTGGTTCCGGAACAGCCAGGAAGAGAAGGCTGGGGTGGTGTCCACAGGCCTGATTC AGA

ATGGAGACTGGACCTTCCAGACCCTGGTGATGCTGGAAACAGTTCCTCGAAGTGGAG AGG

TTTACACCTGCCAAGTGGAGCACCCAAGCGTGACGAGCCCTCTCACAGTGGAATGGA GAG

CACAGTCTGAATCTGCACAGAGCAAGATGCTGAGTGGAGTCGGGGGCTTTGTGCTGG GCC

TGCTCTTCCTTGGGGCCGGGCTATTCATCTACTTCAAGAATCAGAAAGGGCACTCTG GAC

TTCACCCAACAGGACTCGTGAGCTGAAGTGCAGATGACCACATTCAAGGGGGAACCT TCT

GCCCCAGCTTTGCATGATGAAAAGCTTTCCTGCTTGGCTCTTATTCTTCCACAAGAG AGG

ACTTTCTCAGGCCCTGGTTGCTACCGGTTCAGCAACTCTGCAGAAAATGTCCATCCT TGT

GGCTTCCTCAGCTCCTGCCCCTTGGCCTGAAGTCCCAGCATTGATGGCAGTGCCTCA TCT

TCAACTTTAGTGCTCCCCTTTACCTAACCCTACGGCCTCCCATGCATCTGTACTCCC CCT

GTGTGCCACAAATGCACTACGTTATTAAATTTTTCTGAAGCCCAGAGTTAAAAATCA TCT

GTCCACCTGGCTCCAAAGACAAAAAATAAAAA (SEQ ID NO: 36)

As used herein, the term “IFIT1 ” refers to the gene encoding Interferon-induced protein with tetratricopeptide repeats 1 . The terms “IFIT1 ” and "Interferon-induced protein with tetratricopeptide repeats 1" include wild-type forms of the IFIT1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type IFIT1 . Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type IFIT1 nucleic acid sequence (e.g., SEQ ID NO: 37, ENA accession number X03557). SEQ ID NO: 37 is a wild-type gene sequence encoding IFIT1 protein, and is shown below:

CCAGATCTCAGAGGAGCCTGGCTAAGCAAAACCCTGCAGAACGGCTGCCTAATTTAC AGC AAC CAT G AGT AC AAAT G GT GAT GAT CAT C AG GT C AAG GAT AGTCT G G AGC AATT GAG AT G T C ACTTT AC AT G GG AGTT ATCC ATT G ATG ACG AT G AAAT G CCT G ATTT AG AAAAC AG AGT CTTGG AT CAG ATT G AATTCCTAGACACC AAAT ACAGTGTGGG AATACACAACCT ACT AGC CTATGTGAAACACCTGAAAGGCCAGAATGAGGAAGCCCTGAAGAGCTTAAAAGAAGCTGA AAACTTAAT GCAGGAAGAACAT GACAACCAAGCAAAT GT GAGGAGTCTGGT GACCT GGGG CAACTTT GCCT GG AT GT ATT ACC AC AT GGGCAGACT GGCAGAAGCCCAG ACTT ACCT GG A CAAGGTGGAGAACATTTGCAAGAAGCTTTCAAATCCCTTCCGCTATAGAATGGAGTGTCC AGAAAT AGACT GT GAGG AAGGATGGGCCTTGCT G AAGTGTGG AGGAAAG AATT AT GAACG GGCCAAGGCCTGCTTTGAAAAGGTGCTTGAAGTGGACCCTGAAAACCCTGAATCCAGCGC TGGGTATGCGATCTCTGCCTATCGCCTGGATGGCTTTAAATTAGCCACAAAAAATCACAA GCCATTTTCTTTGCTTCCCCTAAGGCAGGCTGTCCGCTTAAATCCAGACAATGGATATAT TAAGGTTCTCCTTGCCCTGAAGCTTCAGGATGAAGGACAGGAAGCTGAAGGAGAAAAGTA C ATT G AAG AAG CTCT AG CC AAC AT GTCCTC AC AG AC CTATGT CTTTCG AT AT G C AG CC AA GTTTTACCGAAGAAAAGGCTCTGTGGATAAAGCTCTTGAGTTATTAAAAAAGGCCTTGCA GGAAACACCCACTTCTGTCTTACTGCATCACCAGATAGGGCTTTGCTACAAGGCACAAAT GATCCAAATCAAGGAGGCTACAAAAGGGCAGCCTAGAGGGCAGAACAGAGAAAAGCTAGA CAAAAT GAT AAG AT CAGCCAT ATTT CATTTT G AAT CTGCAGTGG AAAAAAAGCCCACATT TGAGGTGGCTCATCTAGACCTGGCAAGAATGTATATAGAAGCAGGCAATCACAGAAAAGC T GAAGAG AATTTT CAAAAATT GTT AT GCAT G AAACC AGTGGTAGAAG AAAC AAT GCAAG A CAT AC ATTT CTACTATGGTCG GTTT CAG G AATTT C AAAAG AAAT CTG ACGT C AAT GC AAT T ATCC ATT ATTT AAAAG CTAT AAAAAT AG AAC AG GCAT C ATT AAC AAG GG AT AAAAGTAT CAATTCTTTGAAGAAATTGGTTTTAAGGAAACTTCGGAGAAAGGCATTAGATCTGGAAAG CTT GAGCCTCCTT GGGTTCGT CTACAAATT GG AAGGAAAT AT GAAT G AAGCCCT GGAGT A CT AT G AGCGGGCCCT GAG ACT GGCTGCT GACTTT G AGAACTCT GT GAGACAAGGTCCTT A G GC ACCC AG AT AT C AGC C ACTTT C AC ATTT C ATTT CATTTT ATGCT AAC ATTT ACT AAT C AT CTTTT CTG CTT ACT GTTTT CAG AAAC ATT AT AATT C ACTGT AAT G ATGTAATT CTT G A AT AAT AAAT CT G AC AAAAT ATT (SEQ ID NO: 37) As used herein, the term “IFIT3” refers to the gene encoding Interferon-induced protein with tetratricopeptide repeats 3. The terms “IFIT3” and "Interferon-induced protein with tetratricopeptide repeats 3" include wild-type forms of the IFIT3 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type IFIT3. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type IFIT3 nucleic acid sequence (e.g., SEQ ID NO: 38, ENA accession number AF026939). SEQ ID NO: 38 is a wild-type gene sequence encoding IFIT3 protein, and is shown below:

GTGGAAACCTCTTCAGCATTTGCTTGGAATCAGTAAGCTAAAAACAAAATCAACCGG GAC

CCCAGCTTTTCAGAACTGCAGGGAAACAGCCATCATGAGTGAGGTCACCAAGAATTC CCT

GGAGAAAATCCTCCCACAGCTGAAATGCCATTTCACCTGGAACTTATTCAAGGAAGA CAG

TGTCT C AAGG G AT CTAG AAG AT AG AGT GTGT AAC C AG ATT G AATTTTT AAAC ACT G AGTT

CAAAGCTACAATGTACAACTTGTTGGCCTACATAAAACACCTAGATGGTAACAACGA GGC

AGCCCTGGAATGCTTACGGCAAGCTGAAGAGTTAATCCAGCAAGAACATGCTGACCA AGC

AGAAATCAGAAGTCTAGTCACTTGGGGAAACTACGCCTGGGTCTACTATCACTTGGG CAG

ACTCTCAGATGCTCAGATTTATGTAGATAAGGTGAAACAAACCTGCAAGAAATTTTC AAA

TCCATACAGT ATT G AGT ATT CT GAACTT G ACTGTG AGGAAGGGTGGACAC AACTGAAGTG

TGGAAGAAATGAAAGGGCGAAGGTGTGTTTTGAGAAGGCTCTGGAAGAAAAGCCCAA CAA

CCCAGAATTCTCCTCTGGACTGGCAATTGCGATGTACCATCTGGATAATCACCCAGA GAA

ACAGTTCTCTACTGATGTTTTGAAGCAGGCCATTGAGCTGAGTCCTGATAACCAATA CGT

CAAGGTTCTCTTGGGCCTGAAACTGCAGAAGATGAATAAAGAAGCTGAAGGAGAGCA GTT

TGTTGAAGAAGCCTTGGAAAAGTCTCCTTGCCAAACAGATGTCCTCCGCAGTGCAGC CAA

ATTTT AC AG AAG AAAAG GT G ACCT AG AC AAAG CT ATT G AACTGTTT C AACG G GTGTTGG A

ATCCACACCAAACAATGGCTACCTCTATCACCAGATTGGGTGCTGCTACAAGGCAAA AGT

AAG ACAAATGCAG AAT ACAGG AG AAT CT G AAGCT AGT GG AAATAAAG AGAT GATT G AAGC

ACT AAAG C AAT ATGCTATG G ACT ATTCG AAT AAAG CTCTT GAG AAGG G ACT G AATCCT CT

G AATGC AT ACTCCG AT CTCGCT GAGTTCCTGGAGACGG AATGTT AT CAG ACACCATT CAA

TAAGGAAGTCCCTGATGCTGAAAAGCAACAATCCCATCAGCGCTACTGCAACCTTCA GAA

ATATAATGGGAAGTCTGAAGACACTGCTGTGCAACATGGTTTAGAGGGTTTGTCCAT AAG

C AAAAAAT C AACTG AC AAG G AAG AG AT C AAAG ACC AAC C AC AG AATGTATCC G AAAAT CT

G CTTCC AC AAAAT G C ACC AAATT ATT G GTATCTT C AAG GATT AATT CAT AAGC AG AAT GG

AGATCTGCTGCAAGCAGCCAAATGTTATGAGAAGGAACTGGGCCGCCTGCTAAGGGA TGC

CCCTTCAGGCATAGGCAGTATTTTCCTGTCAGCATCTGAGCTTGAGGATGGTAGTGA GGA

AATGGGCCAGGGCGCAGTCAGCTCCAGTCCCAGAGAGCTCCTCTCTAACTCAGAGCA ACT

GAACTGAGACAGAGGAGGAAAACAGAGCATCAGAAGCCTGCAGTGGTGGTTGTGACG GGT

AGGAGGATAGGAAGACAGGGGGCCCCAACCTGGGATTGCTGAGCAGGGAAGCTTTGC ATG

TTGCTCTAAGGTACATTTTTAAAGAGTTGTTTTTTGGCCGGGCGCAGTGGCTCATGC CTG

TAATCCCAGCACTTTGGGAGGCCGAGGTGGGCGGATCACGAGGTCTGGAGTTTGAGA CCA

TCCTGGCTAACACAGTGAAATCCCGTCTCTACTAAAAATACAAAAAATTAGCCAGGC GTG

GTGGCTGGCACCTGTAGTCCCAGCTACTTGGGAGGCTGAGGCAGGAGAATGGCGTGA ACC TGGAAGGAAGAGGTTGCAGTGAGCCAAGATTGCGCCCCTGCACTCCAGCCTGGGCAACAG

AGCAAGACTC

(SEQ ID NO: 38)

As used herein, the term “IFITM3” refers to the gene encoding Interferon Induced Transmembrane Protein. The terms “IFITM3” and "Interferon Induced Transmembrane Protein" include wild-type forms of the IFITM3 gene, as well as variants (e.g., splice variants and polymorphisms) of wild- type IFITM3. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild- type IFITM3 nucleic acid sequence (e.g., SEQ ID NO: 39, NCBI Reference Sequence: NM_021034.2). SEQ ID NO: 39 is a wild-type gene sequence encoding IFITM3 protein, and is shown below:

AGGAAAAGGAAACTGTTGAGAAACCGAAACTACTGGGGAAAGGGAGGGCTCACTGAG AACCATCCC

AGTAACCCGACCGCCGCTGGTCTTCGCTGGACACCATGAATCACACTGTCCAAACCT TCTTCTCTCC

TGTCAACAGTGGCCAGCCCCCCAACTATGAGATGCTCAAGGAGGAGCACGAGGTGGC TGTGCTGG

GGGCGCCCCACAACCCTGCTCCCCCGACGTCCACCGTGATCCACATCCGCAGCGAGA CCTCCGTG

CCCGACCATGTCGTCTGGTCCCTGTTCAACACCCTCTTCATGAACCCCTGCTGCCTG GGCTTCATAG

CATTCGCCTACTCCGTGAAGTCTAGGGACAGGAAGATGGTTGGCGACGTGACCGGGG CCCAGGCC

TATGCCTCCACCGCCAAGTGCCTGAACATCTGGGCCCTGATTCTGGGCATCCTCATG ACCATTCTGC

TCATCGTCATCCCAGTGCTGATCTTCCAGGCCTATGGATAGATCAGGAGGCATCACT GAGGCCAGG

AGCTCTGCCCATGACCTGTATCCCACGTACTCCAACTTCCATTCCTCGCCCTGCCCC CGGAGCCGA

GTCCTGTATCAGCCCTTTATCCTCACACGCTTTTCTACAATGGCATTCAATAAAGTG CACGTGTTTCT

G GTG CT AAAAAAAAAA

(SEQ ID NO: 39)

As used herein, the term “IFNAR1” refers to the gene encoding Interferon alpha/beta receptor 1 . The terms “IFNAR1” and "Interferon alpha/beta receptor 1" include wild-type forms of the IFNAR1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type IFNAR1. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type IFNAR1 nucleic acid sequence (e.g., SEQ ID NO: 40, ENA accession number J03171). SEQ ID NO: 40 is a wild-type gene sequence encoding IFNAR1 protein, and is shown below:

TTAGGACGGGGCGATGGCGGCTGAGAGGAGCTGCGCGTGCGCGAACATGTAACTGGT GGG

ATCTGCGGCGGCTCCCAGATGATGGTCGTCCTCCTGGGCGCGACGACCCTAGTGCTC GTC

GCCGTGGGCCCATGGGTGTTGTCCGCAGCCGCAGGTGGAAAAAATCTAAAATCTCCT CAA

AAAGTAGAGGTCGACATCATAGATGACAACTTTATCCTGAGGTGGAACAGGAGCGAT GAG

TCTGTCGGGAATGTGACTTTTTCATTCGATTATCAAAAAACTGGGATGGATAATTGG ATA

AAATTGTCTGGGTGTCAGAATATTACTAGTACCAAATGCAACTTTTCTTCACTCAAG CTG

AAT GTTT AT G AAG AAATT AAATT G CGTAT AAG AG C AG AAAAAG AAAACACTT CTT CAT G G TATGAGGTTGACTCATTTACACCATTTCGCAAAGCTCAGATTGGTCCTCCAGAAGTACAT

TTAGAAGCTGAAGATAAGGCAATAGTGATACACATCTCTCCTGGAACAAAAGATAGT GTT

ATGTGGGCTTTGGATGGTTTAAGCTTTACATATAGCTTACTTATCTGGAAAAACTCT TCA

G GTGTAG AAG AAAGG ATT G AAAAT ATTT ATTCC AG AC AT AAAATTT AT AAACT CT C ACC A

GAG ACT ACTT ATT GTCT AAAAGTT AAAG C AGC ACTACTTACGTC AT GG AAAATT G GTGTC

T ATAGTCCAGT AC ATTGTATAAAG ACC ACAGTT G AAAAT G AACT ACCTCCACCAGAAAAT

ATAGAAGTCAGTGTCCAAAATCAGAACTATGTTCTTAAATGGGATTATACATATGCA AAC

ATGACCTTTCAAGTTCAGTGGCTCCACGCCTTTTTAAAAAGGAATCCTGGAAACCAT TTG

TATAAATGGAAACAAATACCTGACTGTGAAAATGTCAAAACTACCCAGTGTGTCTTT CCT

CAAAACGTTTTCCAAAAAGGAATTTACCTTCTCCGCGTACAAGCATCTGATGGAAAT AAC

AC AT CTTTTT GGTCT G AAG AG AT AAAGTTT G ATACT G AAAT AC AAG CTTT CCTACTTCCT

CCAGTCTTTAACATTAGATCCCTTAGTGATTCATTCCATATCTATATCGGTGCTCCA AAA

CAGTCTGGAAACACGCCTGTGATCCAGGATTATCCACTGATTTATGAAATTATTTTT TGG

G AAAAC ACTT CAAAT GCT G AG AG AAAAATTATCG AGAAAAAAACT GAT GTT AC AGTTCCT

AATTT G AAACCACT GACT GT ATATT GT GT GAAAGCCAGAGCACACACCAT GG AT G AAAAG

CT GAATAAAAGCAGT GTTTTTAGT GACGCT GTAT GT GAGAAAACAAAACCAGGAAATACC

TCTAAAATTTGGCTTATAGTTGGAATTTGTATTGCATTATTTGCTCTCCCGTTTGTC ATT

TATG CT G CG AAAGT CTTCTT GAG AT G CAT C AATT ATGTCTT CTTTCC AT C ACTT AAACCT

TCTTCCAGTATAGATGAGTATTTCTCTGAACAGCCATTGAAGAATCTTCTGCTTTCA ACT

TCT G AGG AAC AAATCG AAAAAT GTTT CAT AATT G AAAAT AT AAGC AC AATT GCT AC AGT A

G AAG AAACT AAT C AAACT GAT G AAG AT CAT AAAAAAT AC AGTTCCC AAACT AG CC AAG AT

T CAGGAAATT ATTCT AAT G AAGAT GAAAGCG AAAGT AAAAC AAGTG AAG AACT ACAGC AG

GACTTTGTATGACCAGAAATGAACTGTGTCAAGTATAAGGTTTTTCAGCAGGAGTTA CAC

TGGGAGCCTGAGGTCCTCACCTTCCTCTCAGTAACTACAGAGAGGACGTTTCCTGTT TAG

GGAAAGAAAAAACATCTTCAGATCATAGGTCCTAAAAATACGGGCAAGCTCTTAACT ATT

TAAAAATGAAATTACAGGCCCGGGCACGGTGGCTCACACCTGTAATCCCAGCACTTT GGG

AGGCTGAGGCAGGCAGATCATGAGGTCAAGAGATCGAGACCAGCCTGGCCAACGTGG TGA

AACCCCATCTCTACTAAAAATACAAAAATTAGCCGGGTAGTAGGTAGGCGCGCGCCT GTT

GTCTTAGCTACTCAGGAGGCTGAGGCAGGAGAATCGCTTGAAAACAGGAGGTGGAGG TTG

CAGT GAGCCG AG AT CACGCCACT GCACTCCAGCCT GGTG ACAGCGTGAG ACTCTTT AAAA

AAAG AAATT AAAAGAGTT GAGACAAACGTTTCCTACATT CTTTTCCATGTGTAAAAT CAT

GAAAAAGCCTGTCACCGGACTTGCATTGGATGAGATGAGTCAGACCAAAACAGTGGC CAC

CCGTCTTCCTCCTGTGAGCCTAAGTGCAGCCGTGCTAGCTGCGCACCGTGGCTAAGG ATG

ACGTCTGTGTTCCTGTCCATCACTGATGCTGCTGGCTACTGCATGTGCCACACCTGT CTG

TTCGCCATTCCTAACATTCTGTTTCATTCTTCCTCGGGAGATATTTCAAACATTTGG TCT

TTTCTTTTAACACTGAGGGTAGGCCCTTAGGAAATTTATTTAGGAAAGTCTGAACAC GTT

ATCACTTGGTTTTCTGGAAAGTAGCTTACCCTAGAAAACAGCTGCAAATGCCAGAAA GAT

GATCCCTAAAAATGTTGAGGGACTTCTGTTCATTCATCCCGAGAACATTGGCTTCCA CAT

CACAGTATCTACCCTTACATGGTTTAGGATTAAAGCCAGGCAATCTTTTACTATG

(SEQ ID NO: 40) As used herein, the term “IFNAR2” refers to the gene encoding Interferon alpha/beta receptor 2. The terms “IFNAR2” and "Interferon alpha/beta receptor 2" include wild-type forms of the IFNAR2 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type IFNAR2. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type IFNAR2 nucleic acid sequence (e.g., SEQ ID NO: 41 , ENA accession number X77722). SEQ ID NO: 41 is a wild-type gene sequence encoding IFNAR2 protein, and is shown below:

GCTTTTGTCCCCCGCCCGCCGCTTCTGTCCGAGAGGCCGCCCGCGAGGCGCATCCTG ACC

GCGAGCGTCGGGTCCCAGAGCCGGGCGCGGCTGGGGCCCGAGGCTAGCATCTCTCGG GAG

CCGCAAGGCGAGAGCTGCAAAGTTTAATTAGACACTTCAGAATTTTGATCACCTAAT GTT

G ATTTCAGATGTAAAAGTCAAG AG AAG ACT CT AAAAAT AGCAAAG AT GCTTTT GAGCCAG

AATGCCTTCATCGTCAGATCACTTAATTTGGTTCTCATGGTGTATATCAGCCTCGTG TTT

G GT ATTT CAT AT G ATTCG CCT GATT AC AC AG AT G AAT CTTG C ACTTT C AAG AT AT CATT G

CGAAATTTCCGGTCCATCTTATCATGGGAATTAAAAAACCACTCCATTGTACCAACT CAC

T AT AC ATT GCTGTAT AC AAT CAT G AGT AAACC AG AAG ATTT G AAGGTG GTT AAG AACT GT

GCAAATACCACAAGATCATTTTGTGACCTCACAGATGAGTGGAGAAGCACACACGAG GCC

T ATGTCACCGTCCT AG AAGGATTCAGCGGG AAC ACAACGTT GTT CAGTT GCT CAC ACAAT

TTCTGGCTGGCCATAGACATGTCTTTTGAACCACCAGAGTTTGAGATTGTTGGTTTT ACC

AAC CAC ATT AAT GT GAT G GTG AAATTTCC AT CT ATTGTT GAG G AAG AATT AC AGTTT GAT

TTAT CTCTCGT CATT G AAG AACAGT CAG AGGGAATT GTT AAGAAGCAT AAACCCG AAATA

AAAG G AAAC AT G AGTG G AAATTT CAC CTATAT CATT G AC AAGTT AATT C C AAAC ACG AAC

TACTGTGTATCTGTTTATTTAGAGCACAGTGATGAGCAAGCAGTAATAAAGTCTCCC TTA

AAATGCACCCTCCTTCCACCTGGCCAGGAATCAGAATCAGCAGAATCTGCCAAAATA GGA

GGAATAATT ACT GT GTTTTT GATAGCATT GGTCTT G ACAAGC ACC AT AGTGACACT G AAA

TGGATTGGTTATATATGCTTAAGAAATAGCCTCCCCAAAGTCTTGAGGCAAGGTCTC ACT

AAGGGCTGGAATGCAGTGGCTATTCACAGGTGCAGTCATAATGCACTACAGTCTGAA ACT

CCTGAGCTCAAACAGTCGTCCTGCCTAAGCTTCCCCAGTAGCTGGGATTACAAGCGT GCA

TCCCT GT GCCCCAGT GATTAAGTTTTATT AT GT AGAAAAT AAAG AG C AAAC AGTTAC AAA

AGAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA

(SEQ ID NO: 41)

As used herein, the term “IGF1” refers to the gene encoding Insulin-like growth factor I. The terms “IGF1” and "Insulin-like growth factor I" include wild-type forms of the IGF1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type IGF1. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type IGF1 nucleic acid sequence (e.g., SEQ ID NO: 42, ENA accession number X00173). SEQ ID NO: 42 is a wild-type gene sequence encoding IGF1 protein, and is shown below: CTTCAGAAGCAATGGGAAAAATCAGCAGTCTTCCAACCCAATTATTTAAGTGCTGCTTTT

GTGATTTCTTGAAGGTGAAGATGCACACCATGTCCTCCTCGCATCTCTTCTACCTGG CGC

TGTGCCTGCTCACCTTCACCAGCTCTGCCACGGCTGGACCGGAGACGCTCTGCGGGG CTG

AGCTGGTGGATGCTCTTCAGTTCGTGTGTGGAGACAGGGGCTTTTATTTCAACAAGC CCA

CAGGGTATGGCTCCAGCAGTCGGAGGGCGCCTCAGACAGGTATCGTGGATGAGTGCT GCT

TCCGGAGCTGTGATCTAAGGAGGCTGGAGATGTATTGCGCACCCCTCAAGCCTGCCA AGT

CAGCTCGCTCTGTCCGTGCCCAGCGCCACACCGACATGCCCAAGACCCAGAAGGAAG TAC

ATTT GAAG AACGCAAGT AG AGGG AGTGCAGG AAACAAG AACT AC AGGAT GT AGG AAG ACC

CTCCTGAGGAGTGAAGAGTGACATGCCACCGCAGGATCCTTTGCTCTGCACGAGTTA CCT

GTTAAACTTTGGAACACCTACCAAAAAATAAGTTTGATAACATTTAAAAGATGGGCG TTT

CCCCCAATGAAATACACAAGTAAACATTCCAACATTGTCTTTAGGAGTGATTTGCAC CTT

G C AAAAAT G GTCCTG G AGTT G GT AG ATT G CTGTTG AT CTTTT AT C AAT AATGTT CTAT AG

AAAAG

(SEQ ID NO: 42)

As used herein, the term “IL10RA” refers to the gene encoding Interleukin-10 receptor subunit alpha. The terms “IL10RA” and "Interleukin-10 receptor subunit alpha" include wild-type forms of the IL10RA gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type IL10RA.

Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type IL10RA nucleic acid sequence (e.g., SEQ ID NO: 43, ENA accession number U00672). SEQ ID NO: 43 is a wild- type gene sequence encoding IL10RA protein, and is shown below:

AAAGAGCTGGAGGCGCGCAGGCCGGCTCCGCTCCGGCCCCGGACGATGCGGCGCGCC CAG

GATGCTGCCGTGCCTCGTAGTGCTGCTGGCGGCGCTCCTCAGCCTCCGTCTTGGCTC AGA

CGCTCATGGGACAGAGCTGCCCAGCCCTCCGTCTGTGTGGTTTGAAGCAGAATTTTT CCA

CCACATCCTCC ACT GG ACACCC ATCCCAAAT CAGT CT G AAAGT ACCT GOT AT GAAGT GGC

GCTCCTGAGGTATGGAATAGAGTCCTGGAACTCCATCTCCAACTGTAGCCAGACCCT GTC

CTATGACCTTACCGCAGTGACCTTGGACCTGTACCACAGCAATGGCTACCGGGCCAG AGT

GCGGGCTGTGGACGGCAGCCGGCACTCCAACTGGACCGTCACCAACACCCGCTTCTC TGT

GGAT GAAGTG ACT CT GACAGTT GGCAGTGTG AACCT AGAG ATCCACAAT GGCTT CATCCT

CGGGAAGATTCAGCTACCCAGGCCCAAGATGGCCCCCGCGAATGACACATATGAAAG CAT

CTTCAGTCACTTCCGAGAGTATGAGATTGCCATTCGCAAGGTGCCGGGAAACTTCAC GTT

CACACACAAGAAAGTAAAACATGAAAACTTCAGCCTCCTAACCTCTGGAGAAGTGGG AGA

GTTCTGTGTCCAGGTGAAACCATCTGTCGCTTCCCGAAGTAACAAGGGGATGTGGTC TAA

AGAGGAGT GC AT CTCCCTCACCAGGCAGT ATTT CACCGT GACCAACGTCAT CAT CTTCTT

TGCCTTTGTCCTGCTGCTCTCCGGAGCCCTCGCCTACTGCCTGGCCCTCCAGCTGTA TGT

GCGGCGCCGAAAGAAGCTACCCAGTGTCCTGCTCTTCAAGAAGCCCAGCCCCTTCAT CTT

CATCAGCCAGCGTCCCTCCCCAGAGACCCAAGACACCATCCACCCGCTTGATGAGGA GGC

CTTTTTGAAGGTGTCCCCAGAGCTGAAGAACTTGGACCTGCACGGCAGCACAGACAG TGG

CTTTGGCAGCACCAAGCCATCCCTGCAGACTGAAGAGCCCCAGTTCCTCCTCCCTGA CCC TCACCCCCAGGCTGACAGAACGCTGGGAAACGGGGAGCCCCCTGTGCTGGGGGACAGCTG

CAGTAGTGGCAGCAGCAATAGCACAGACAGCGGGATCTGCCTGCAGGAGCCCAGCCT GAG

CCCCAGCACAGGGCCCACCTGGGAGCAACAGGTGGGGAGCAACAGCAGGGGCCAGGA TGA

CAGTGGCATTGACTTAGTTCAAAACTCTGAGGGCCGGGCTGGGGACACACAGGGTGG CTC

GGCCTT GGGCCACCACAGTCCCCCGGAGCCT GAGGT GCCT GGGGAAGAAGACCCAGCTGC

T GTGGCATTCCAGGGTT ACCT G AGGC AG ACC AG ATGTGCT GAAG AG AAGGC AACCAAGAC

AGGCTGCCTGGAGGAAGAATCGCCCTTGACAGATGGCCTTGGCCCCAAATTCGGGAG ATG

CCTGGTTGATGAGGCAGGCTTGCATCCACCAGCCCTGGCCAAGGGCTATTTGAAACA GGA

TCCTCTAGAAATGACTCTGGCTTCCTCAGGGGCCCCAACGGGACAGTGGAACCAGCC CAC

TGAGGAATGGTCACTCCTGGCCTTGAGCAGCTGCAGTGACCTGGGAATATCTGACTG GAG

CTTTGCCCATGACCTTGCCCCTCTAGGCTGTGTGGCAGCCCCAGGTGGTCTCCTGGG CAG

CTTTAACTCAGACCTGGTCACCCTGCCCCTCATCTCTAGCCTGCAGTCAAGTGAGTG ACT

CGGGCTGAGAGGCTGCTTTTGATTTTAGCCATGCCTGCTCCTCTGCCTGGACCAGGA GGA

GGGCCCTGGGGCAGAAGTTAGGCACGAGGCAGTCTGGGCACTTTTCTGCAAGTCCAC TGG

GGCTGGCCCAGCCAGGCTGCAGGGCTGGTCAGGGTGTCTGGGGCAGGAGGAGGCCAA CTC

ACTGAACTAGT GCAGGGTATGT GGGT GGCACT GACCT GTTCT GTTGACTGGGGCCCT GCA

GACTCTGGCAGAGCTGAGAAGGGCAGGGACCTTCTCCCTCCTAGGAACTCTTTCCTG TAT

CATAAAGGATTATTTGCTCAGGGGAACCATGGGGCTTTCTGGAGTTGTGGTGAGGCC ACC

AGGCTGAAGTCAGCTCAGACCCAGACCTCCCTGCTTAGGCCACTCGAGCATCAGAGC TTC

CAGCAGGAGGAAGGGCTGTAGGAATGGAAGCTTCAGGGCCTTGCTGCTGGGGTCATT TTT

AGGGGAAAAAGGAGGATATGATGGTCACATGGGGAACCTCCCCTCATCGGGCCTCTG GGG

CAGGAAGCTTGTCACTG GAAG AT CTT AAG GTATAT ATTTT CTG G AC ACT C AAAC AC AT C A

TAATGGATTCACTGAGGGGAGACAAAGGGAGCCGAGACCCTGGATGGGGCTTCCAGC TCA

GAACCCATCCCTCTGGTGGGTACCTCTGGCACCCATCTGCAAATATCTCCCTCTCTC CAA

CAAATGGAGTAGCATCCCCCTGGGGCACTTGCTGAGGCCAAGCCACTCACATCCTCA CTT

TGCTGCCCCACCATCTTGCTGACAACTTCCAGAGAAGCCATGGTTTTTTGTATTGGT CAT

AACTCAGCCCTTTGGGCGGCCTCTGGGCTTGGGCACCAGCTCATGCCAGCCCCAGAG GGT

CAGGGTTGGAGGCCTGTGCTTGTGTTTGCTGCTAATGTCCAGCTACAGACCCAGAGG ATA

AGCCACTGGGCACTGGGCTGGGGTCCCTGCCTTGTTGGTGTTCAGCTGTGTGATTTT GGA

CTAGCCACTTGTCAGAGGGCCTCAATCTCCCATCTGTGAAATAAGGACTCCACCTTT AGG

GGACCCTCCATGTTTGCTGGGTATTAGCCAAGCTGGTCCTGGGAGAATGCAGATACT GTC

CGTGG ACT ACC AAGCTGGCTT GTTT CTT AT GCCAGAGGCT AACAG ATCCAATGGG AGTCC

ATGGTGTCATGCCAAGACAGTATCAGACACAGCCCCAGAAGGGGGCATTATGGGCCC TGC

CTCCCCATAGGCCATTTGGACTCTGCCTTCAAACAAAGGCAGTTCAGTCCACAGGCA TGG

AAGCTGTGAGGGGACAGGCCTGTGCGTGCCATCCAGAGTCATCTCAGCCCTGCCTTT CTC

TGGAGCATTCTGAAAACAGATATTCTGGCCCAGGGAATCCAGCCATGACCCCCACCC CTC

T GCCAAAGTACTCTTAGGT GCCAGTCT GGTAACT GAACTCCCTCTGGAGGCAGGCTT GAG

GGAGGATTCCTCAGGGTTCCCTTGAAAGCTTTATTTATTTATTTTGTTCATTTATTT ATT

GGAGAGGCAGCATTGCACAGTGAAAGAATTCTGGATATCTCAGGAGCCCCGAAATTC TAG

CTCTGACTTTGCTGTTTCCAGTGGTATGACCTTGGAGAAGTCACTTATCCTCTTGGA GCC

TCAGTTTCCTCATCTGCAGAATAATGACTGACTTGTCTAATTCATAGGGATGTGAGG TTC

TGCT G AGGAAAT GGGTAT GAAT GT GCCTT G AACACAAAGCT CTGTCAAT AAGTGATACAT GTTTTTTATTCCAAT AAATT GT CAAGACCACA (SEQ ID NO: 43)

As used herein, the term “IL1 A” refers to the gene encoding lnterleukin-1 alpha. The terms “IL1 A” and "lnterleukin-1 alpha" include wild-type forms of the IL1A gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type IL1A. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type IL1 A nucleic acid sequence (e.g., SEQ ID NO: 44, ENA accession number X02531). SEQ ID NO: 44 is a wild-type gene sequence encoding IL1A protein, and is shown below:

ATGGCCAAAGTTCCAGACATGTTTGAAGACCTGAAGAACTGTTACAGTGAAAATGAA GAA

GACAGTTCCTCCATTGATCATCTGTCTCTGAATCAGAAATCCTTCTATCATGTAAGC TAT

GGCCCACTCCATGAAGGCTGCATGGATCAATCTGTGTCTCTGAGTATCTCTGAAACC TCT

AAAACATCCAAGCTTACCTTCAAGGAGAGCATGGTGGTAGTAGCAACCAACGGGAAG GTT

CT GAAG AAG AG ACGGTT GAGTTT AAGCC AATCCAT CACT GAT GAT G ACCT GG AGGCCATC

GCCAATGACTCAGAGGAAGAAATCATCAAGCCTAGGTCAGCACCTTTTAGCTTCCTG AGC

AAT GT G AAAT AC AACTTT AT GAGG AT CAT CAAAT ACGAATTC ATCCT GAAT G ACGCCCT C

AATCAAAGTATAATTCGAGCCAATGATCAGTACCTCACGGCTGCTGCATTACATAAT CTG

GAT GAAGC AGTG AAATTT GACATGGGTGCTTATAAGT CAT CAAAGGAT GAT GCT AAAATT

ACCGT GATTCT AAG AAT CT CAAAAACT CAATT GT AT GT GACTGCCCAAGAT G AAGACCAA

CCAGT GCTGCT G AAGGAG AT GCCT GAG AT ACCCAAAACC AT CACAGGT AGTG AG ACC AAC

CTCCTCTTCTTCTGGGAAACTCACGGCACTAAGAACTATTTCACATCAGTTGCCCAT CCA

AACTTGTTTATTGCCACAAAGCAAGACTACTGGGTGTGCTTGGCAGGGGGGCCACCC TCT

ATCACTGACTTTCAGATACTGGAAAACCAGGCGTAGGTCTGGAGTCTCACTTGTCTC ACT

TGTGCAGTGTTGACAGTTCATATGTACCATGTACATGAAGAAGCTAAATCCTTTACT GTT

AGT CATTT GCT GAG CAT GTACT G AG CCTT GT AATT CT AAAT GAAT GTTT AC ACT CTTTGT

AAG AGT G G AAC C AAC ACTAAC AT AT AAT GTTGTT ATTT AAAG AACAC C CTAT ATTTT GCA

T AGTACC AAT C ATTTT AATT ATT ATT CTT CAT AAC AATTTT AG GAGG AC C AG AGCT ACTG

ACTATGGCTACCAAAAAGACTCTACCCATATTACAGATGGGCAAATTAAGGCATAAG AAA

ACTAAGAAATATGCACAATAGCAGTTGAAACAAGAAGCCACAGACCTAGGATTTCAT GAT

TT CATTT C AACT GTTT GCCTTCTG CTTTT AAGTTGCTG AT G AACT CTT AAT CAAAT AG C A

TAAGTTTCTGGGACCTCAGTTTTATCATTTTCAAAATGGAGGGAATAATACCTAAGC CTT

CCTGCCGCAACAGTTTTTTATGCTAATCAGGGAGGTCATTTTGGTAAAATACTTCTC GAA

GCCGAGCCTCAAGATGAAGGCAAAGCACGAAATGTTATTTTTT AATT ATT ATTTATATAT

GTATTT AT AAAT AT ATTT AAG AT AATT AT AAT ATACTAT ATTT AT G GG AACC CCTT CAT C

CTCTGAGTGTGACCAGGCATCCTCCACAATAGCAGACAGTGTTTTCTGGGATAAGTA AGT

TTGATTTCATTAATACAGGGCATTTTGGTCCAAGTTGTGCTTATCCCATAGCCAGGA AAC

T CTGC ATT CTAGTACTT GGG AG ACCT GT AAT CAT AT AAT AAAT GT AC ATT AATT ACCTTG

AGCCAGTAATTGGTCCGATCTTTGACTCTTTTGCCATTAAACTTACCTGGGCATTCT TGT

TT C ATT C AATTCC ACCT G C AAT C AAGTCCT AC AAG CT AAAATT AG AT G AACT C AACTTT G ACAACC AT AG ACC ACT GTT AT CAAAACTTTCTTTT CT GG AATGTAAT CAAT GTTTCTTCT AGGTTCT AAAAATTGTG AT C AG ACC AT AAT GTT AC ATT ATT AT C AAC AAT AGT GATT GAT AGAGTGTTATCAGTCATAACTAAATAAAGCTTGCAAGTGAGGGAGTCATTTCATTGGCGT TT G AGT C AG C AAAG AAGTC AAG (SEQ ID NO: 44)

As used herein, the term “IL1B” refers to the gene encoding lnterleukin-1 beta. The terms “IL1 B” and "lnterleukin-1 beta" include wild-type forms of the IL1 B gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type IL1 B. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type IL1 B nucleic acid sequence (e.g., SEQ ID NO: 45, ENA accession number X02770). SEQ ID NO: 45 is a wild-type gene sequence encoding IL1 B protein, and is shown below:

ACAAACCTTTTCGAGGCAAAAGGCAAAAAAGGCTGCTCTGGGATTCTCTTCAGCCAA TCT

TCAATGCTCAAGTGTCTGAAGCAGCCATGGCAGAAGTACCTAAGCTCGCCAGTGAAA TGA

TGGCTTATTACAGTGGCAATGAGGATGACTTGTTCTTTGAAGCTGATGGCCCTAAAC AGA

TGAAGTGCTCCTTCCAGGACCTGGACCTCTGCCCTCTGGATGGCGGCATCCAGCTAC GAA

TCTCCGACCACCACTACAGCAAGGGCTTCAGGCAGGCCGCGTCAGTTGTTGTGGCCA TGG

ACAAGCTGAGGAAGATGCTGGTTCCCTGCCCACAGACCTTCCAGGAGAATGACCTGA GCA

CCTTCTTTCCCTTCATCTTTGAAGAAGAACCTATCTTCTTCGACACATGGGATAACG AGG

CTTAT GT GCACGATGCACCT GTACGATCACT GAACT GCACGCTCCGGGACTCACAGCAAA

AAAGCTTGGTGATGTCTGGTCCATATGAACTGAAAGCTCTCCACCTCCAGGGACAGG ATA

TGGAGCAACAAGTGGTGTTCTCCATGTCCTTTGTACAAGGAGAAGAAAGTAATGACA AAA

TACCTGTGGCCTTGGGCCTCAAGGAAAAGAATCTGTACCTGTCCTGCGTGTTGAAAG ATG

ATAAGCCCACTCT ACAGCT GG AG AGTGT AG ATCCCAAAAATT ACCCAAAG AAGAAGATGG

AAAAGCG ATTT GT CTT CAACAAGAT AGAAAT CAATAACAAGCTGGAATTT GAGTCT GCCC

AGTTCCCCAACTGGTACATCAGCACCTCTCAAGCAGAAAACATGCCCGTCTTCCTGG GAG

GGACCAAAGGCGGCCAGGATATAACTGACTTCACCATGCAATTTGTGTCTTCCTAAA GAG

AGCTGTACCCAGAGAGTCCTGTGCTGAATGTGGACTCAATCCCTAGGGCTGGCAGAA AGG

GAACAGAAAGGTTTTTGAGTACGGCTATAGCCTGGACTTTCCTGTTGTCTACACCAA TGC

CCAACTGCCTGCCTTAGGGTAGTGCTAAGAGGATCTCCTGTCCATCAGCCAGGACAG TCA

GCTCTCTCCTTTCAGGGCCAATCCCAGCCCTTTTGTTGAGCCAGGCCTCTCTCACCT CTC

CTACTCACTTAAAGCCCGCCTGACAGAAACCAGGCCACATTTTGGTTCTAAGAAACC CTC

CTCTGTCATTCGCTCCCACATTCTGATGAGCAACCGCTTCCCTATTTATTTATTTAT TTG

TTTGTTTGTTTTGATTCATTGGTCTAATTTATTCAAAGGGGGCAAGAAGTAGCAGTG TCT

GTAAAAGAGCCTAGTTTTTAATAGCTATGGAATCAATTCAATTTGGACTGGTGTGCT CTC

TTT AAAT C AAGTCCTTT AATT AAG ACT G AAAAT ATATAAGCT C AG ATT ATTT AAAT G GG A

AT ATTT AT AAAT G AGC AAAT AT CAT ACTGTT C AAT G GTTCT C AAAT AAACTT C ACT

(SEQ ID NO: 45) As used herein, the term “IL1RAP” refers to the gene encoding lnterleukin-1 receptor accessory protein. The terms “IL1 RAP” and "lnterleukin-1 receptor accessory protein" include wild-type forms of the IL1 RAP gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type IL1 RAP. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type IL1 RAP nucleic acid sequence (e.g., SEQ ID NO: 46, ENA accession number AF029213). SEQ ID NO: 46 is a wild-type gene sequence encoding IL1 RAP protein, and is shown below:

T CTCAAAGG AT G ACACTT CT GT GGT GT GT AGTG AGTCT CTACTTTT AT GGAATCCTGCAA

AGTGATGCCTCAGAACGCTGCGATGACTGGGGACTAGACACCATGAGGCAAATCCAA GTG

TTTGAAGATGAGCCAGCTCGCATCAAGTGCCCACTCTTTGAACACTTCTTGAAATTC AAC

TACAGCACAGCCCATTCAGCTGGCCTTACTCTGATCTGGTATTGGACTAGGCAGGAC CGG

GACCTTGAGGAGCCAATTAACTTCCGCCTCCCCGAGAACCGCATTAGTAAGGAGAAA GAT

GTGCTGTGGTTCCGGCCCACTCTCCTCAATGACACTGGCAACTATACCTGCATGTTA AGG

AAC ACT ACAT ATTGCAGCAAAGTT GCATTTCCCTTGGAAGTT GTT CAAAAAG ACAGCT GT

TTCAATTCCCCCATGAAACTCCCAGTGCATAAACTGTATATAGAATATGGCATTCAG AGG

ATCACTTGTCCAAATGTAGATGGATATTTTCCTTCCAGTGTCAAACCGACTATCACT TGG

TATATGGGCTGTTATAAAATACAGAATTTTAATAATGTAATACCCGAAGGTATGAAC TTG

AGTTTCCTCATTGCCTTAATTTCAAATAATGGAAATTACACATGTGTTGTTACATAT CCA

GAAAATGGACGTACGTTTCATCTCACCAGGACTCTGACTGTAAAGGTAGTAGGCTCT CCA

AAAAATGCAGTGCCCCCTGTGATCCATTCACCTAATGATCATGTGGTCTATGAGAAA GAA

CCAGGAGAGGAGCTACTCATTCCCTGTACGGTCTATTTTAGTTTTCTGATGGATTCT CGC

AAT GAGGTTT GGTGGACCATT GAT GG AAAAAAACCT GAT G AC AT CACT ATT GATGTCACC

ATTAACGAAAGTAT AAGTCATAGT AGAACAG AAG AT G AAACAAG AACT CAGATTTT GAGC

ATCAAGAAAGTTACCTCTGAGGATCTCAAGCGCAGCTATGTCTGTCATGCTAGAAGT GCC

AAAGGCGAAGTTGCCAAAGCAGCCAAGGTGAAGCAGAAAGTGCCAGCTCCAAGATAC ACA

GTGGAACTGGCTTGTGGTTTTGGAGCCACAGTCCTGCTAGTGGTGATTCTCATTGTT GTT

TACCATGTTTACTGGCTAGAGATGGTCCTATTTTACCGGGCTCATTTTGGAACAGAT GAA

ACCATTTTAGATGGAAAAGAGTATGATATTTATGTATCCTATGCAAGGAATGCGGAA GAA

G AAGAATTT GT ATTACT GACCCTCCGT GG AGTTTT GG AG AAT G AATTT GG AT ACAAGCT G

TGCATCTTTGACCGAGACAGTCTGCCTGGGGGAATTGTCACAGATGAGACTTTGAGC TTC

ATTCAGAAAAGCAGACGCCTCCTGGTTGTTCTAAGCCCCAACTACGTGCTCCAGGGA ACC

CAAGCCCTCCTGGAGCTCAAGGCTGGCCTAGAAAATATGGCCTCTCGGGGCAACATC AAC

GTCATTTTAGTACAGTACAAAGCTGTGAAGGAAACGAAGGTGAAAGAGCTGAAGAGG GCT

AAGACGGTGCTCACGGTCATTAAATGGAAAGGGGAAAAATCCAAGTATCCACAGGGC AGG

TTCTGGAAGCAGCTGCAGGTGGCCATGCCAGTGAAGAAAAGTCCCAGGCGGTCTAGC AGT

GATGAGCAGGGCCTCTCGTATTCATCTTTGAAAAATGTATGAAAGGAATAATGAAAA GGA

(SEQ ID NO: 46)

As used herein, the term “INPP5D” refers to the gene encoding Phosphatidylinositol 3,4,5- trisphosphate 5-phosphatase 1. The terms “INPP5D” and "Phosphatidylinositol 3,4,5-trisphosphate 5- phosphatase 1" include wild-type forms of the INPP5D gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type INPP5D. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type INPP5D nucleic acid sequence (e.g., SEQ ID NO: 47, ENA accession number X98429). SEQ ID NO: 47 is a wild-type gene sequence encoding INPP5D protein, and is shown below:

GTTGCTGTCGCCGTTGCTGTCGGCCGAGGCCACCAAGAGGCAACGGGCGGCAGGTTG CAG

TGGAGGGGCCTCCGCTCCCCTCGGTGGTGTGTGGGTCCTGGGGGTGCCTGCCGGCCC AGC

CGAGGAGGCCCACGCCCACCATGGTCCCCTGCTGGAACCATGGCAACATCACCCGCT CCA

AGGCGGAGGAGCTGCTTTCCAGGACAGGCAAGGACGGGAGCTTCCTCGTGCGTGCCA GCG

AGTCCATCTCCCGGGCATACGCGCTCTGCGTGCTGTATCGGAATTGCGTTTACACTT ACA

GAATTCTGCCCAATGAAGATGATAAATTCACTGTTCAGGCATCCGAAGGCGTCTCCA TGA

GGTTCTTCACCAAGCTGGACCAGCTCATCGAGTTTTACAAGAAGGAAAACATGGGGC TGG

TGACCCATCTGCAATACCCTGTGCCGCTGGAGGAAGAGGACACAGGCGACGACCCTG AGG

AGGACACAGAAAGTGTCGTGTCTCCACCCGAGCTGCCCCCAAGAAACATCCCGCTGA CTG

CCAGCTCCTGTGAGGCCAAGGAGGTTCCTTTTTCAAACGAGAATCCCCGAGCGACCG AGA

CCAGCCGGCCGAGCCTCTCCGAGACATTGTTCCAGCGACTGCAAAGCATGGACACCA GTG

GGCTTCCAGAAGAGCATCTTAAGGCCATCCAAGATTATTTAAGCACTCAGCTCGCCC AGG

ACTCTGAATTTGTGAAGACAGGGTCCAGCAGTCTTCCTCACCTGAAGAAACTGACCA CAC

TGCTCTGCAAGGAGCTCTATGGAGAAGTCATCCGGACCCTCCCATCCCTGGAGTCTC TGC

AGAGGTTATTTGACCAGCAGCTCTCCCCGGGCCTCCGTCCACGTCCTCAGGTTCCTG GTG

AGGCCAATCCCATCAACATGGTGTCCAAGCTCAGCCAACTGACAAGCCTGTTGTCGT CCA

TTGAAGACAAGGTCAAGGCCTTGCTGCACGAGGGTCCTGAGTCTCCGCACCGGCCCT CCC

TTATCCCTCCAGTCACCTTTGAGGTGAAGGCAGAGTCTCTGGGGATTCCTCAGAAAA TGC

AGCTCAAAGTCGACGTTGAGTCTGGGAAACTGATCATTAAGAAGTCCAAGGATGGTT CTG

AGG ACAAGTT CT ACAGCCAC AAG AAAATCCT GCAGCT GATT AAGT CACAGAAATTTCT GA

ATAAGTTGGTGATCTTGGTGGAAACGGAGAAGGAGAAGATCCTGCGGAAGGAATATG TTT

TTGCTGACTCCAAAAAGAGAGAAGGCTTCTGCCAGCTCCTGCAGCAGATGAAGAACA AGC

ACTCAGAGCAGCCGGAGCCCGACATGATCACCATCTTCATCGGCACCTGGAACATGG GTA

ACGCCCCCCCTCCCAAGAAGATCACGTCCTGGTTTCTCTCCAAGGGGCAGGGAAAGA CGC

GGGACGACTCTGCGGACTACATCCCCCATGACATTTACGTGATCGGCACCCAAGAGG ACC

CCCT GAGT G AG AAGGAGTGGCT GG AG ATCCT CAAACACTCCCTGCAAG AAATCACCAGT G

TGACTTTTAAAACAGTCGCCATCCACACGCTCTGGAACATCCGCATCGTGGTGCTGG CCA

AGCCT GAGCACGAGAACCGGATCAGCCACATCT GTACT GACAACGT GAAGACAGGCATT G

CAAACACACTGGGGAACAAGGGAGCCGTGGGGGTGTCGTTCATGTTCAATGGAACCT CCT

TAGGGTTCGTCAACAGCCACTTGACTTCAGGAAGTGAAAAGAAACTCAGGCGAAACC AAA

ACTATATGAACATTCTCCGGTTCCTGGCCCTGGGCGACAAGAAGCTGAGTCCCTTTA ACA

TCACTCACCGCTTCACGCACCTCTTCTGGTTTGGGGATCTTAACTACCGTGTGGATC TGC

CTACCTGGGAGGCAGAAACCATCATCCAGAAAATCAAGCAGCAGCAGTACGCAGACC TCC

TGTCCCACGACCAGCTGCTCACAGAGAGGAGGGAGCAGAAGGTCTTCCTACACTTCG AGG AGGAAGAAATCACGTTTGCCCCAACCTACCGTTTTGAGAGACTGACTCGGGACAAATACG

CCT AC ACCAAGCAGAAAGCG ACAGGGAT G AAGTACAACTTGCCTTCCTGGTGTG ACCG AG

TCCTCTGGAAGTCTTATCCCCTGGTGCACGTGGTGTGTCAGTCTTATGGCAGTACCA GCG

ACATCATGACGAGTGACCACAGCCCTGTCTTTGCCACATTTGAGGCAGGAGTCACTT CCC

AGTTTGTCTCCAAGAACGGTCCCGGGACTGTTGACAGCCAAGGACAGATTGAGTTTC TCA

GGTGCTATGCCACATTGAAGACCAAGTCCCAGACCAAATTCTACCTGGAGTTCCACT CGA

GCTGCTTGGAGAGTTTTGTCAAGAGTCAGGAAGGAGAAAATGAAGAAGGAAGTGAGG GGG

AGCT GGT GGTG AAGTTTGGT GAGACTCTTCCAAAGCT GAAGCCCATT AT CT CT GACCCT G

AGTACCTGCTAGACCAGCACATCCTCATCAGCATCAAGTCCTCTGACAGCGACGAAT CCT

ATGGCGAGGGCTGCATTGCCCTTCGGTTAGAGGCCACAGAAACGCAGCTGCCCATCT ACA

CGCCTCTCACCCACCATGGGGAGTTGACAGGCCACTTCCAGGGGGAGATCAAGCTGC AGA

CCTCTCAGGGCAAGACGAGGGAGAAGCTCTATGACTTTGTGAAGACGGAGCGTGATG AAT

CCAGTGGGCCAAAGACCCTGAAGAGCCTCACCAGCCACGACCCCATGAAGCAGTGGG AAG

TCACTAGCAGGGCCCCTCCGTGCAGTGGCTCCAGCATCACTGAAATCATCAACCCCA ACT

ACATGGGAGTGGGGCCCTTTGGGCCACCAATGCCCCTGCACGTGAAGCAGACCTTGT CCC

CTGACCAGCAGCCCACAGCCTGGAGCTACGACCAGCCGCCCAAGGACTCCCCGCTGG GGC

CCTGCAGGGGAGAAAGTCCTCCGACACCTCCCGGCCAGCCGCCCATATCACCCAAGA AGT

TTTTACCCTCAACAGCAAACCGGGGTCTCCCTCCCAGGACACAGGAGTCAAGGCCCA GTG

ACCTGGGGAAGAACGCAGGGGACACGCTGCCTCAGGAGGACCTGCCGCTGACGAAGC CCG

AGATGTTTGAGAACCCCCTGTATGGGTCCCTGAGTTCCTTCCCTAAGCCTGCTCCCA GGA

AGGACCAGGAATCCCCCAAAATGCCGCGGAAGGAACCCCCGCCCTGCCCGGAACCCG GCA

TCTTGTCGCCCAGCATCGTGCTCACCAAAGCCCAGGAGGCTGATCGCGGCGAGGGGC CCG

GCAAGCAGGTGCCCGCGCCCCGGCTGCGCTCCTTCACGTGCTCATCCTCTGCCGAGG GCA

GGGCGGCCGGCGGGGACAAGAGCCAAGGGAAGCCCAAGACCCCGGTCAGCTCCCAGG CCC

CGGTGCCGGCCAAGAGGCCCATCAAGCCTTCCAGATCGGAAATCAACCAGCAGACCC CGC

CCACCCCGACGCCGCGGCCGCCGCTGCCAGTCAAGAGCCCGGCGGTGCTGCACCTCC AGC

ACTCCAAGGGCCGCGACTACCGCGACAACACCGAGCTCCCGTATCACGGCAAGCACC GGC

CGGAGGAGGGGCCACCAGGGCCTCTAGGCAGGACTGCCATGCAGTGAAGCCCTCAGT GAG

CTGCCACTGAGTCGGGAGCCCAGAGGAACGGCGTGAAGCCACTGGACCCTCTCCCGG GAC

CTCCTGCTGGCTCCTCCTGCCCAGCTTCCTATGCAAGGCTTTGTGTTTTCAGGAAAG GGC

CTAGCTTCT GT GT GGCCCACAGAGTTCACT GCCT GTGAGACTTAGCACCAAGT GCTGAGG

CTGGAAGAAAAACGCACACCAGACGGGCAACAAACAGTCTGGGTCCCCAGCTCGCTC TTG

GTACTTGGGACCCCAGTGCCTTGTTGAGGGCGCCATTCTGAAGAAAGGAACTGCAGC GCC

GATTTGAGGGTGGAGATATAGATAATAATAATATTAATAATAATAATGGCCACATGG ATC

GAACACTCATGGTGTGCCAAGTGCTGTGCTAAGTGCTTTACGAACATTCGTCATATC AGG

ATGACCTCGAGAGCTGAGGCTCTAGCACCTAAAACCACGTGCCCAAACCCACCAGTT TAA

AACGGTGTGTGTTCGGAGGGGTGAAAGCATTAAGAAGCCCAGTGCCCTCCTGGAGTG AGA

CAAGGGCTCGGCCTTAAGGAGCTGAAGAGTCTGGGTAGCTTGTTTAGGGTACAAGAA GCC

TGTTCTGTCCAGCTTCAGTGACACAAGCTGCTTTAGCTAAAGTCCCGCGGGTTCCGG CAT

GGCTAGGCTGAGAGCAGGGATCTACCTGGCTTCTCAGTTCTTTGGTTGGAAGGAGCA GGA

AATCAGCTCCTATTCTCCAGTGGAGAGATCTGGCCTCAGCTTGGGCTAGAGATGCCA AGG

CCTGTGCCAGGTTCCCTGTGCCCTCCTCGAGGTGGGCAGCCATCACCAGCCACAGTT AAG CCAAGCCCCCCAACATGTATTCCATCGTGCTGGTAGAAGAGTCTTTGCTGTTGCTCCCGA

AAGCCGTGCTCTCCAGCCTGGCTGCCAGGGAGGGTGGGCCTCTTGGTTCCAGGCTCT TGA

AATAGTGCAGCCTTTTCTTCCTATCTCTGTGGCTTTCAGCTCTGCTTCCTTGGTTAT TAG

GAGAATAGATGGGTGATGTCTTTCCTTATGTTGCTTTTTCAACATAGCAGAATTAAT GTA

GGGAGCTAAATCCAGTGGTGTGTGTGAATGCAGAAGGGAATGCACCCCACATTCCCA TGA

TGGAAGTCTGCGTAACCAATAAATTGTGCCTTTCTCACTCAAAACC

(SEQ ID NO: 47)

As used herein, the term “ITGAM” refers to the gene encoding Integrin Subunit Alpha M. The terms “ITGAM” and "Integrin Subunit Alpha M" include wild-type forms of the ITGAM gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type ITGAM. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type ITGAM nucleic acid sequence (e.g., SEQ ID NO: 48, NCBI Reference Sequence: NM_000632.3). SEQ ID NO: 48 is a wild-type gene sequence encoding ITGAM protein, and is shown below:

TTTTCTGCCCTTCTTTGCTTTGGTGGCTTCCTTGTGGTTCCTCAGTGGTGCCTGCAA CCCCTGGTTCA

CCTCCTTCCAGGTTCTGGCTCCTTCCAGCCATGGCTCTCAGAGTCCTTCTGTTAACA GCCTTGACCT

TATGTCATGGGTTCAACTTGGACACTGAAAACGCAATGACCTTCCAAGAGAACGCAA GGGGCTTCGG

GCAGAGCGTGGTCCAGCTTCAGGGATCCAGGGTGGTGGTTGGAGCCCCCCAGGAGAT AGTGGCTG

CCAACCAAAGGGGCAGCCTCTACCAGTGCGACTACAGCACAGGCTCATGCGAGCCCA TCCGCCTGC

AGGTCCCCGTGGAGGCCGTGAACATGTCCCTGGGCCTGTCCCTGGCAGCCACCACCA GCCCCCCT

CAGCTGCTGGCCTGTGGTCCCACCGTGCACCAGACTTGCAGTGAGAACACGTATGTG AAAGGGCTC

TGCTTCCTGTTTGGATCCAACCTACGGCAGCAGCCCCAGAAGTTCCCAGAGGCCCTC CGAGGGTGT

CCT CAAGAGG AT AGT GACATT GCCTT CTT GATT GAT GGCTCTGGT AGCAT CATCCCACAT GACTTTCG

GCGGATGAAGGAGTTTGTCTCAACTGTGATGGAGCAATTAAAAAAGTCCAAAACCTT GTTCTCTTTGA

TGCAGTACTCTGAAGAATTCCGGATTCACTTTACCTTCAAAGAGTTCCAGAACAACC CTAACCCAAGA

TCACTGGTGAAGCCAATAACGCAGCTGCTTGGGCGGACACACACGGCCACGGGCATC CGCAAAGT

GGTACGAGAGCTGTTTAACATCACCAACGGAGCCCGAAAGAATGCCTTTAAGATCCT AGTTGTCATC

ACGGATGGAGAAAAGTTTGGCGATCCCTTGGGATATGAGGATGTCATCCCTGAGGCA GACAGAGAG

GGAGTCATTCGCTACGTCATTGGGGTGGGAGATGCCTTCCGCAGTGAGAAATCCCGC CAAGAGCTT

AATACCATCGCATCCAAGCCGCCTCGTGATCACGTGTTCCAGGTGAATAACTTTGAG GCTCTGAAGA

CCATTCAGAACCAGCTTCGGGAGAAGATCTTTGCGATCGAGGGTACTCAGACAGGAA GTAGCAGCT

CCTTTGAGCATGAGATGTCTCAGGAAGGCTTCAGCGCTGCCATCACCTCTAATGGCC CCTTGCTGAG

CACTGTGGGGAGCTATGACTGGGCTGGTGGAGTCTTTCTATATACATCAAAGGAGAA AAGCACCTTC

ATCAACATGACCAGAGTGGATTCAGACATGAATGATGCTTACTTGGGTTATGCTGCC GCCATCATCTT

ACGGAACCGGGTGCAAAGCCTGGTTCTGGGGGCACCTCGATATCAGCACATCGGCCT GGTAGCGAT

GTTCAGGCAGAACACTGGCATGTGGGAGTCCAACGCTAATGTCAAGGGCACCCAGAT CGGCGCCTA

CTTCGGGGCCTCCCTCTGCTCCGTGGACGTGGACAGCAACGGCAGCACCGACCTGGT CCTCATCG

GGGCCCCCCATTACTACGAGCAGACCCGAGGGGGCCAGGTGTCCGTGTGCCCCTTGC CCAGGGGG

AGGGCTCGGTGGCAGTGTGATGCTGTTCTCTACGGGGAGCAGGGCCAACCCTGGGGC CGCTTTGG GGCAGCCCTAACAGTGCTGGGGGACGTAAATGGGGACAAGCTGACGGACGTGGCCATTGG GGCCC CAGGAGAGGAGGACAACCGGGGTGCTGTTTACCTGTTTCACGGAACCTCAGGATCTGGCA TCAGCC CCTCCCATAGCCAGCGGATAGCAGGCTCCAAGCTCTCTCCCAGGCTCCAGTATTTTGGTC AGTCACT GAGTGGGGGCCAGGACCTCACAATGGATGGACTGGTAGACCTGACTGTAGGAGCCCAGGG GCACG TGCTGCTGCTCAGGTCCCAGCCAGTACTGAGAGTCAAGGCAATCATGGAGTTCAATCCCA GGGAAG TGGCAAGGAATGTATTTGAGTGTAATGATCAGGTGGTGAAAGGCAAGGAAGCCGGAGAGG TCAGAG T CTGCCTCCAT GTCCAGAAG AGCACACGGGATCGGCT AAG AG AAGGACAGATCCAGAGT GTTGTGA CTTATGACCTGGCTCTGGACTCCGGCCGCCCACATTCCCGCGCCGTCTTCAATGAGACAA AGAACA GCACACGCAGACAGACACAGGTCTTGGGGCTGACCCAGACTTGTGAGACCCTGAAACTAC AGTTGC CGAATTGCATCGAGGACCCAGTGAGCCCCATTGTGCTGCGCCTGAACTTCTCTCTGGTGG GAACGC CATTGTCTGCTTTCGGGAACCTCCGGCCAGTGCTGGCGGAGGATGCTCAGAGACTCTTCA CAGCCT TGTTTCCCTTTGAGAAGAATTGTGGCAATGACAACATCTGCCAGGATGACCTCAGCATCA CCTTCAGT TTCATGAGCCTGGACTGCCTCGTGGTGGGTGGGCCCCGGGAGTTCAACGTGACAGTGACT GTGAGA AATGATGGTGAGGACTCCTACAGGACACAGGTCACCTTCTTCTTCCCGCTTGACCTGTCC TACCGGA AGGTGTCCACGCTCCAGAACCAGCGCTCACAGCGATCCTGGCGCCTGGCCTGTGAGTCTG CCTCCT CCACCGAAGTGTCTGGGGCCTTGAAGAGCACCAGCTGCAGCATAAACCACCCCATCTTCC CGGAAA ACTCAGAGGTCACCTTTAATATCACGTTTGATGTAGACTCTAAGGCTTCCCTTGGAAACA AACTGCTC CTCAAGGCCAATGTGACCAGTGAGAACAACATGCCCAGAACCAACAAAACCGAATTCCAA CTGGAGC TGCCGGTGAAATATGCTGTCTACATGGTGGTCACCAGCCATGGGGTCTCCACTAAATATC TCAACTT CACGGCCTCAGAGAATACCAGTCGGGTCATGCAGCATCAATATCAGGTCAGCAACCTGGG GCAGAG GAGCCTCCCCATCAGCCTGGTGTTCTTGGTGCCCGTCCGGCTGAACCAGACTGTCATATG GGACCG CCCCCAGGTCACCTTCTCCGAGAACCTCTCGAGTACGTGCCACACCAAGGAGCGCTTGCC CTCTCA CTCCGACTTTCTGGCTGAGCTTCGGAAGGCCCCCGTGGTGAACTGCTCCATCGCTGTCTG CCAGAG AATCCAGTGTGACATCCCGTTCTTTGGCATCCAGGAAGAATTCAATGCTACCCTCAAAGG CAACCTC TCGTTTGACTGGTACATCAAGACCTCGCATAACCACCTCCTGATCGTGAGCACAGCTGAG ATCTTGT TTAACGATTCCGTGTTCACCCTGCTGCCGGGACAGGGGGCGTTTGTGAGGTCCCAGACGG AGACCA AAGTGGAGCCGTTCGAGGTCCCCAACCCCCTGCCGCTCATCGTGGGCAGCTCTGTCGGGG GACTG CTGCTCCTGGCCCTCATCACCGCCGCGCTGTACAAGCTCGGCTTCTTCAAGCGGCAATAC AAGGAC ATGATGAGTGAAGGGGGTCCCCCGGGGGCCGAACCCCAGTAGCGGCTCCTTCCCGACAGA GCTGC CTCTCGGTGGCCAGCAGGACTCTGCCCAGACCACACGTAGCCCCCAGGCTGCTGGACACG TCGGA CAGCGAAGTATCCCCGACAGGACGGGCTTGGGCTTCCATTTGTGTGTGTGCAAGTGTGTA TGTGCG TGTGTGCAAGTGTCTGTGTGCAAGTGTGTGCACATGTGTGCGTGTGCGTGCATGTGCACT TGCACG CCCATGTGTGAGTGTGTGCAAGTATGTGAGTGTGTCCAAGTGTGTGTGCGTGTGTCCATG TGTGTGC AAGTGTGTGCATGTGTGCGAGTGTGTGCATGTGTGTGCTCAGGGGCGTGTGGCTCACGTG TGTGAC TCAGATGTCTCTGGCGTGTGGGTAGGTGACGGCAGCGTAGCCTCTCCGGCAGAAGGGAAC TGCCT GGGCTCCCTTGTGCGTGGGTGAAGCCGCTGCTGGGTTTTCCTCCGGGAGAGGGGACGGTC AATCC TGTGGGTGAAGACAGAGGGAAACACAGCAGCTTCTCTCCACTGAAAGAAGTGGGACTTCC CGTCGC CTGCGAGCCTGCGGCCTGCTGGAGCCTGCGCAGCTTGGATGGAGACTCCATGAGAAGCCG TGGGT GGAACCAGG AACCTCCTCCAC ACC AGCGCT GATGCCCAAT AAAG AT GCCC ACT GAGG AAT GAT G AA G CTTCCTTT CTG GATT C ATTT ATT ATTT C AAT GT G ACTTT AATTTTTT G GAT G GAT AAG CTTGTCTATGG T AC AAAAAT CAC AAGG C ATT C AAGT GT AC AGT G AAAAGT CTCC CTTTCC AG AT ATT C AAGT C AC CTCC TTAAAGGTAGTCAAGATTGTGTTTTGAGGTTTCCTTCAGACAGATTCCAGGCGATGTGCA AGTGTATG C ACGTGTG C AC AC AC AC C AC AC AT AC AC AC AC AC AAG CTTTTTT AC AC AAAT G GT AGC AT ACTTT AT A TTGGTCTGTATCTTG CTTTTTTT C ACC AAT ATTT CT C AG AC ATCG GTT CAT ATT AAG AC AT AAATT ACTT TTTCATTCTTTTATACCGCTGCATAGTATTCCATTGTGTGAGTGTACCATAATGTATTTA ACCAGTCTT CTTTT GAT ATACT ATTTT C ATT CTCTTGTT ATT GC AT C AAT G CTG AGTT AAT AAAT C AAAT ATATGTC AT TTTTGCATATATGTAAGGATAA (SEQ ID NO: 48)

As used herein, the term “ITGAX” refers to the gene encoding Integrin alpha-X. The terms “ITGAX” and "Integrin alpha-X" include wild-type forms of the ITGAX gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type ITGAX. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type ITGAX nucleic acid sequence (e.g., SEQ ID NO: 49, ENA accession number M81695). SEQ ID NO: 49 is a wild-type gene sequence encoding ITGAX protein, and is shown below:

GAATTCCTGCCACTCTTCCTGCAACGGCCCAGGAGCTCAGAGCTCCACATCTGACCT TCT

AGTCATGACCAGGACCAGGGCAGCACTCCTCCTGTTCACAGCCTTAGCAACTTCTCT AGG

TTTCAACTTGGACACAGAGGAGCTGACAGCCTTCCGTGTGGACAGCGCTGGGTTTGG AGA

CAGCGTGGTCCAGTATGCCAACTCCTGGGTGGTGGTTGGAGCCCCCCAAAAGATAAC AGC

TGCCAACCAAACGGGTGGCCTCTACCAGTGTGGCTACAGCACTGGTGCCTGTGAGCC CAT

CGGCCTGCAGGTGCCCCCGGAGGCCGTGAACATGTCCCTGGGCCTGTCCCTGGCGTC TAC

CACCAGCCCTTCCCAGCTGCTGGCCTGCGGCCCCACCGTGCACCACGAGTGCGGGAG GAA

CATGTACCTCACCGGACTCTGCTTCCTCCTGGGCCCCACCCAGCTCACCCAGAGGCT CCC

GGTGTCCAGGCAGGAGTGCCCAAGACAGGAGCAGGACATTGTGTTCCTGATCGATGG CTC

AGGCAGCATCTCCTCCCGCAACTTTGCCACGATGATGAACTTCGTGAGAGCTGTGAT AAG

CCAGTTCCAGAGACCCAGCACCCAGTTTTCCCTGATGCAGTTCTCCAACAAATTCCA AAC

ACACTTCACTTTCGAGGAATTCAGGCGCACGTCAAACCCCCTCAGCCTGTTGGCTTC TGT

TCACCAGCTGCAAGGGTTTACATACACGGCCACCGCCATCCAAAATGTCGTGCACCG ATT

GTTCCATGCCTCATATGGGGCCCGTAGGGATGCCACCAAAATTCTCATTGTCATCAC TGA

TGGGAAGAAAGAAGGCGACAGCCTGGATTATAAGGATGTCATCCCCATGGCTGATGC AGC

AGGCATCATCCGCTATGCAATTGGGGTTGGATTAGCTTTTCAAAACAGAAATTCTTG GAA

AGAATTAAATGACATTGCATCGAAGCCCTCCCAGGAACACATATTTAAAGTGGAGGA CTT

T GATGCT CT G AAAGAT ATT CAAAACCAACT G AAGG AG AAG AT CTTTGCC ATT G AGGGTAC

GGAGACCACAAGCAGTAGCTCCTTCGAATTGGAGATGGCACAGGAGGGCTTCAGCGC TGT

GTTCACACCTGATGGCCCCGTTCTGGGGGCTGTGGGGAGCTTCACCTGGTCTGGAGG TGC

CTTCCTGTACCCCCCAAATATGAGCCCTACCTTCATCAACATGTCTCAGGAGAATGT GGA

CATGAGGGACTCTTACCTGGGTTACTCCACCGAGCTGGCCCTCTGGAAAGGGGTGCA GAG

CCTGGTCCTGGGGGCCCCCCGCTACCAGCACACCGGGAAGGCTGTCATCTTCACCCA GGT

GTCCAGGCAATGGAGGATGAAGGCCGAAGTCACGGGGACTCAGATCGGCTCCTACTT CGG

GGCCTCCCTCTGCTCCGTGGACGTAGACACCGACGGCAGCACCGACCTGGTCCTCAT CGG

GGCCCCCCATTACTACGAGCAGACCCGAGGGGGCCAGGTGTCTGTGTGTCCCTTGCC CAG GGGGTGGAGAAGGTGGTGGTGTGATGCTGTTCTCTACGGGGAGCAGGGCCACCCCTGGGG

TCGCTTTGGGGCGGCTCTGACAGTGCTGGGGGATGTGAATGGGGACAAGCTGACAGA CGT

GGTCATCGGGGCCCCAGGAGAGGAGGAGAACCGGGGTGCTGTCTACCTGTTTCACGG AGT

CTTGGGACCCAGCATCAGCCCCTCCCACAGCCAGCGGATCGCGGGCTCCCAGCTCTC CTC

CAGGCTGCAGTATTTTGGGCAGGCACTGAGCGGGGGTCAAGACCTCACCCAGGATGG ACT

GGTGGACCTGGCTGTGGGGGCCCGGGGCCAGGTGCTCCTGCTCAGGACCAGACCTGT GCT

CTGGGTGGGGGTGAGCATGCAGTTCATACCTGCCGAGATCCCCAGGTCTGCGTTTGA GTG

TCGGGAGCAGGTGGTCTCTGAGCAGACCCTGGTACAGTCCAACATCTGCCTTTACAT TGA

CAAACGTTCTAAGAACCTGCTTGGGAGCCGTGACCTCCAAAGCTCTGTGACCTTGGA CCT

GGCCCTCGACCCTGGCCGCCTGAGTCCCCGTGCCACCTTCCAGGAAACAAAGAACCG GAG

TCTGAGCCGAGTCCGAGTCCTCGGGCTGAAGGCACACTGTGAAAACTTCAACCTGCT GCT

CCCGAGCTGCGTGGAGGACTCTGTGACCCCCATTACCTTGCGTCTGAACTTCACGCT GGT

GGGCAAGCCCCTCCTTGCCTTCAGAAACCTGCGGCCTATGCTGGCCGCACTGGCTCA GAG

ATACTTCACGGCCTCCCTACCCTTTGAGAAGAACTGTGGAGCCGACCATATCTGCCA GGA

CAATCTCGGCATCTCCTTCAGCTTCCCAGGCTTGAAGTCCCTGCTGGTGGGGAGTAA CCT

GGAGCTGAACGCAGAAGTGATGGTGTGGAATGACGGGGAAGACTCCTACGGAACCAC CAT

CACCTTCTCCCACCCCGCAGGACTGTCCTACCGCTACGTGGCAGAGGGCCAGAAACA AGG

GCAGCTGCGTTCCCTGCACCTGACATGTGACAGCGCCCCAGTTGGGAGCCAGGGCAC CTG

GAGCACCAGCTGCAGAATCAACCACCTCATCTTCCGTGGCGGCGCCCAGATCACCTT CTT

GGCTACCTTTGACGTCTCCCCCAAGGCTGTCCTGGGAGACCGGCTGCTTCTGACAGC CAA

TGTGAGCAGTGAGAACAACACTCCCAGGACCAGCAAGACCACCTTCCAGCTGGAGCT CCC

GGTGAAGTATGCTGTCTACACTGTGGTTAGCAGCCACGAACAATTCACCAAATACCT CAA

CTTCTCAGAGTCTGAGGAGAAGGAAAGCCATGTGGCCATGCACAGATACCAGGTCAA TAA

CCTGGGACAGAGGGACCTGCCTGTCAGCATCAACTTCTGGGTGCCTGTGGAGCTGAA CCA

GGAGGCTGTGTGGATGGATGTGGAGGTCTCCCACCCCCAGAACCCATCCCTTCGGTG CTC

CTCAGAGAAAATCGCACCCCCAGCATCTGACTTCCTGGCGCACATTCAGAAGAATCC CGT

GCTGGACTGCTCCATTGCTGGCTGCCTGCGGTTCCGCTGTGACGTCCCCTCCTTCAG CGT

CCAGGAGGAGCTGGATTTCACCCTGAAGGGCAACCTCAGCTTTGGCTGGGTCCGCCA GAT

ATTGCAG AAG AAGGT GTCGGTCGT GAGT GTGGCT G AAATT ACGTTCGACACATCCGT GT A

CTCCCAGCTTCCAGGACAGGAGGCATTTATGAGAGCTCAGACGACAACGGTGCTGGA GAA

GTACAAGGTCCACAACCCCACCCCCCTCATCGTAGGCAGCTCCATTGGGGGTCTGTT GCT

GCTGGCACTCATCACAGCGGTACTGTACAAAGTTGGCTTCTTCAAGCGTCAGTACAA GGA

AATGATGGAGGAGGCAAATGGACAAATTGCCCCAGAAAACGGGACACAGACCCCCAG CCC

GCCCAGTGAGAAATGATCCCTCTTTGCCTTGGACTTCTTCTCCCGCGATTTTCCCCA CTT

ACTTACCCTCACCTGTCAGGCTGACGGGGAGGAACCACTGCACCACCGAGAGAGGCT GGG

ATGGGCCTGCTTCCTGTCTTTGGGAGAAAACGTCTTGCTTGGGAAGGGGCCTTTGTC TTG

TCAAGGTTCCAACT GGAAACCCTTAGGACAGGGTCCCT GCT GT GTTCCCCAAAAGGACTT

G ACTTGCAATTTCT ACCT AGAAAT ACAT GG ACAATACCCCC AGGCCT CAGTCTCCCTT CT

CCCAT G AGGCACGAAT GATCTTT CTTTCCTTTCCTTTTTTTTTTTTTT CTTTT CTTTTTT

TTTTTTTTTGAGACGGAGTCTCGCTCTGTCACCCAGGCTGGAGTGCAATGGCGTGAT CTC

GGCTCGCTGCAACCTCCGCCTCCCGGGTTCAAGTAATTCTGCTGTCTCAGCCTCCTG CGT

AGCTGGGACTACAGGCACACGCCACCTCGCCCGGCCCGATCTTTCTAAAATACAGTT CTG AATATGCTGCTCATCCCCACCTGTCTTCAACAGCTCCCCATTACCCTCAGGACAATGTCT

GAACTCTCCAGCTTCGCGTGAGAAGTCCCCTTCCATCCCAGAGGGTGGGCTTCAGGG CGC

ACAGCATGAGAGCCTCTGTGCCCCCATCACCCTCGTTTCCAGTGAATTAGTGTCATG TCA

GCATCAGCTCAGGGCTTCATCGTGGGGCTCTCAGTTCCGATTCCCCAGGCTGAATTG GGA

GTGAGATGCCTGCATGCTGGGTTCTGCACAGCTGGCCTCCCGCGGTTGGGTCAACAT TGC

TGGCCTGGAAGGGAGGAGCGCCCTCTAGGGAGGGACATGGCCCCGGTGCGGCTGCAG CTC

ACCAGCCCCAGGGGCAGAAGAGACCCAACCACTTCCTATTTTTTGAGGCTATGAATA TAG

T ACCT G AAAAAAT GCC AAGCACT AG ATTATTTTTTTAAAAAGCGT ACTTT AAAT GTTTGT

GTTAATACACATTAAAACATCGCACAAAAACGATGCATCTACCGCTCCTTGGGAAAT AAT

CTGAAAGGTCTAAAAATAAAAAAGCCTTCTGTGG

(SEQ ID NO: 49)

As used herein, the term “LILRB4” refers to the gene encoding Leukocyte immunoglobulin-like receptor subfamily B member 4. The terms “LILRB4” and "Leukocyte immunoglobulin-like receptor subfamily B member 4" include wild-type forms of the LILRB4 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type LILRB4. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type LILRB4 nucleic acid sequence (e.g., SEQ ID NO: 50, ENA accession number U91925). SEQ ID NO: 50 is a wild-type gene sequence encoding LILRB4 protein, and is shown below:

TGAGATGAGAGCTGCCGACAGTTGGGGGTCAAGGGAGGAGACGCCATGATCCCCACC TTC

ACGGCTCTGCTCTGCCTCGGGCTGAGTCTGGGCCCCAGGACCCACATGCAGGCAGGG CCC

CTCCCCAAACCCACCCTCTGGGCTGAGCCAGGCTCTGTGATCAGCTGGGGGAACTCT GTG

ACCATCTGGTGTCAGGGGACCCTGGAGGCTCGGGAGTACCGTCTGGATAAAGAGGAA AGC

CCAGCACCCTGGGACAGACAGAACCCACTGGAGCCCAAGAACAAGGCCAGATTCTCC ATC

CCATCCATGACAGAGGACTATGCAGGGAGATACCGCTGTTACTATCGCAGCCCTGTA GGC

TGGTCACAGCCCAGTGACCCCCTGGAGCTGGTGATGACAGGAGCCTACAGTAAACCC ACC

CTTTCAGCCCTGCCGAGTCCTCTTGTGACCTCAGGAAAGAGCGTGACCCTGCTGTGT CAG

TCACGGAGCCCAATGGACACTTTCCTTCTGATCAAGGAGCGGGCAGCCCATCCCCTA CTG

CATCTGAGATCAGAGCACGGAGCTCAGCAGCACCAGGCTGAATTCCCCATGAGTCCT GTG

ACCTCAGTGCACGGGGGGACCTACAGGTGCTTCAGCTCACACGGCTTCTCCCACTAC CTG

CTGTCACACCCCAGTGACCCCCTGGAGCTCATAGTCTCAGGATCCTTGGAGGGTCCC AGG

CCCTCACCCACAAGGTCCGTCTCAACAGCTGCAGGCCCTGAGGACCAGCCCCTCATG CCT

ACAGGGTCAGTCCCCCACAGTGGTCTGAGAAGGCACTGGGAGGTACTGATCGGGGTC TTG

GTGGTCTCCATCCTGCTTCTCTCCCTCCTCCTCTTCCTCCTCCTCCAACACTGGCGT CAG

GGAAAACACAGGACATTGGCCCAGAGACAGGCTGATTTCCAACGTCCTCCAGGGGCT GCC

GAGCCAGAGCCCAAGGACGGGGGCCTACAGAGGAGGTCCAGCCCAGCTGCTGACGTC CAG

GGAGAAAACTT CTGTGCTGCCGTG AAGAACACACAGCCT GAGGACGGGGT GG AAAT GG AC

ACTCGGCAGAGCCCACACGATGAAGACCCCCAGGCAGTGACGTATGCCAAGGTGAAA CAC

TCCAGACCTAGGAGAGAAATGGCCTCTCCTCCCTCCCCACTGTCTGGGGAATTCCTG GAC ACAAAGGACAGACAGGCAGAAGAGGACAGACAGAT GGACACTGAGGCT GCT GCATCT GAA

GCCCCCCAGGATGTGACCTACGCCCAGCTGCACAGCTTTACCCTCAGACAGAAGGCA ACT

GAGCCTCCTCCATCCCAGGAAGGGGCCTCTCCAGCTGAGCCCAGTGTCTATGCCACT CTG

GCCATCCACTAATCCAGGGGGGACCCAGACCCCACAAGCCATGGAGACTCAGGACCC CAG

AAGGCATGGAAGCTGCCTCCAGTAGACATCACTGAACCCCAGCCAGCCCAGACCCCT GAC

ACAGACCACTAGAAGATTCCGGGAACGTTGGGAGTCACCTGATTCTGCAAAGATAAA TAA

TATCCCT GC ATT AT C AAAAT AAAGTAG CAGACCTCT C AATT C A

(SEQ ID NO: 50)

As used herein, the term “LPL” refers to the gene encoding Lipoprotein lipase. The terms “LPL” and "Lipoprotein lipase" include wild-type forms of the LPL gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type LPL. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type LPL nucleic acid sequence (e.g., SEQ ID NO: 51 , ENA accession number M15856). SEQ ID NO: 51 is a wild-type gene sequence encoding LPL protein, and is shown below:

CCCCTCTTCCTCCTCCTCAAGGGAAAGCTGCCCACTTCTAGCTGCCCTGCCATCCCC TTT

AAAGGGCGACTTGCTCAGCGCCAAACCGCGGCTCCAGCCCTCTCCAGCCTCCGGCTC AGC

CGGCTCATCAGTCGGTCCGCGCCTTGCAGCTCCTCCAGAGGGACGCGCCCCGAGATG GAG

AGCAAAGCCCTGCTCGTGCTGACTCTGGCCGTGTGGCTCCAGAGTCTGACCGCCTCC CGC

GGAGGGGTGGCCGCCGCCGACCAAAGAAGAGATTTTATCGACATCGAAAGTAAATTT GCC

CTAAGGACCCCTGAAGACACAGCTGAGGACACTTGCCACCTCATTCCCGGAGTAGCA GAG

TCCGTGGCTACCTGTCATTTCAATCACAGCAGCAAAACCTTCATGGTGATCCATGGC TGG

ACGGTAACAGGAATGTATGAGAGTTGGGTGCCAAAACTTGTGGCCGCCCTGTACAAG AGA

GAACCAGACTCCAATGTCATTGTGGTGGACTGGCTGTCACGGGCTCAGGAGCATTAC CCA

GTGTCCGCGGGCTACACCAAACTGGTGGGACAGGATGTGGCCCGGTTTATCAACTGG ATG

GAGGAGGAGTTTAACTACCCTCTGGACAATGTCCATCTCTTGGGATACAGCCTTGGA GCC

CATGCTGCTGGCATTGCAGGAAGTCTGACCAATAAGAAAGTCAACAGAATTACTGGC CTC

GATCCAGCTGGACCTAACTTTGAGTATGCAGAAGCCCCGAGTCGTCTTTCTCCTGAT GAT

GCAGATTTTGTAGACGTCTTACACACATTCACCAGAGGGTCCCCTGGTCGAAGCATT GGA

ATCCAGAAACCAGTTGGGCATGTTGACATTTACCCGAATGGAGGTACTTTTCAGCCA GGA

TGTAACATTGGAGAAGCTATCCGCGTGATTGCAGAGAGAGGACTTGGAGATGTGGAC CAG

CTAGTGAAGTGCTCCCACGAGCGCTCCATTCATCTCTTCATCGACTCTCTGTTGAAT GAA

GAAAATCCAAGTAAGGCCTACAGGTGCAGTTCCAAGGAAGCCTTTGAGAAAGGGCTC TGC

TTGAGTTGTAGAAAGAACCGCTGCAACAATCTGGGCTATGAGATCAATAAAGTCAGA GCC

AAAAGAAGCAGCAAAATGTACCTGAAGACTCGTTCTCAGATGCCCTACAAAGTCTTC CAT

T ACCAAGTAAAGATT CATTTTT CTGGG ACT GAGAGT GAAACCC AT ACCAAT CAGGCCTTT

GAGATTTCTCTGTATGGCACCGTGGCCGAGAGTGAGAACATCCCATTCACTCTGCCT GAA

GTTTCCACAAAT AAGACCT ACTCCTT CCT AATTT ACACAG AGGTAGAT ATTGG AG AACT A

CT C ATGTT G AAG CT C AAAT GG AAG AGTG ATT CAT ACTTT AG CTG GT C AG ACT G GTG G AGC

AGTCCCGGCTTCGCCATTCAGAAGATCAGAGTAAAAGCAGGAGAGACTCAGAAAAAG GTG ATCTTCTGTTCTAGGGAGAAAGTGTCTCATTTGCAGAAAGGAAAGGCACCTGCGGTATTT

GTGAAATGCCAT G ACAAGT CT CT G AATAAGAAGT CAGGCT GAAACT GGGCG AAT CT AC AG

AAC AAAG AACGGC AT GT GAATTCT GT G AAG AAT GAAGTGGAGGAAGT AACTTTT ACAAAA

CATACCCAGTGTTTGGGGTGTTTCAAAAGTGGATTTTCCTGAATATTAATCCCAGCC CTA

CCCTTGTTAGTTATTTTAGGAGACAGTCTCAAGCACTAAAAAGTGGCTAATTCAATT TAT

GGGGTATAGTGGCCAAATAGCACATCCTCCAACGTTAAAAGACAGTGGATCATGAAA AGT

GCTGTTTTGTCCTTTGAGAAAGAAATAATTGTTTGAGCGCAGAGTAAAATAAGGCTC CTT

CATGTGGCGTATTGGGCCATAGCCTATAATTGGTTAGAACCTCCTATTTTAATTGGA ATT

CT GGATCTTTCGG ACT GAGGCCTTCT CAAACTTT ACT CTAAGTCTCCAAGAAT ACAG AAA

ATGCTTTTCCGCGGCACGAATCAGACTCATCTACACAGCAGTATGAATGATGTTTTA GAA

T GATTCCCT CTT GCT ATT GGAAT GT GGTCCAGACGTCAACCAGG AAC AT GT AACTTGG AG

AGGGACGAAGAAAGGGTCTGATAAACACAGAGGTTTTAAACAGTCCCTACCATTGGC CTG

CAT CAT G AC AAAGTT AC AAATT C AAGG AG AT AT AAAAT CTAG AT C AATT AATTCTT AAT A

GGCTTTATCGTTTATTGCTTAATCCCTCTCTCCCCCTTCTTTTTTGTCTCAAGATTA TAT

TATAATAATGTTCTCTGGGTAGGTGTTGAAAATGAGCCTGTAATCCTCAGCTGACAC ATA

ATTT GAAT GGTGCAG AAAAAAAAAAGAT ACCGT AATTTT ATTATTAGATT CTCCAAAT GA

TTTT CAT C AATTT AAAAT C ATT C AAT ATCT G AC AGTT ACTCTT C AGTTTT AG GCTT ACCT

TGGTCATGCTTCAGTTGTACTTCCAGTGCGTCTCTTTTGTTCCTGGCTTTGACATGA AAA

GAT AGGTTT G AGTT CAAATTTT GCATT GTGTG AGCTT CTACAG ATTTTAGACAAGGACCG

TTTTTACTAAGTAAAAGGGTGGAGAGGTTCCTGGGGTGGATTCCTAAGCAGTGCTTG TAA

ACCATCGCGTGCAATGAGCCAGATGGAGTACCATGAGGGTTGTTATTTGTTGTTTTT AAC

AACT AAT C AAG AGT G AGT G AAC AACT ATTT AT AAACT AG AT CTCCT ATTTTT C AG AAT G C

TCTTCTACGTATAAATATGAAATGATAAAGATGTCAAATATCTCAGAGGCTATAGCT GGG

AAC CCG ACT GT G AAAGT ATGT GAT ATCT G AAC AC AT ACT AG AAAGCT CT GC AT GTGTGTT

GTCCTTCAGCATAATTCGGAAGGGAAAACAGTCGATCAAGGGATGTATTGGAACATG TCG

GAGTAGAAATTGTTCCTGATGTGCCAGAACTTCGACCCTTTCTCTGAGAGAGATGAT CGT

GCCTATAAATAGTAGGACCAATGTTGTGATTAACATCATCAGGCTTGGAATGAATTC TCT

CT AAAAAT AAAAT GAT GT AT GATTT GTTGTT GGCATCCCCTTT ATTAATT CATTAAATTT

CTGGATTTGGGTTGTGACCCAGGGTGCATTAACTTAAAAGATTCACTAAAGCAGCAC ATA

GCACTGGGAACTCTGGCTCCGAAAAACTTTGTTATATATATCAAGGATGTTCTGGCT TTA

CATTTTATTTATTAGCTGTAAATACATGTGTGGATGTGTAAATGGAGCTTGTACATA TTG

GAAAGGTCATTGTGGCTATCTGCATTTATAAATGTGTGGTGCTAACTGTATGTGTCT TTA

T CAGTGATGGT CTCACAG AGCCAACTC ACT CTT AT G AAATGGGCTTT AACAAAACAAGAA

AG AAACGTACTT AACT GT GTG AAG AAAT G GAAT C AGCTTTT AAT AAAATT G AC AAC ATTT

TATTACCAC

(SEQ ID NO: 51)

As used herein, the term “MEF2C” refers to the gene encoding Myocyte-specific enhancer factor 2C. The terms “MEF2C” and "Myocyte-specific enhancer factor 2C" include wild-type forms of the MEF2C gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type MEF2C.

Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type MEF2C nucleic acid sequence (e.g., SEQ ID NO: 52, ENA accession number L08895). SEQ ID NO: 52 is a wild- type gene sequence encoding MEF2C protein, and is shown below:

GAATTCCCAGCTCTCTGCTCGCTCTGCTCGCAGTCACAGACACTTGAGCACACGCGT ACA

CCCAGACATCTTCGGGCTGCTATTGGATTGACTTTGAAGGTTCTGTGTGGGTCGCCG TGG

CTGCATGTTTGAATCAGGTGGAGAAGCACTTCAACGCTGGACGAAGTAAAGATTATT GTT

GTTATTTTTTTTTTCTCTCTCTCTCTCTCTTAAGAAAGGAAAATATCCCAAGGACTA ATC

TGATCGGGTCTTCCTTCATCAGGAACGAATGCAGGAATTTGGGAACTGAGCTGTGCA AGT

G CT G AAG AAG G AG ATTT GTTT G G AGG AAAC AG G AAAG AG AAAG AAAAG G AAG G AAAAAAT

ACATAATTTCAGGGACGAGAGAGAGAAGAAAAACGGGGACTATGGGGAGAAAAAAGA TTC

AG ATT ACG AG GATT AT G GAT G AACGT AAC AG AC AG GT G AC ATTT AC AAAG AGG AAATTT G

GGTTGATGAAGAAGGCTTATGAGCTGAGCGTGCTGTGTGACTGTGAGATTGCGCTGA TCA

TCTTCAACAGCACCAACAAGCTGTTCCAGTATGCCAGCACCGACATGGACAAAGTGC TTC

T CAAGT ACACGGAGT AC AACG AGCCGC AT GAGAGCCGGACAAACT CAG ACATCGT GGAGA

CGTTGAGAAAGAAGGGCCTTAATGGCTGTGACAGCCCAGACCCCGATGCGGACGATT CCG

TAGGTCACAGCCCTGAGTCTGAGGACAAGTACAGGAAAATTAACGAAGATATTGATC TAA

TGATCAGCAGGCAAAGATTGTGTGCTGTTCCACCTCCCAACTTCGAGATGCCAGTCT CCA

TCCCAGTGTCCAGCCACAACAGTTTGGTGTACAGCAACCCTGTCAGCTCACTGGGAA ACC

CCAACCTATTGCCACTGGCTCACCCTTCTCTGCAGAGGAATAGTATGTCTCCTGGTG TAA

CACATCGACCTCCAAGTGCAGGTAACACAGGTGGTCTGATGGGTGGAGACCTCACGT CTG

GTGCAGGCACCAGTGCAGGGAACGGGTATGGCAATCCCCGAAACTCACCAGGTCTGC TGG

TCTCACCTGGTAACTTGAACAAGAATATGCAAGCAAAATCTCCTCCCCCAATGAATT TAG

GAATGAATAACCGTAAACCAGATCTCCGAGTTCTTATTCCACCAGGCAGCAAGAATA CGA

TGCCATCAGTGTCTGAGGATGTCGACCTGCTTTTGAATCAAAGGATAAATAACTCCC AGT

CGGCTCAGTCATTGGCTACCCCAGTGGTTTCCGTAGCAACTCCTACTTTACCAGGAC AAG

GAATGGGAGGATATCCATCAGCCATTTCAACAACATATGGTACCGAGTACTCTCTGA GTA

GTGCAGACCTGTCATCTCTGTCTGGGTTTAACACCGCCAGCGCTCTTCACCTTGGTT CAG

TAACTGGCTGGCAACAGCAACACCTACATAACATGCCACCATCTGCCCTCAGTCAGT TGG

GAGCTTGCACTAGCACTCATTTATCTCAGAGTTCAAATCTCTCCCTGCCTTCTACTC AAA

GCCTCAACATCAAGTCAGAACCTGTTTCTCCTCCTAGAGACCGTACCACCACCCCTT CGA

GATACCCACAACACACGCGCCACGAGGCGGGGAGATCTCCTGTTGACAGCTTGAGCA GCT

GTAGCAGTTCGTACGACGGGAGCGACCGAGAGGATCACCGGAACGAATTCCACTCCC CCA

TTGGACTCACCAGACCTTCGCCGGACGAAAGGGAAAGTCCCTCAGTCAAGCGCATGC GAC

TTT CT G AAG GAT G GG C AAC AT GAT CAG ATT ATT ACTT ACT AGTTTTTTTTTTTTT CTTG C

AGTGTGTGTGTGTGCTATACCTTAATGGGGAAGGGGGGTCGATATGCATTATATGTG CCG

T GTGTGGAAAAAAAAAAAGTCAGGT ACT CTGTTTTGTAAAAGT ACTTTT AAATTGCCT CA

GTG AT AC AGTAT AAAG AT AAAC AG AAAT G CT GAG AT AAG CTT AG C ACTT G AGTTGTAC AA

CAGAACACTTGTACAAAAT AG ATTTT AAGGCT AACTT CTTTTCACTGTT GT GCTCCTTT G

CAAAAT GTATGTT AC AAT AG AT AGTGT CATGTT GCAGGTTCAACGTTATTTACAT GT AAA

TAGACAAAAGGAAACATTTGCCAAAAGCGGCAGATCTTTACTGAAAGAGAGAGCAGC TGT

TATGCAACATATAGAAAAATGTATAGATGCTTGGACAGACCCGGTAATGGGTGGCCA TTG GTAAATGTTAGGAACACACCAGGTCACCTGACATCCCAAGAATGCTCACAAACCTGCAGG

CATATCATTGGCGTATGGCACTCATTAAAAAGGATCAGAGACCATTAAAAGAGGACC ATA

CCTATTAAAAAAAAATGTGGAGTTGGAGGGCTAACATATTTAATTAAATAAATAAAT AAA

TCTGGGTCTG CAT CTCTT ATT AAAT AAAAAT AT AAAAAT ATGTAC ATT AC ATTTT G CTTA

TTTTCATATAAAAGGTAAGACAGAGTTTGCAAAGCATTTGTGGCTTTTTGTAGTTTA CTT

AAGCCAAAATGTGTTTTTTTCCCCTTGATAGCTTCGCTAATATTTTAAACAGTCCTG TAA

AAAACCAAAAAGGACTTTTTGTATAGAAAGCACTACCCTAAGCCATGAAGAACTCCA TGC

TTTGCTAACC AAG AT AACTGTTTTCT CTTTGTAG AAGTTTT GTTTTT G AAAT GT GT ATTT

CT AATT AT AT AAAAT ATT AAG AAT CTTTT AAAAAAAT CTGTG AAATT AAC ATGCTT GTGT

AT AGCTTT CT AAT AT AT AT AAT ATT ATG GT AAT AGO AG AAGTTTTGTT AT CTT AAT AG CG

GGAGGGGGGTATATTTGTGCAGTTGCACATTTGAGTAACTATTTTCTTTCTGTTTTC TTT

TACTCTGCTTACATTTTATAAGTTTAAGGTCAGCTGTCAAAAGGATAACCTGTGGGG TTA

GAACATATCACATTGCAACACCCTAAATTGTTTTTAATACATTAGCAATCTATTGGG TCA

ACT G AC ATCC ATTGTAT AT ACT AGTTT CTTT C ATGC T ATTTTT ATTTT GTTTTTT GC ATT

TTTATCAAATGCAGGGCCCCTTTCTGATCTCACCATTTCACCATGCATCTTGGAATT CAG

TAAGTGCATATCCTAACTTGCCCATATTCTAAATCATCTGGTTGGTTTTCAGCCTAG AAT

TTGATACGCTTTTTAGAAATATGCCCAGAATAGAAAAGCTATGTTGGGGCACATGTC CTG

CAAATATGGCCCTAGAAACAAGTGATATGGAATTTACTTGGTGAATAAGTTATAAAT TCC

C AC AG AAG AAAAAT GT G AAAG ACT G GGTGCT AG AC AAG AAG G AAGC AG GT AAAG GG AT AG

TTGCTTT GT CATCCGTTTTTAATTATTTT AACT G ACCCTT G ACAATCTT GT CAGCAAT AT

AGGACTGTTGAACAATCCCGGTGTGTCAGGACCCCCAAATGTCACTTCTGCATAAAG CAT

GTATGT CAT CTATTTTTT CTT CAAT AAAGAG ATTT AATAGCC ATTT CAAG AAATCCCAT A

AAG AAC CTCTCTAT GTCCCTTTTTTT AATTT AAAAAAAT GACTCTTGTCT AAT ATTCGT C

TATAAGGGATTAATTTTCAGACCCTTTAATAAGTGAGTGCCATAAGAAAGTCAATAT ATA

TT GTTT AAAAG AT ATTT C AGTCT AGG AAAG ATTTTCCTT CTCTT GG AAT GT G AAG AT CTG

TCGATTCATCTCCAATCATATGCATTGACATACACAGCAAAGAAGATATAGGCAGTA ATA

T CAACACTGCT AT ATC AT GTGTAGG ACATTTCTT ATCCATTTTTT CT CTTTT ACTT GCAT

AGTTGCTATGTGTTTCTCATTGTAAAAGGCTGCCGCTGGGTGGCAGAAGCCAAGAGA CCT

T ATT AACT AG GCT AT ATTTTT CTT AACTT G ATCT G AAATCC AC AATT AG ACC AC AAT GCA

CCTTTGGTTGTATCCATAAAGGATGCTAGCCTGCCTTGTACTAATGTTTTATATATT

(SEQ ID NO: 52)

As used herein, the term “MMP12” refers to the gene encoding Macrophage metalloelastase. The terms “MMP12” and "Macrophage metalloelastase" include wild-type forms of the MMP12 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type MMP12. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type MMP12 nucleic acid sequence (e.g., SEQ ID NO: 53, ENA accession number L23808). SEQ ID NO: 53 is a wild-type gene sequence encoding MMP12 protein, and is shown below:

TAGAAGTTTACAATGAAGTTTCTTCTAATACTGCTCCTGCAGGCCACTGCTTCTGGA GCT CTTCCCCTGAACAGCTCTACAAGCCTGGAAAAAAATAATGTGCTATTTGGTGAGAGATAC

TT AG AAAAATTTT ATG GCCTT GAG AT AAAC AAACTT CC AGT G AC AAAAAT G AAAT ATAGT

GGAAACTTAATGAAGGAAAAAATCCAAGAAATGCAGCACTTCTTGGGTCTGAAAGTG ACC

GGGCAACT GG AC AC AT CT ACCCT GGAG AT GATGCACGCACCTCGAT GT GG AGTCCCCGAT

CTCCATCATTTCAGGGAAATGCCAGGGGGGCCCGTATGGAGGAAACATTATATCACC TAC

AGAATCAATAATTACACACCTGACATGAACCGTGAGGATGTTGACTACGCAATCCGG AAA

GCTTTCCAAGTATGGAGTAATGTTACCCCCTTGAAATTCAGCAAGATTAACACAGGC ATG

GCTGACATTTTGGTGGTTTTTGCCCGTGGAGCTCATGGAGACTTCCATGCTTTTGAT GGC

AAAGGTGGAATCCTAGCCCATGCTTTTGGACCTGGATCTGGCATTGGAGGGGATGCA CAT

TTCG AT GAG G ACG AATT CTGG ACT AC AC ATT C AG G AG GC AC AAACTT GTTCCTCACTGCT

GTTCACGAGATTGGCCATTCCTTAGGTCTTGGCCATTCTAGTGATCCAAAGGCTGTA ATG

TTCCCCACCTACAAATATGTCGACATCAACACATTTCGCCTCTCTGCTGATGACATA CGT

GGCATTCAGTCCCTGTATGGAGACCCAAAAGAGAACCAACGCTTGCCAAATCCTGAC AAT

T CAG AACCAGCT CTCT GTG ACCCC AATTT GAGTTTT GATGCT GT CACT ACCGTGGGAAAT

AAGATCTTTTTCTTCAAAGACAGGTTCTTCTGGCTGAAGGTTTCTGAGAGACCAAAG ACC

AGTGTTAATTTAATTTCTTCCTTATGGCCAACCTTGCCATCTGGCATTGAAGCTGCT TAT

GAAATTGAAGCCAGAAATCAAGTTTTTCTTTTTAAAGATGACAAATACTGGTTAATT AGC

AATTTAAGACCAGAGCCAAATTATCCCAAGAGCATACATTCTTTTGGTTTTCCTAAC TTT

GTGAAAAAAATTGATGCAGCTGTTTTTAACCCACGTTTTTATAGGACCTACTTCTTT GTA

GATAACCAGTATTGGAGGTATGATGAAAGGAGACAGATGATGGACCCTGGTTATCCC AAA

CTGATTACCAAGAACTTCCAAGGAATCGGGCCTAAAATTGATGCAGTCTTCTATTCT AAA

AAC AAAT ACTACT ATTT CTTCC AAG G ATCT AACC AATTT G AAT AT G ACTTCCT ACTCC AA

CGTATCACCAAAACACTGAAAAGCAATAGCTGGTTTGGTTGTTAGAAATGGTGTAAT TAA

TGGTTTTTGTTAGTTCACTTCAGCTTAATAAGTATTTATTGCATATTTGCTATGTCC TCA

GTGTACC ACTACTT AG AG AT ATGTAT CAT AAAAAT AAAAT CTGT AAACC AT AG GT AAT G A

TT AT AT AAAAT AC AT AAT ATTTTT C AATTTT G AAAACT CT AATT GTCC ATT CTTG CTT G A

CTCTACT ATT AAGTTT G AAAAT AGTT ACCTT C AAAG C AAG AT AATT CT ATTT G AAG CAT G

CTCTGTAAGTTGCTTCCT AAC ATCCTT GG ACT G AG AAATT ATACTTACTTCT G GC AT AAC

T AAA ATT AAGTATATATATTTTGGCT C A AAT AAA ATT G

(SEQ ID NO: 53)

As used herein, the term “MS4A4A” refers to the gene encoding Membrane Spanning 4-Domains A4A. The terms “MS4A4A” and "Membrane Spanning 4-Domains A4A" include wild-type forms of the MS4A4A gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type MS4A4A. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type MS4A4A nucleic acid sequence (e.g., SEQ ID NO: 54, NCBI Reference Sequence: NM_148975.2). SEQ ID NO:

54 is a wild-type gene sequence encoding MS4A4A protein, and is shown below:

ATTCTCAGCACAGCCTTTAAGGTTCCAAACATCTGCTAGAAGAGGAATGCAGATTTA AACTGAGTGAG

GTGTGGAGTGGGGGAAGTTGATTGGGTCTAGACCAAAGAACTTTGAGGAACTTGCCC AGAGCCCTG CATGCATCAGACCTACAGCAGACATTGCAGGCCTGAAGAAAGCACCTTTTCTGCTGCCAT GACAACC

ATGCAAGGAATGGAACAGGCCATGCCAGGGGCTGGCCCTGGTGTGCCCCAGCTGGGA AACATGGC

TGTCATACATTCACATCTGTGGAAAGGATTGCAAGAGAAGTTCTTGAAGGGAGAACC CAAAGTCCTT

GGGGTTGTGCAGATTCTGACTGCCCTGATGAGCCTTAGCATGGGAATAACAATGATG TGTATGGCAT

CTAATACTTATGGAAGTAACCCTATTTCCGTGTATATCGGGTACACAATTTGGGGGT CAGTAATGTTT

ATTATTTCAGGATCCTTGTCAATTGCAGCAGGAATTAGAACTACAAAAGGCCTGGTC CGAGGTAGTCT

AGGAATGAATATCACCAGCTCTGTACTGGCTGCATCAGGGATCTTAATCAACACATT TAGCTTGGCGT

TTTATTCATTCCATCACCCTTACTGTAACTACTATGGCAACTCAAATAATTGTCATG GGACTATGTCCA

TCTTAATGGGTCTGGATGGCATGGTGCTCCTCTTAAGTGTGCTGGAATTCTGCATTG CTGTGTCCCT

CTCTGCCTTTGGATGTAAAGTGCTCTGTTGTACCCCTGGTGGGGTTGTGTTAATTCT GCCATCACATT

CTCACATGGCAGAAACAGCATCTCCCACACCACTTAATGAGGTTTGAGGCCACCAAA AGATCAACAG

AC AAAT GOT CC AG AAAT CTATGCTGACTGT G AC AC AAG AG CCT C AC AT G AG AAATT AC CAGT ATCC AA

CTTCGATACTGATAGACTTGTTGATATTATTATTATATGTAATCCAATTATGAACTG TGTGTGTATAGA

GAG AT AAT AAATT C AAAATT ATGTTCT C ATTTTTTTCCCT GG AACT C AAT AACT C ATTT C ACT GG CTCTT

T ATCG AG AGTACT AG AAGTTAAATT AAT AAAT AAT GCATTTAAT G AGGCAACAGCACTT G AAAGTTTTT

CATTCATCATAAGAACTTTATATAAAGGCATTACATTGGCAAATAAGGTTTGGAAGC AGAAGAGCAAA

AAAAAGATATTGTTAAAATGAGGCCTCCATGCAAAACACATACTTCCCTCCCATTTA TTTAACTTTTTTT

TTCTCCTACCTATGGGGACCAAAGTGCTTTTTCCTTCAGGAAGTGGAGATGCATGGC CATCTCCCCC

TCCCTTTTTCCTTCTCCTGCTTTTCTTTCCCCATAGAAAGTACCTTGAAGTAGCACA GTCCGTCCTTG

CATGTGCACGAGCTATCATTTGAGTAAAAGTATACATGGAGTAAAAATCATATTAAG CATCAGATTCA

ACTTATATTTTCTATTTCATCTTCTTCCTTTCCCTTCTCCCACCTTCTACTGGGCAT AATTATATCTTAA

TCATATATGGAAATGTGCAACATATGGTATTTGTTAAATACGTTTGTTTTTATTGCA GAGCAAAAATAA

AT C AAATT AG AAGC AAT AAAAAAAAAAAAAAAAAAAA

(SEQ ID NO: 54)

As used herein, the term “MS4A6A” refers to the gene encoding Membrane-spanning 4-domains subfamily A member 6A. The terms “MS4A6A” and "Membrane-spanning 4-domains subfamily A member 6A" include wild-type forms of the MS4A6A gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type MS4A6A. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type MS4A6A nucleic acid sequence (e.g., SEQ ID NO: 55, ENA accession number AB013104). SEQ ID NO: 55 is a wild-type gene sequence encoding MS4A6A protein, and is shown below:

GAGAACCAGAGTTAAAACCTCTTTGGAGCTTCTGAGGACTCAGCTGGAACCAACGGG CAC

AGTTGGCAACACCATCATGACATCACAACCTGTTCCCAATGAGACCATCATAGTGCT CCC

ATCAAATGTCATCAACTTCTCCCAAGCAGAGAAACCCGAACCCACCAACCAGGGGCA GGA

T AG CCT G AAG AAAC AT CT AC ACGC AG AAAT C AAAGTT ATT GG G ACT ATCC AG ATCTTGTG

TGGCATGATGGTATTGAGCTTGGGGATCATTTTGGCATCTGCTTCCTTCTCTCCAAA TTT

T ACCC AAGT G ACTT CTACACTGTT G AACT CTGCTT ACCCATT CATAGG ACCCTTTTTTTT

TATCATCTCTGGCTCTCTATCAATCGCCACAGAGAAAAGGTTAACCAAGCTTTTGGT GCA TAGCAGCCTGGTTGGAAGCATTCTGAGTGCTCTGTCTGCCCTGGTGGGTTTCATTATCCT GTCTGTCAAACAGGCCACCTTAAATCCTGCCTCACTGCAGTGGAACTCTCTCTCTGATGC TGATTTGCACTCTGCTGGAATTCTGCCTAGCTGTGCTCACTGCTGTGCTGCGGTGGAAAC AGGCTTACTCTGACTTCCCTGGGAGTGGACTTTTCCTGCCTCACAGTTACATTGGTAATT CT GGCATGTCCT CAAAAAT G ACT CAT GACTGTGG AT AT GAAG AACT ATT GACTTCTT AAG AAAAAAGGG AG AAAT ATTAAT CAGAAAGTT G ATTCTT AT GATAATAT GG AAAAGTT AACC ATT AT AG AAAAGC AAAG CTT G AGTTTCCT AAAT GT AAG CTTTT AAAGTAAT G AACATT AA AAAAAACCATTATTTCACTGTC (SEQ ID NO: 55)

As used herein, the term “NLRP3” refers to the gene encoding NACHT, LRR and PYD domains- containing protein 3. The terms “NLRP3” and "NACHT, LRR and PYD domains-containing protein 3" include wild-type forms of the NLRP3 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type NLRP3. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type NLRP3 nucleic acid sequence (e.g., SEQ ID NO: 56, ENA accession number AF410477). SEQ ID NO: 56 is a wild-type gene sequence encoding NLRP3 protein, and is shown below:

GTAGAT GAGG AAACT GAAGTT GAGG AAT AGTG AAGAGTTTGTCCAAT GT CATAGCCCCGT

AATCAACGGGACAAAAATTTTCTTGCTGATGGGTCAAGATGGCATCGTGAAGTGGTT GTT

CACCGTAAACTGTAATACAATCCTGTTTATGGATTTGTTTGCATATTTTTCCCCCCA TAG

GGAAACCTTTTTTCCATGGCTCAGGACACACTCCTGGATCGAGCCAACAGGAGAACT TTC

TGGTAAGCATTTGGCTAACTTTTTTTTTTTTGAGATGGAGTCTTGCTGTGTCGCCTA GGC

TGGAGTGCAGTGGCGTGATCTTGGCTCACTGCAGCCTCCACCTCCCGGGTTCAATCA ATT

CTCCTACCTCAACTTCCTGAGTAGCTGGGATTACAGGCGCCCGCCACCACACCCGGC TCA

TTTTTGTACTTTTAGTAGAGACACAGTTTTGCCATGTTGGCCAGGCTGGTCTTGAAT TCC

TCAGCTCAGGTGATATGCCTGCCTTGGCCTCTCAAAGTGCTGGGATTACAGGCGTGA GCC

ACTGTGCCCGGCCTTGGCTAACTTTTCAAAATTAAAGATTTTGACTTGTTACAGTCA TGT

G ACATTTTTTT CTTTCTGTTTGGT GAGTTTTT GAT AATTT AT AT CT CTCAAAGT GGAG AC

TTTAAAAAAGACTCATCTGTGTGCCGTGTTCACTGCCTGGTATCTTAGTGTGGACCG AAG

CCTAAGGACCCTGAAAACAGCTGCAGATGAAGATGGCAAGCACCCGCTGCAAGCTGG CCA

GGTACCTGGAGGACCTGGAGGATGTGGACTTGAAGAAATTTAAGATGCACTTAGAGG ACT

ATCCTCCCCAGAAGGGCTGCATCCCCCTCCCGAGGGGTCAGACAGAGAAGGCAGACC ATG

TGGATCTAGCCACGCTAATGATCGACTTCAATGGGGAGGAGAAGGCGTGGGCCATGG CCG

TGTG GAT CTTCGCTGCGAT C AAC AG G AG AG ACCTTT AT G AG AAAG C AAAAAG AG AT G AGC

CGAAGTGGGGTTCAGATAATGCACGTGTTTCGAATCCCACTGTGATATGCCAGGAAG ACA

GCATTGAAGAGGAGTGGATGGGTTTACTGGAGTACCTTTCGAGAATCTCTATTTGTA AAA

T GAAG AAAG ATT ACCGTAAGAAGT ACAG AAAGT ACGT G AG AAG C AG ATT C C AGT GC ATT G

AAG ACAGG AATGCCCGTCTGGGTG AG AGT GT GAGCCT CAACAAACGCT ACACACGACT GC

GTCTCATCAAGGAGCACCGGAGCCAGCAGGAGAGGGAGCAGGAGCTTCTGGCCATCG GCA

AGACCAAGACGTGTG AG AGCCCCGTGAGTCCCATTAAG AT GG AGTT GCT GTTT GACCCCG ATGATGAGCATTCTGAGCCTGTGCACACCGTGGTGTTCCAGGGGGCGGCAGGGATTGGGA

AAACAATCCTGGCCAGGAAGATGATGTTGGACTGGGCGTCGGGGACACTCTACCAAG ACA

GGTTTGACTATCTGTTCTATATCCACTGTCGGGAGGTGAGCCTTGTGACACAGAGGA GCC

TGGGGGACCTGATCATGAGCTGCTGCCCCGACCCAAACCCACCCATCCACAAGATCG TGA

GAAAACCCTCCAGAATCCTCTTCCTCATGGACGGCTTCGATGAGCTGCAAGGTGCCT TTG

ACGAGCACATAGGACCGCTCTGCACTGACTGGCAGAAGGCCGAGCGGGGAGACATTC TCC

TGAGCAGCCTCATCAGAAAGAAGCTGCTTCCCGAGGCCTCTCTGCTCATCACCACGA GAC

CTGTGGCCCTGGAGAAACTGCAGCACTTGCTGGACCATCCTCGGCATGTGGAGATCC TGG

GTTTCTCCGAGGCCAAAAGGAAAGAGTACTTCTTCAAGTACTTCTCTGATGAGGCCC AAG

CCAGGGCAGCCTTCAGTCTGATTCAGGAGAACGAGGTCCTCTTCACCATGTGCTTCA TCC

CCCTGGTCTGCTGGATCGTGTGCACTGGACTGAAACAGCAGATGGAGAGTGGCAAGA GCC

TTGCCCAGACATCCAAGACCACCACCGCGGTGTACGTCTTCTTCCTTTCCAGTTTGC TGC

AGCCCCGGGGAGGGAGCCAGGAGCACGGCCTCTGCGCCCACCTCTGGGGGCTCTGCT CTT

TGGCTGCAGATGGAATCTGGAACCAGAAAATCCTGTTTGAGGAGTCCGACCTCAGGA ATC

ATGGACTGCAGAAGGCGGATGTGTCTGCTTTCCTGAGGATGAACCTGTTCCAAAAGG AAG

TGGACTGCGAGAAGTTCTACAGCTTCATCCACATGACTTTCCAGGAGTTCTTTGCCG CCA

TGTACTACCTGCTGGAAGAGGAAAAGGAAGGAAGGACGAACGTTCCAGGGAGTCGTT TGA

AGCTTCCCAGCCGAGACGTGACAGTCCTTCTGGAAAACTATGGCAAATTCGAAAAGG GGT

ATTTGATTTTTGTTGTACGTTTCCTCTTTGGCCTGGTAAACCAGGAGAGGACCTCCT ACT

TGGAGAAGAAATTAAGTTGCAAGATCTCTCAGCAAATCAGGCTGGAGCTGCTGAAAT GGA

TTGAAGTGAAAGCCAAAGCTAAAAAGCTGCAGATCCAGCCCAGCCAGCTGGAATTGT TCT

ACTGTTTGTACGAGATGCAGGAGGAGGACTTCGTGCAAAGGGCCATGGACTATTTCC CCA

AG ATT GAG AT C AAT CT CTCC ACC AG AAT G G ACC AC AT G GTTT CTTCCTTTT G C ATT GAGA

ACTGTCATCGGGTGGAGTCACTGTCCCTGGGGTTTCTCCATAACATGCCCAAGGAGG AAG

AGGAGGAGGAAAAGGAAGGCCGACACCTTGATATGGTGCAGTGTGTCCTCCCAAGCT CCT

CTCATGCTGCCTGTTCTCATGGATTGGTGAACAGCCACCTCACTTCCAGTTTTTGCC GGG

GCCT CTTTT CAGTT CT GAGCACC AGCCAG AGT CTAACT G AATT GG ACCT CAGTG ACAATT

CTCTGGGGGACCCAGGGATGAGAGTGTTGTGTGAAACGCTCCAGCATCCTGGCTGTA ACA

TTCGGAGATTGTGGTTGGGGCGCTGTGGCCTCTCGCATGAGTGCTGCTTCGACATCT CCT

TGGTCCTCAGCAGCAACCAGAAGCTGGTGGAGCTGGACCTGAGTGACAACGCCCTCG GTG

ACTTCGGAATCAGACTTCTGTGTGTGGGACTGAAGCACCTGTTGTGCAATCTGAAGA AGC

TCTGGTTGGTCAGCTGCTGCCTCACATCAGCATGTTGTCAGGATCTTGCATCAGTAT TGA

GCACCAGCCATTCCCTGACCAGACTCTATGTGGGGGAGAATGCCTTGGGAGACTCAG GAG

TCGCAATTTT AT GT G AAAAAGCC AAG AATCCACAGT GT AACCT GC AG AAACT GGGGTTGG

TGAATTCTGGCCTTACGTCAGTCTGTTGTTCAGCTTTGTCCTCGGTACTCAGCACTA ATC

AGAATCTCACGCACCTTTACCTGCGAGGCAACACTCTCGGAGACAAGGGGATCAAAC TAC

T CT GT GAGGGACTCTTGCACCCCG ACT GC AAGCTT CAGGTGTT GG AATT AG ACAACT GCA

ACCTCACGTCACACTGCTGCTGGGATCTTTCCACACTTCTGACCTCCAGCCAGAGCC TGC

GAAAGCTGAGCCTGGGCAACAATGACCTGGGCGACCTGGGGGTCATGATGTTCTGTG AAG

TGCTGAAACAGCAGAGCTGCCTCCTGCAGAACCTGGGGTTGTCTGAAATGTATTTCA ATT

ATGAGACAAAAAGTGCGTTAGAAACACTTCAAGAAGAAAAGCCTGAGCTGACCGTCG TCT

TTGAGCCTTCTTGGTAGGAGTGGAAACGGGGCTGCCAGACGCCAGTGTTCTCCGGTC CCT CCAGCTGGGGGCCCTCAGGTGGAGAGAGCTGCGATCCATCCAGGCCAAGACCACAGCTCT GTGATCCTTCCGGT GGAGT GTCGGAGAAGAGAGCTT GCCGACGAT GCCTTCCTGT GCAGA GCTTGGGCATCTCCTTTACGCCAGGGTGAGGAAGACACCAGGACAATGACAGCATCGGGT GTTGTTGTCATCACAGCGCCTCAGTTAGAGGATGTTCCTCTTGGTGACCTCATGTAATTA G CT C ATT C AAT AAAGC ACTTT CTTT ATTTT (SEQ ID NO: 56)

As used herein, the term “NME8” refers to the gene encoding Thioredoxin domain-containing protein 3. The terms “NME8” and "Thioredoxin domain-containing protein 3" include wild-type forms of the NME8 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type NME8. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type NME8 nucleic acid sequence (e.g., SEQ ID NO: 57, ENA accession number AF202051). SEQ ID NO: 57 is a wild-type gene sequence encoding NME8 protein, and is shown below:

CGGCCACAACGAGGGAGCCGATTTAGATCCTCTGGGCCTGTTCCTTCCTTTTCTTTA AAC GTCCCAGTCTAGCTTAGAGGAGGACCTGTTTTGTTAGATAAATGGCAAGCAAAAAACGAG AAGTCCAGTTACAGACAGTCATCAATAATCAAAGCCTGTGGGATGAGATGTTGCAGAACA AAGGCTT AAC AGTG ATT GAT GTTT ACCAAGCCTGGT GTGGACCTT GCAGAGCAATGC AAC CTTTATT CAG AAAATT GAAAAAT G AACT G AACGAAG ACG AAATT CT GC ATTTTGCT GTCG CAGAAGCT G AC AACATT GTG ACTTTGCAGCCATTT AGAGAT AAATGTGAACCT GTTTTT C TCTTTAGTGTTAATGGCAAAATTATCGAAAAGATTCAGGGTGCAAATGCACCGCTTGTTA AT AAAAAAGTT ATT AATTT G ATCG AT GAG G AG AG AAAAATT G C AGC AG GT G AAAT GG CTC GACCTCAGTATCCTGAAATTCCATTAGTAGACTCAGATTCAGAAGTTAGTGAAGAATCAC CATGTGAAAGTGTTCAGGAATTATACAGTATTGCTATTATCAAACCGGATGCTGTGATTA GTAAAAAAGTT CT AG AAATT AAAAG AAAAATT ACC AAAGCT GG ATTT ATT AT AG AAG CAG AGCATAAGACAGTGCTCACTGAAGAACAAGTTGTCAACTTCTATAGTCGAATAGCAGACC AGTGTGACTTCGAAGAGTTTGTCTCTTTTATGACAAGTGGCTTAAGCTATATTCTAGTTG T ATCT CAAGGAAGT AAACACAATCCTCCCT CT G AAGAAACCG AACC AC AG ACTGACACCG AACCTAACGAACGATCTGAGGATCAACCTGAGGTCGAAGCCCAGGTTACACCTGGAATGA T G AAG AAC AAAC AAG AC AGTTT AC AAG AAT ATCTG G AAAG AC AAC ATTT AGCT CAG CTCT GTGACATTGAAGAGGATGCAGCTAATGTTGCTAAGTTCATGGATGCTTTCTTCCCCGATT TT AAAAAAAT G AAAAG CAT G AAATT AG AAAAG AC ATT G GC ATT ACTTCG ACC AAAT CTCT TT CAT G AAAG G AAAG AT G ATGTTTT G CGT ATT ATT AAAG AT G AAG ACTT C AAAAT ACTGG AGCAAAGACAAGTAGTATTATCGGAAAAAGAAGCACAAGCACTGTGCAAGGAATATGAAA AT G AAGACT ATTTTAAT AAACTT AT AG AAAACAT G ACCAGTGGTCCAT CTCT AGCCCTT G TTTT ATT GAG AG AC AAT GGCTTGC AAT ACT GG AAACAATT ACTGGG ACC AAG AACTGTT G AAGAAGCCATTGAATATTTTCCAGAGAGTTTATGTGCACAGTTTGCGATGGACAGTTTGC CGGTCAACCAGTTGTATGGCAGCGATTCATTAGAAACCGCTGAAAGGGAAATACAGCATT T CTTTCCT CTT C AAAG C ACTTT AGG CTT GATT AAACCT CAT G C AAC AAGT G AAC AAAG AG AGCAG ATCCT GAAGAT AGTTAAGGAGGCT GG ATTTG AT CT G AC ACAGGT GAAGAAAAT GT TCCTAACTCCT GAG C AAAT AG AG AAAATTT ATCC AAAAGT AAC AGG AAAAG ACTTTT AT A AAG ATTT ATT G G AAAT GTTATCTGT GG GTCCAT CTATG GT CAT GATT CT G ACC AAGTG G A ATGCTGTTGCAGAATGGAGACGATTGATGGGCCCAACAGACCCAGAAGAAGCAAAATTAC TTTCCCCTGACTCCATCCGAGCCCAGTTTGGAATAAGTAAATTGAAAAACATTGTCCATG G AGCATCT AACGCCT AT GAAGC AAAAG AGGTTGTT AAT AG ACT CTTT GAGG ATCCT G AGG AAAACT AAAGT ATATACTGT G AAAACTTT GAG AAG AT AAT AC AT AT GTT C ACGTC AAT AT ACAACC ATTTGGCACAGCTTCCTGGGAGG AAT AAT AAGAAAAAC AT GCTTTGGAGG AAAA CTCAAGATACAAAAATGAATGGCTATGCATAATAACAATAAAAATGTATTCCCCAAAC (SEQ ID NO: 57)

As used herein, the term “NOS2” refers to the gene encoding Nitric oxide synthase, inducible. The terms “NOS2” and "Nitric oxide synthase, inducible" include wild-type forms of the NOS2 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type NOS2. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type NOS2 nucleic acid sequence (e.g., SEQ ID NO: 58, ENA accession number L24553). SEQ ID NO: 58 is a wild-type gene sequence encoding NOS2 protein, and is shown below:

AAGCCCCACAGTGAAGAACATCTGAGCTCAAATCCAGATAAGTGACATAAGTGACCT GCT

TTGTAAAGCCATAGAGATGGCCTGTCCTTGGAAATTTCTGTTCAAGACCAAATTCCA CCA

GTATGCAATGAATGGGGAAAAAGACATCAACAACAATGTGGAGAAAGCCCCCTGTGC CAC

CTCCAGTCCAGT GACACAGG AT GACCTT CAGTAT CAC AACCT CAGCAAGCAGCAGAAT G A

GTCCCCGCAGCCCCTCGTGGAGACGGGAAAGAAGTCTCCAGAATCTCTGGTCAAGCT GGA

TGCAACCCCATTGTCCTCCCCACGGCATGTGAGGATCAAAAACTGGGGCAGCGGGAT GAC

TTTCCAAGACACACTTCACCATAAGGCCAAAGGGATTTTAACTTGCAGGTCCAAATC TTG

CCTGGGGTCCATTATGACTCCCAAAAGTTTGACCAGAGGACCCAGGGACAAGCCTAC CCC

TCCAGATGAGCTTCTACCTCAAGCTATCGAATTTGTCAACCAATATTACGGCTCCTT CAA

AGAGGCAAAAATAGAGGAACATCTGGCCAGGGTGGAAGCGGTAACAAAGGAGATAGA AAC

AACAGGAACCTACCAACTGACGGGAGATGAGCTCATCTTCGCCACCAAGCAGGCCTG GCG

CAATGCCCCACGCTGCATTGGGAGGATCCAGTGGTCCAACCTGCAGGTCTTCGATGC CCG

CAGCTGTTCCACTGCCCGGGAAATGTTTGAACACATCTGCAGACACGTGCGTTACTC CAC

CAACAATGGCAACATCAGGTCGGCCATCACCGTGTTCCCCCAGCGGAGTGATGGCAA GCA

CGACTTCCGGGTGTGGAATGCTCAGCTCATCCGCTATGCTGGCTACCAGATGCCAGA TGG

CAGCATCAGAGGGGACCCTGCCAACGTGGAATTCACTCAGCTGTGCATCGACCTGGG CTG

GAAGCCCAAGTACGGCCGCTTCGATGTGGTCCCCCTGGTCCTGCAGGCCAATGGCCG TGA

CCCTGAGCTCTTCGAAATCCCACCTGACCTTGTGCTTGAGGTGGCCATGGAACATCC CAA

ATACGAGTGGTTTCGGGAACTGGAGCTAAAGTGGTACGCCCTGCCTGCAGTGGCCAA CAT

GCTGCTTGAGGTGGGCGGCCTGGAGTTCCCAGGGTGCCCCTTCAATGGCTGGTACAT GGG

CACAGAGATCGGAGTCCGGGACTTCTGTGACGTCCAGCGCTACAACATCCTGGAGGA AGT

GGGCAGGAGAATGGGCCTGGAAACGCACAAGCTGGCCTCGCTCTGGAAAGACCAGGC TGT

CGTTGAGATCAACATTGCTGTGCTCCATAGTTTCCAGAAGCAGAATGTGACCATCAT GGA CCACCACTCGGCTGCAGAATCCTTCATGAAGTACATGCAGAATGAATACCGGTCCCGTGG

GGGCTGCCCGGCAGACTGGATTTGGCTGGTCCCTCCCATGTCTGGGAGCATCACCCC CGT

GTTTCACCAGGAGATGCTGAACTACGTCCTGTCCCCTTTCTACTACTATCAGGTAGA GGC

CTGGAAAACCCATGTCTGGCAGGACGAGAAGCGGAGACCCAAGAGAAGAGAGATTCC ATT

GAAAGTCTTGGTCAAAGCTGTGCTCTTTGCCTGTATGCTGATGCGCAAGACAATGGC GTC

CCGAGTCAGAGTCACCATCCTCTTTGCGACAGAGACAGGAAAATCAGAGGCGCTGGC CTG

GGACCTGGGGGCCTTATTCAGCTGTGCCTTCAACCCCAAGGTTGTCTGCATGGATAA GTA

CAGGCT GAGCT GCCT GGAGGAGGAACGGCT GCT GTTGGTGGT GACCAGTACGTTT GGCAA

TGGAGACTGCCCTGGCAATGGAGAGAAACTGAAGAAATCGCTCTTCATGCTGAAAGA GCT

CAACAACAAATTCAGGTACGCTGTGTTTGGCCTCGGCTCCAGCATGTACCCTCGGTT CTG

CGCCTTTGCTCATGACATTGATCAGAAGCTGTCCCACCTGGGGGCCTCTCAGCTCAC CCC

GATGGGAGAAGGGGATGAGCTCAGTGGGCAGGAGGACGCCTTCCGCAGCTGGGCCGT GCA

AACCTTCAAGGCAGCCTGTGAGACGTTTGATGTCCGAGGCAAACAGCACATTCAGAT CCC

CAAGCTCTACACCTCCAATGTGACCTGGGACCCGCACCACTACAGGCTCGTGCAGGA CTC

ACAGCCTTTGGACCTCAGCAAAGCCCTCAGCAGCATGCATGCCAAGAACGTGTTCAC CAT

GAGGCTCAAATCTCGGCAGAATCTACAAAGTCCGACATCCAGCCGTGCCACCATCCT GGT

GGAACTCTCCTGTGAGGATGGCCAAGGCCTGAACTACCTGCCGGGGGAGCACCTTGG GGT

TTGCCCAGGCAACCAGCCGGCCCTGGTCCAAGGCATCCTGGAGCGAGTGGTGGATGG CCC

CACACCCCACCAGACAGT GCGCCTGGAGGCCCT GGAT GAGAGT GGCAGCTACT GGGTCAG

TGACAAGAGGCTGCCCCCCTGCTCACTCAGCCAGGCCCTCACCTACTTCCTGGACAT CAC

CACACCCCCAACCCAGCTGCTGCTCCAAAAGCTGGCCCAGGTGGCCACAGAAGAGCC TGA

GAGACAGAGGCTGGAGGCCCTGTGCCAGCCCTCAGAGTACAGCAAGTGGAAGTTCAC CAA

CAGCCCCACATTCCTGGAGGTGCTAGAGGAGTTCCCGTCCCTGCGGGTGTCTGCTGG CTT

CCTGCTTTCCCAGCTCCCCATTCTGAAGCCCAGGTTCTACTCCATCAGCTCCTCCCG GGA

T CACACGCCC ACGGAGATCCACCT G ACT GTGGCCGTGGT CACCT ACC AC ACCCG AGAT GG

CCAGGGTCCCCTGCACCACGGCGTCTGCAGCACATGGCTCAACAGCCTGAAGCCCCA AGA

CCCAGTGCCCTGCTTTGTGCGGAATGCCAGCGGCTTCCACCTCCCCGAGGATCCCTC CCA

TCCTTGCATCCTCATCGGGCCTGGCACAGGCATCGCGCCCTTCCGCAGTTTCTGGCA GCA

ACGGCTCCATGACTCCCAGCACAAGGGAGTGCGGGGAGGCCGCATGACCTTGGTGTT TGG

GTGCCGCCGCCCAGATGAGGACCACATCTACCAGGAGGAGATGCTGGAGATGGCCCA GAA

GGGGGTGCTGCATGCGGTGCACACAGCCTATTCCCGCCTGCCTGGCAAGCCCAAGGT CTA

TGTTCAGGACATCCTGCGGCAGCAGCTGGCCAGCGAGGTGCTCCGTGTGCTCCACAA GGA

GCCAGGCCACCTCTATGTTTGCGGGGATGTGCGCATGGCCCGGGACGTGGCCCACAC CCT

GAAGCAGCTGGTGGCTGCCAAGCTGAAATTGAATGAGGAGCAGGTCGAGGACTATTT CTT

T CAGCT CAAG AGCCAG AAGCGCT AT CACG AAG AT ATCTTT GGTGCTGT ATTTCCTT ACGA

GGCGAAGAAGGACAGGGTGGCGGTGCAGCCCAGCAGCCTGGAGATGTCAGCGCTCTG AGG

GCCTACAGGAGGGGTTAAAGCTGCCGGCACAGAACTTAAGGATGGAGCCAGCTCT

(SEQ ID NO: 58)

As used herein, the term “PICALM” refers to the gene encoding Phosphatidylinositol-binding clathrin assembly protein. The terms “PICALM” and "Phosphatidylinositol-binding clathrin assembly protein" include wild-type forms of the PICALM gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type PICALM. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type PICALM nucleic acid sequence (e.g., SEQ ID NO: 59, ENA accession number U45976). SEQ ID NO: 59 is a wild-type gene sequence encoding PICALM protein, and is shown below:

GCGCGGCCCCGAACCGCCGCCAGGCCGGCACGGGGGAAGGAGCCGGTGGGGGTAGGG GGT

GCGGTGGGGGGTGGGGACCCTCCGGCTCTTGGGGGTCCCAGTCCCCGCCGGCTGCTG AGC

GGGTGGGGTGGTGGAGGAGCTGCAGAGATGTCCGGCCAGAGCCTGACGGACCGAATC ACT

GCCGCCCAGCACAGTGTCACCGGCTCTGCCGTATCCAAGACAGTATGCAAGGCCACG ACC

CACGAGATCATGGGGCCCAAGAAAAAGCACCTGGACTACTTAATTCAGTGCACAAAT GAG

AT G AAT GT G AAC ATCCC AC AGTT G GC AG AC AGTTT ATTT G AAAG AACT ACT AAT AGTAGT

TGGGTGGTGGTCTT C AAAT CTCT C ATT AC AACTC AT C ATTT GAT G GTGTATG G AAAT GAG

CGTTTTATTCAGTATTTGGCTTCAAGAAACACGTTGTTTAACTTAAGCAATTTTTTG GAT

AAAAGT GG ATT G C AAGG AT AT G AC AT GTCT AC ATTT ATT AG GCG GT ATAGTAG AT ATTT A

AAT GAG AAAG C AGTTT CAT AC AG AC AAGTT G C ATTT G ATTT C AC AAAAGT G AAG AG AG GG

G CT GAT G G AGTT AT GAG AAC AAT G AAC AC AG AAAAACTCCT AAAAACT GTAC C AATT ATT

C AG AAT C AAAT GG ATGC ACTTCTT G ATTTT AAT GTT AAT AG C AAT G AACTT AC AAAT G GG

GTAATAAATGCTGCCTTCATGCTCCTGTTCAAAGATGCCATTAGACTGTTTGCAGCA TAC

CAT G AAGG AATTATT AATTT GTTGGAAAAAT ATTTT GAT AT GAAAAAG AACC AAT GCAAA

G AAGGTCTT G AC AT CTAT AAG AAGTTCCT AACT AG GAT G AC AAG AAT CT C AG AGTTCCT C

AAAGTTGCAGAGCAAGTTGGAATTGACAGAGGTGATATACCAGACCTTTCACAGGCC CCT

AGCAGTCTTCTTGATGCTTTGGAACAACATTTAGCTTCCTTGGAAGGAAAGAAAATC AAA

GATTCTACAGCTGCAAGCAGGGCAACTACACTTTCCAATGCAGTGTCTTCCCTGGCA AGC

ACTGGTCTATCTCT G AC C AAAGT G GAT G AAAGG G AAAAG C AGGC AGC ATT AG AG G AAG AA

CAGGCACGTTTGAAAGCTTTAAAGGAACAGCGCCTAAAAGAACTTGCAAAGAAACCT CAT

ACCTCTTTAACAACTGCAGCCTCTCCTGTATCCACCTCAGCAGGAGGGATAATGACT GCA

CCAGCCATTGACATATTTTCTACCCCTAGTTCTTCTAACAGCACATCAAAGCTGCCC AAT

GAT CT GCTT G ATTT GCAGCAGCCAACTTTT CACCCATCTGTACATCCT ATGTCAACT GCT

TCTCAGGTAGCAAGTACATGGGGAGATCCTTTCTCTGCTACTGTAGATGCTGTTGAT GAT

GCCATTCCAAGCTTAAATCCTTTCCTCACAAAAAGTAGTGGTGATGTTCACCTTTCC ATT

T CTTCAGATGTATCT ACTTTT ACT ACT AGG AC ACCT ACTCAT G AAATGTTTGTT GGATT C

ACTCCTTCTCCAGTTGCACAGCCACACCCTTCAGCTGGCCTTAATGTTGACTTTGAA TCT

GTGTTTGGAAATAAATCTACAAATGTTATTGTAGATTCTGGGGGCTTTGATGAACTA GGT

GGACTTCTCAAACCAACAGTGGCCTCTCAGAACCAGAACCTTCCTGTTGCCAAACTC CCA

CCTAGCAAGTTAGTATCTGATGACTTGGATTCATCTTTAGCCAACCTTGTGGGCAAT CTT

GGCATCGGAAATGGAACCACTAAGAATGATGTAAATTGGAGTCAACCAGGTGAAAAG AAG

TTAACTGGGGGATCTAACTGCGAACCAAAGGTTGCACCAACAACCGCTTGGAATGCT GCA

ACAAT GGCACCCCCT GT AAT GGCCTAT CCT GCT ACTACACCAAC AGGC AT G ATAGG AT AT

GGAATTCCTCCACAAATGGGAAGTGTTCCTGTAATGACGCAACCAACCTTAATATAC AGC

CAGCCTGTCATGAGACCTCCAAACCCCTTTGGCCCTGTATCAGGAGCACAGATACAG TTT ATGTAACTTG AT GG AAG AAAAT G G AATT ACTCC AAAAAG AC AAGT GCT C AAG C AG C AAAA

TCCTTACTTCCAGCAAAATCCAAACTGCTGTCTCTTAAATCTCTTAAACTCTCTTCT TCC

ATTAGGATGCTACAAGTANCTCAGTGAAGGCCCATGAAGGGAATTGGGGACTAGTTT ATA

GGGNGAACGTATTCATTACAGTTTATAAAGGCCAGGATTGGNTTGGATTTTAGGATT ANG

TTC

(SEQ ID NO: 59)

As used herein, the term “PILRA” refers to the gene encoding Paired Immunoglobin Like Type 2 Receptor Alpha. The terms “PILRA” and "Paired Immunoglobin Like Type 2 Receptor Alpha" include wild-type forms of the PILRA gene, as well as variants (e.g., splice variants and polymorphisms) of wild- type PILRA. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild- type PILRA nucleic acid sequence (e.g., SEQ ID NO: 60, NCBI Reference Sequence: NM_013439.2). SEQ ID NO: 60 is a wild-type gene sequence encoding PILRA protein, and is shown below:

AATAGGGGAAAATAAGCCAGATGGATAAAGGAAGTGCTGGTCACCCTGGAGGTGCAC TGGTTTGGG

GAAGGCTCCTGGCCCCCACAGCCCTCTTCGGAGCCTGAGCCCGGCTCTCCTCACTCA CCTCAACCC

CCAGGCGGCCCCTCCACAGGGCCCCTCTCCTGCCTGGACGGCTCTGCTGGTCTCCCC GTCCCCTG

GAGAAGAACAAGGCCATGGGTCGGCCCCTGCTGCTGCCCCTACTGCCCTTGCTGCTG CCGCCAGC

ATTTCTGCAGCCTAGTGGCTCCACAGGATCTGGTCCAAGCTACCTTTATGGGGTCAC TCAACCAAAA

CACCTCTCAGCCTCCATGGGTGGCTCTGTGGAAATCCCCTTCTCCTTCTATTACCCC TGGGAGTTAG

CCACAGCTCCCGACGTGAGAATATCCTGGAGACGGGGCCACTTCCACAGGCAGTCCT TCTACAGCA

CAAGGCCGCCTTCCATTCACAAGGATTATGTGAACCGGCTCTTTCTGAACTGGACAG AGGGTCAGAA

GAGCGGCTTCCTCAGGATCTCCAACCTGCAGAAGCAGGACCAGTCTGTGTATTTCTG CCGAGTTGA

GCTGGACACACGGAGCTCAGGGAGGCAGCAGTGGCAGTCCATCGAGGGGACCAAACT CTCCATCA

CCCAGGCTGTCACGACCACCACCCAGAGGCCCAGCAGCATGACTACCACCTGGAGGC TCAGTAGC

ACAACCACCACAACCGGCCTCAGGGTCACACAGGGCAAACGACGCTCAGACTCTTGG CACATAAGT

CTGGAGACTGCTGTGGGGGTGGCAGTGGCTGTCACTGTGCTCGGAATCATGATTTTG GGACTGATC

TGCCTCCTCAGGTGGAGGAGAAGGAAAGGTCAGCAGCGGACTAAAGCCACAACCCCA GCCAGGGA

ACCCTT CC AAAACACAG AGG AGCCATAT G AG AAT ATCAGG AAT G AAGGACAAAAT AC AG ATCCC AAG

CTAAATCCCAAGGATGACGGCATCGTCTATGCTTCCCTTGCCCTCTCCAGCTCCACC TCACCCAGAG

CACCTCCCAGCCACCGTCCCCTCAAGAGCCCCCAGAACGAGACCCTGTACTCTGTCT TAAAGGCCT

AACCAATGGACAGCCCTCTCAAGACTGAATGGTGAGGCCAGGTACAGTGGCGCACAC CTGTAATCC

CAGCTACTCTGAAGCCTGAGGCAGAATCAAGTGAGCCCAGGAGTTCAGGGCCAGCTT TGATAATGG

AGCG AGATGCCATCT CT AGTT AAAAAT AT AT ATT AACAATAAAGT AACAAATTT AAAAAG AT AAAAAAA

(SEQ ID NO: 60)

As used herein, the term “PLCG2” refers to the gene encoding 1 -phosphatidylinositol 4,5- bisphosphate phosphodiesterase gamma-2. The terms “PLCG2” and "1-phosphatidylinositol 4,5- bisphosphate phosphodiesterase gamma-2" include wild-type forms of the PLCG2 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type PLCG2. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type PLCG2 nucleic acid sequence (e.g., SEQ ID NO: 61 , ENA accession number M37238). SEQ ID NO: 61 is a wild-type gene sequence encoding PLCG2 protein, and is shown below:

GAATTCGGCGCTGAGTGACCCGAGTCGGGACGCGGGCTGCGCGCGCGGGACCCCGGA GCC

CAAACCCGGGGCAGGCGGGCAGCTGTGCCCGGGCGGCACGGCCAGCTTCCTGATTTC TCC

CGATTCCTTCCTTCTCCCTGGAGCGGCCGACAATGTCCACCACGGTCAATGTAGATT CCC

TTGCGGAATATGAGAAGAGCCAGATCAAGAGAGCCCTGGAGCTGGGGACGGTGATGA CTG

TGTTCAGCTTCCGCAAGTCCACCCCCGAGCGGAGAACCGTCCAGGTGATCATGGAGA CGC

GGCAGGTGGCCTGGAGCAAGACCGCCGACAAGATCGAGGGCTTCTTGGATATCATGG AAA

TAAAAGAAATCCGCCCAGGGAAGAACTCCAAAGATTTCGAGCGAGCAAAAGCAGTTC GCC

AGAAAGAAGACTGCTGCTTCACCATCCTATATGGCACTCAGTTCGTCCTCAGCACGC TCA

GCTTGGCAGCTGACTCTAAAGAGGATGCAGTTAACTGGCTCTCTGGCTTGAAAATCT TAC

ACCAGGAAGCGATGAATGCGTCCACGCCCACCATTATCGAGAGTTGGCTGAGAAAGC AGA

T ATATT CTGTGGATC AAACCAGAAG AAACAGC AT CAGTCTCCGAG AGTT GAAGACCAT CT

TGCCCCTGATCAACTTTAAAGTGAGCAGTGCCAAGTTCCTTAAAGATAAGTTTGTGG AAA

T AG GAG C AC AC AAAG AT G AGCT C AG CTTT G AAC AGTTCC AT CTCTTCTAT AAAAAACTT A

TGTTTGAACAGCAAAAATCGATTCTCGATGAATTCAAAAAGGATTCGTCCGTGTTCA TCC

T GGGGAACACTGACAGGCCGGAT GCCTCT GCT GTTTACCT GCAT GACTTCCAGAGGTTTC

TCATACATGAACAGCAGGAGCATTGGGCTCAGGATCTGAACAAAGTCCGTGAGCGGA TGA

CAAAGTTCATT GAT GACACCATGCGT G AAACTGCT GAGCCTTTCTTGTTTGTGGAT G AGT

TCCT CACGTACCT GTTTTCACG AG AAAACAGC AT CT GGGAT GAGAAGTAT GACGCGGTGG

ACAT GCAGG AC AT GAACAACCCCCTGTCT CATTACT GG AT CTCCTCGT CACAT AACACGT

ACCTTACAGGTGACCAGCTGCGGAGCGAGTCGTCCCCAGAAGCTTACATCCGCTGCC TGC

GCATGGGCTGTCGCTGCATTGAACTGGACTGCTGGGACGGGCCCGATGGGAAGCCGG TCA

TCTACCATGGCTGGACGCGGACTACCAAGATCAAGTTTGATGACGTCGTGCAGGCCA TCA

AAG ACCACGCCTTTGTT ACCTCGAGCTTCCCAGT GATCCT GTCCATCG AGGAGCACT GCA

GCGTGGAGCAACAGCGTCACATGGCCAAGGCCTTCAAGGAAGTATTTGGCGACCTGC TGT

TGACGAAGCCCACGGAGGCCAGTGCTGACCAGCTGCCCTCGCCCAGCCAGCTGCGGG AGA

AGATCATCATCAAGCATAAGAAGCTGGGCCCCCGAGGCGATGTGGATGTCAACATGG AGG

ACAAGAAGGACGAACACAAGCAACAGGGGGAGCTGTACATGTGGGATTCCATTGACC AGA

AATGGACTCGGCACTACTGCGCCATTGCTGATGCCAAGCTGTCCTTCAGTGATGACA TTG

AACAGACTATGGAGGAGGAAGTGCCCCAGGATATACCCCCTACAGAACTACATTTTG GGG

AGAAATGGTTCCACAAGAAGGTGGAGAAGAGGACGAGTGCCGAGAAGTTGCTGCAGG AAT

ACTGCATGGAGACGGGGGGCAAGGATGGCACCTTCCTGGTTCGGGAGAGCGAGACCT TCC

CCAATGACTACACCCTGTCCTTCTGGCGGTCAGGCCGGGTCCAGCACTGCCGGATCC GCT

CCACCATGG AGGGCGGGACCCT G AAAT ACT ACTT GACT G AC AACCT GAGGTT CAGGAGG A

TGTATGCCCTCATCCAGCACTACCGCGAGACGCACCTGCCGTGCGCCGAGTTCGAGC TGC

GGCTCACGGACCCTGTGCCCAACCCCAACCCCCACGAGTCCAAGCCGTGGTACTATG ACA

GCCTGAGCCGCGGAGAGGCAGAGGACATGCTGATGAGGATTCCCCGGGACGGGGCCT TCC TGATCCGGAAGCGAGAGGGGAGCGACTCCTATGCCATCACCTTCAGGGCTAGGGGCAAGG

TAAAGCATTGTCGCATCAACCGGGACGGCCGGCACTTTGTGCTGGGGACCTCCGCCT ATT

TT GAGAGT CTGGT GGAGCTCGT CAGTT ACT ACGAGAAGCATT CACT CT ACCGAAAG AT GA

GACTGCGCTACCCCGTGACCCCCGAGCTCCTGGAGCGCTACAATACGGAAAGAGATA TAA

ACTCCCTCTACGACGTCAGCAGAATGTATGTGGATCCCAGTGAAATCAATCCGTCCA TGC

CTCAGAGAACCGTGAAAGCTCTGTATGACTACAAAGCCAAGCGAAGCGATGAGCTGA GCT

TCTGCCGTGGTGCCCTCATCCACAATGTCTCCAAGGAGCCCGGGGGCTGGTGGAAAG GAG

ACTATGGAACCAGGATCCAGCAGTACTTCCCATCCAACTACGTCGAGGACATCTCAA CTG

CAGACTTCGAGGAGCTAGAAAAGCAGATTATTGAAGACAATCCCTTAGGGTCTCTTT GCA

GAGGAATATTGGACCTCAATACCTATAACGTCGTGAAAGCCCCTCAGGGAAAAAACC AGA

AGTCCTTTGTCTTCATCCTGGAGCCCAAGGAGCAGGGCGATCCTCCGGTGGAGTTTG CCA

CAGACAGGGTGGAGG AGCT CTTT GAGT GGTTT CAG AGCATCCG AG AG ATCACGTGG AAGA

TTGACAGCAAGGAGAACAACATGAAGTACTGGGAGAAGAACCAGTCCATCGCCATCG AGC

TCTCTGACCTGGTTGTCTACTGCAAACCAACCAGCAAAACCAAGGACAACTTAGAAA ATC

CTGACTTCCGAGAAATCCGCTCCTTTGTGGAGACGAAGGCTGACAGCATCATCAGAC AGA

AGCCCGTCGACCTCCTGAAGTACAATCAAAAGGGCCTGACCCGCGTCTACCCAAAGG GAC

AAAGAGTTGACTCTTCAAACTACGACCCCTTCCGCCTCTGGCTGTGCGGTTCTCAGA TGG

TGGCACTCAATTTCCAGACGGCAGATAAGTACATGCAGATGAATCACGCATTGTTTT CTC

TCAACGGGCGCACGGGCTACGTTCTGCAGCCTGAGAGCATGAGGACAGAGAAATATG ACC

CGATGCCACCCGAGTCCCAGAGGAAGATCCTGATGACGCTGACAGTCAAGGTTCTCG GTG

CTCGCCATCTCCCCAAACTTGGACGAAGTATTGCCTGTCCCTTTGTAGAAGTGGAGA TCT

GTGGAGCCGAGTATGGCAACAACAAGTTCAAGACGACGGTTGTGAATGATAATGGCC TCA

GCCCTATCTGGGCTCCAACACAGGAGAAGGTGACATTTGAAATTTATGACCCAAACC TGG

CATTT CTGCGCTTT GTGGTTT AT GAAG AAG AT ATGTT CAGCGATCCC AACTTT CTT GCTC

ATGCCACTTACCCCATTAAAGCAGTCAAATCAGGATTCAGGTCCGTTCCTCTGAAGA ATG

GGTACAGCGAGGACATAGAGCTGGCTTCCCTCCTGGTTTTCTGTGAGATGCGGCCAG TCC

TGGAGAGCGAAGAGGAACTTTACTCCTCCTGTCGCCAGCTGAGGAGGCGGCAAGAAG AAC

TGAACAACCAGCTCTTTCTGTATGACACACACCAGAACTTGCGCAATGCCAACCGGG ATG

CCCTGGTTAAAGAGTTCAGTGTTAATGAGAACCACTCCAGCTGTACCAGGAGAAATG CAA

C AAG AGGTT AAG AG AG AAG AG AGTC AG C AAC AGC AAGTTTT ACTC AT AG AAG CTGGGGTA

TGTGTGTAAGGGTATTGTGTGTGTGCGCATGTGTGTTTGCATGTAGGAGAACGTGCC CTA

TTCACACTCTGGGAAGACGCTAATCTGTGACATCTTTTCTTCAAGCCTGCCATCAAG GAC

ATTTCTTAAGACCCAACTGGCATGAGTTGGGGTAATTTCCTATTATTTTCATCTTGG ACA

ACTTCTAACTTATATCTTTATAGAGGATTCCCCAAAATGTGCTCCTCATTTTTGGCC TCT

CATGTTCCAAACCTCATTGAATAAAAAGCAATGAAAACCTTG

(SEQ ID NO: 61)

As used herein, the term “PTK2B” refers to the gene encoding Protein-tyrosine kinase 2-beta.

The terms “PTK2B” and "Protein-tyrosine kinase 2-beta" include wild-type forms of the PTK2B gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type PTK2B. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type PTK2B nucleic acid sequence (e.g., SEQ ID NO: 62, ENA accession number U33284). SEQ ID NO: 62 is a wild-type gene sequence encoding PTK2B protein, and is shown below:

CGGTACAGGTAAGTCGGCCGGGCAGGTAGGGGTGCCCGAGGAGTAGTCGCTGGAGTC CGC

GCCTCCCTGGGACTGCAATGTGCCGGTCTTAGCTGCTGCCTGAGAGGATGTCTGGGG TGT

CCGAGCCCCTGAGCCGAGTAAAGTTGGGCACATTACGCCGGCCTGAAGGCCCTGCAG AGC

CCATGGTGGTGGTACCAGTAGATGTGGAAAAGGAGGACGTGCGTATCCTCAAGGTCT GCT

TCTATAGCAACAGCTTCAATCCTGGGAAGAACTTCAAACTGGTCAAATGCACTGTCC AGA

CGGAGATCCGGGAGATCATCACCTCCATCCTGCTGAGCGGGCGGATCGGGCCCAACA TCC

GGTTGGCTGAGTGCTATGGGCTGAGGCTGAAGCACATGAAGTCCGATGAGATCCACT GGC

T GCACCCACAGAT GACGGT GGGT GAGGT GCAGGACAAGTATGAGTGTCT GCACGT GGAAG

CCGAGTGGAGGTATGACCTTCAAATCCGCTACTTGCCAGAAGACTTCATGGAGAGCC TGA

AGGAGGACAGGACCACGCTGCTCTATTTTTACCAACAGCTCCGGAACGACTACATGC AGC

GCTACGCCAGCAAGGTCAGCGAGGGCATGGCCCTGCAGCTGGGCTGCCTGGAGCTCA GGC

GGTTCTTCAAGGATATGCCCCACAATGCACTTGACAAGAAGTCCAACTTCGAGCTCC TAG

AAAAGGAAGTGGGGCTGGACTTGTTTTTCCCAAAGCAGATGCAGGAGAACTTAAAGC CCA

AACAGTTCCGGAAGATGATCCAGCAGACCTTCCAGCAGTACGCCTCGCTCAGGGAGG AGG

AGTGCGTCATGAAGTTCTTCAACACTCTCGCCGGCTTCGCCAACATCGACCAGGAGA CCT

ACCGCT GT G AACT CATT CAAGG ATGGAACATT ACT GT GG ACCTGGT CATTGGCCCT AAAG

GGATCCGCCAGCTGACTAGTCAGGACGCAAAGCCCACCTGCCTGGCCGAGTTCAAGC AGA

TCAGGTCCATCAGGTGCCTCCCGCTGGAGGAGGGCCAGGCAGTACTTCAGCTGGGCA TTG

AAGGTGCCCCCCAGGCCTTGTCCATCAAAACCTCATCCCTAGCAGAGGCTGAGAACA TGG

CTGACCTCATAGACGGCTACTGCCGGCTGCAGGGTGAGCACCAAGGCTCTCTCATCA TCC

ATCCTAGGAAAGATGGTGAGAAGCGGAACAGCCTGCCCCAGATCCCCATGCTAAACC TGG

AGGCCCGGCGGTCCCACCTCTCAGAGAGCTGCAGCATAGAGTCAGACATCTACGCAG AGA

TTCCCGACGAAACCCTGCGAAGGCCCGGAGGTCCACAGTATGGCATTGCCCGTGAAG ATG

TGGTCCTGAATCGTATTCTTGGGGAAGGCTTTTTTGGGGAGGTCTATGAAGGTGTCT ACA

CAAATCACAAAGGGGAGAAAATCAATGTAGCTGTCAAGACCTGCAAGAAAGACTGCA CTC

TGGACAACAAGGAGAAGTTCATGAGCGAGGCAGTGATCATGAAGAACCTCGACCACC CGC

ACATCGTGAAGCTGATCGGCATCATTGAAGAGGAGCCCACCTGGATCATCATGGAAT TGT

ATCCCTATGGGGAGCTGGGCCACTACCTGGAGCGGAACAAGAACTCCCTGAAGGTGC TCA

CCCTCGTGCTGTACTCACTGCAGATATGCAAAGCCATGGCCTACCTGGAGAGCATCA ACT

GCGTGCACAGGGACATTGCTGTCCGGAACATCCTGGTGGCCTCCCCTGAGTGTGTGA AGC

TGGGGGACTTTGGTCTTTCCCGGTACATTGAGGACGAGGACTATTACAAAGCCTCTG TGA

CTCGTCTCCCCATCAAATGGATGTCCCCAGAGTCCATTAACTTCCGACGCTTCACGA CAG

CCAGTGACGTCTGGATGTTCGCCGTGTGCATGTGGGAGATCCTGAGCTTTGGGAAGC AGC

CCTTCTTCTGGCTGGAGAACAAGGATGTCATCGGGGTGCTGGAGAAAGGAGACCGGC TGC

CCAAGCCTGATCTCTGTCCACCGGTCCTTTATACCCTCATGACCCGCTGCTGGGACT ACG

ACCCCAGTGACCGGCCCCGCTTCACCGAGCTGGTGTGCAGCCTCAGTGACGTTTATC AGA

TGGAGAAGGACATTGCCATGGAGCAAGAGAGGAATGCTCGCTACCGAACCCCCAAAA TCT

TGGAGCCCACAGCCTTCCAGGAACCCCCACCCAAGCCCAGCCGACCTAAGTACAGAC CCC CTCCGCAAACCAACCTCCTGGCTCCAAAGCTGCAGTTCCAGGTTCCTGAGGGTCTGTGTG

CCAGCTCTCCTACGCTCACCAGCCCTATGGAGTATCCATCTCCCGTTAACTCACTGC ACA

CCCCACCTCTCCACCGGCACAATGTCTTCAAACGCCACAGCATGCGGGAGGAGGACT TCA

TCCAACCCAGCAGCCGAGAAGAGGCCCAGCAGCTGTGGGAGGCTGAAAAGGTCAAAA TGC

GGCAAATCCTGGACAAACAGCAGAAGCAGATGGTGGAGGACTACCAGTGGCTCAGGC AGG

AGG AGAAGTCCCTGGACCCCATGGTTTAT AT GAAT GAT AAGTCCCC ATT GACGCCAG AG A

AGGAGGTCGGCTACCTGGAGTTCACAGGGCCCCCACAGAAGCCCCCGAGGCTGGGCG CAC

AGTCCATCCAGCCCACAGCTAACCTGGACCGGACCGATGACCTGGTGTACCTCAATG TCA

TGGAGCTGGTGCGGGCCGTGCTGGAGCTCAAGAATGAGCTCTGTCAGCTGCCCCCCG AGG

GCTACGTGGTGGTGGTGAAGAATGTGGGGCTGACCCTGCGGAAGCTCATCGGGAGCG TGG

ATGATCTCCTGCCTTCCTTGCCGTCATCTTCACGGACAGAGATCGAGGGCACCCAGA AAC

TGCTCAACAAAGACCTGGCAGAGCTCATCAACAAGATGCGGCTGGCGCAGCAGAACG CCG

T GACCTCCCT G AGTG AGG AGTGCAAGAGGCAG ATGCT G ACGGCTT CAC ACACCCT GGCTG

TGGACGCCAAGAACCTGCTCGACGCTGTGGACCAGGCCAAGGTTCTGGCCAATCTGG CCC

ACCCACCTGCAGAGTGACGGAGGGTGGGGGCCACCTGCCTGCGTCTTCCGCCCCTGC CTG

CCATGTACCTCCCCTGCCTTGCTGTTGGTCATGTGGGTCTTCCAGGGAGAAGGCCAA GGG

GAGTCACCTTCCCTTGCCACTTTGCACGACGCCCTCTCCCCACCCCTACCCCTGGCT GTA

CTGCTCAGGCTGCAGCTGGACAGAGGGGACTCTGGGCTATGGACACAGGGTGACGGT GAC

AAAGATGGCTCAGAGGGGGACTGCTGCTGCCTGGCCACTGCTCCCTAAGCCAGCCT

(SEQ ID NO: 62)

As used herein, the term “SCIMP” refers to the gene encoding SLP Adaptor and CSK Interacting Membrane Protein. The terms “SCIMP” and "SLP Adaptor and CSK Interacting Membrane Protein" include wild-type forms of the SCIMP gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type SCIMP. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type SCIMP nucleic acid sequence (e.g., SEQ ID NO: 63, NCBI Reference Sequence: NM_207103.3). SEQ ID NO: 63 is a wild-type gene sequence encoding SCIMP protein, and is shown below:

ACTGTCTCTAGCAGTGGGTGAAGGCCTGTGAGTGAGGAATGCCTCTCACCAGCTGTG CCTGAGCTG

CAGCACTCCAGCCACTGCTGTCTCCTTAGCTGCTCACATATGGATACTTTCACAGTT CAGGATTCCAC

TGCAATGAGCTGGTGGAGGAATAATTTCTGGATCATCTTAGCTGTGGCCATCATCGT TGTCTCTGTG

GGTCTGGGCCTCATCCTGTACTGTGTCTGTAAGTGGCAGCTTAGACGAGGCAAGAAA TGGGAAATT

GCCAAGCCCCTGAAACACAAGCAAGTAGATGAAGAAAAGATGTATGAGAATGTTCTT AATGAGTCGC

CAGTTCAATTACCGCCTCTGCCACCGAGGAATTGGCCTTCTCTAGAAGACTCTTCCC CACAGGAAGC

CCCAAGTCAGCCGCCCGCTACATACTCACTGGTAAATAAAGTTAAAAATAAGAAGAC TGTTTCCATCC

CAAGCTACATTGAGCCTGAAGATGACTATGACGATGTTGAAATCCCTGCAAATACTG AAAAAGCATCA

TTTTGAAACAGCCATTTCTTCTTTTTGGCAAAACTGAAGAGGGTTCACACAACTTAT TTTAAAACAATC

AAGAATGGTTGAACTTCAGTAGGTCTCTGGGCCCTGAAAGCCAGTGGTGATTTTATG AAGCTCTATA

AGATAAAGCACTTCCCAAACCTTAGATGAAGACACCCCTGCGATCGGATGACTGCAG CCAGAGGAG ACACATGGGTGCTCGGCTCTGAGGACTTAGAGGGGTCAGCCTTGTGCTGTTGAGGAAACT TTCCAT

GGGAAGGACCACGGGGCTCCATGGCTCCCACCTGTGGGAAACTACTCATTTCTTGGC ATTCTTTCCC

CCTTCATTCCCTTTGGTTTGCATGGTTCTGAGTGATATTAAATCTCAGCATTTGGTT GTGCAGACCCT

CCCAGGCTCCCATCCCCAGCAAGGCCCTCACCAAGCATGCTGGTCTTTACCCTCTCA CCCCACCCA

CCTCCTGCACTGTGAGGCTGTGGGTGAGTTACAGCTGAGTGCTCTCGTGCCCAGGTT CCCACACCA

CATCTCGCGAGTTTGCAAGGGCAGGGAGTACCTTTTGTTCTCGTGAACCCTCCCCAC CTAGACACCC

T GCAAACCCCAGT GCCTTTATAT GATGTAGGCCAAATT GACC AT AG AGATTT G AGTTTT CACCT AG GT

TTTCTCCCCGT GCTTGCAAGTT GT ACT GT AAC AAT GG ACAAAGG ACAAAAGTT ACCTTCT GATTTACA

CCTAGAAGCATCATTTTGCAATAGGTGTGTTGGGGGTGCTACAGGAAAAATACATTT CCCCCAGGAC

AAATCATGGGGAACAGGAAAGAAAAGGGGCATGTAACAATGGCATATACAAGATGAG AGTTCAGGG

GGCTTAATATCCCCTGTCCATCATTTTCATCAGTACTTACTCGAGTTCTAGGAAAAC AGCCTCAAGCC

CCTTCCTTCCAGATCACTGTCCCTGGGCATCTGGGAGGAGGCAGAAGGTCCACTGTG ATGTGCTGC

AGCCAATGAGATGGGCCAGGGACATGGGCAGATGTCTTGTTAAACAAGTGTCCTAAT GGGGTCAAC

AAGGCCCGAGTCAGCTTTATAGGCTCTTAGACCTCATCAATTCCTTCTAGCTGATCG CCAGAGCCCT

AGGACTTGACTCATTCTAACTATACTCACAAGATGCTGGTTTCTAAGTGACCTCTGG GAAATCTGGCA

AAT GAACAGCCTT GCAGAGAGAGCACTGT GAACCT GGAAAGGCCT GAGAGT GACTCAGATTTCCCT

CAAGAGATGGGAAAATGTGTTCCTCCCATTTTCAAGCTTTCTCCCTCAATCAACGCT GGAGCACTGG

GGACCTGGGCTTCCTCCCTGGTTCTCTCTTTCCAGACTCTATGAAGGCTTCCACCTT GCTATTAATAC

CTCCTTGGGAGGCCAAGGTGGGCGGATCACCTGAGGTCGGGAGTTCGAGACCAGCCT GACCAACA

TGGAGAAACCCCATTTCTACTAAAAATACAAAATTAGTCAGGCATGGTCGCGCATGC CTGTAATCCCA

GCTACTTGGGAGGCTGAGGCAGAAGAATCGCTTGAAACTGGGAGGCGGAGGTTGCGG TGAGCCGA

G AACATGCCATT GC ACTCCAGCCT GG ACAACAAG AGT GAAACTCCATCT AAAAAT AAATAAAT AAAT A

AATAAATAAACCCTCCTTATGTTAGGCCAGTAGTTATCTAACTATGGCCTTATGGGA CTCTGGTATCC

CACCAGCCAAAGAGAGGACTCTTCCCAAATTATAGAACAAAAATAAGCCAAAGGATT GGAGTGTTTC

AAAC ACATGCTTTCGT CTTATAAATGTT CTGTAAACCCTCCAT G ACT AT G ACAAAAGTT AAAAACAAAT

GCCAGACAAA

(SEQ ID NO: 63)

As used herein, the term “SLC24A4” refers to the gene encoding Solute Carrier Family 24 Member 4. The terms “SLC24A4” and "Solute Carrier Family 24 Member 4" include wild-type forms of the SLC24A4 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type SLC24A4. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type SLC24A4 nucleic acid sequence (e.g., SEQ ID NO: 64, NCBI Reference Sequence: NM_153646.3). SEQ ID NO:

64 is a wild-type gene sequence encoding SLC24A4 protein, and is shown below:

AGACGGCACCCAGGCGCTCCGGGATGGCGCTCCGCGGGACCCTCCGGCCGCTCAAAG TTCGCAG

GAGGCGAGAGATGCTGCCGCAGCAAGTCGGCTTCGTGTGCGCGGTGCTGGCCCTGGT GTGCTGTG

CGTCCGGCCTCTTCGGCAGCTTGGGGCACAAAACAGCTTCTGCTAGCAAACGTGTCC TGCCAGACA

CGTGGAGAAATAGAAAGTTGATGGCCCCAGTGAATGGGACACAGACAGCCAAGAACT GCACAGATC

CTGCGATTCACGAGTTCCCCACAGATCTGTTCTCCAATAAGGAGCGACAGCACGGAG CCGTCCTGC TGCACATCCTTGGTGCTCTGTATATGTTCTATGCCTTGGCCATAGTGTGCGATGACTTCT TTGTTCCG

TCTCTAGAGAAGATCTGTGAGAGACTCCATCTGAGCGAAGATGTGGCTGGAGCCACC TTCATGGCT

GCAGGAAGCTCAACGCCAGAGCTGTTTGCGTCTGTTATTGGGGTGTTCATCACCCAT GGGGACGTC

GGGGTGGGCACCATCGTGGGCTCTGCTGTGTTCAACATCCTGTGCATAATTGGAGTG TGCGGACTG

TTTGCTGGCCAGGTGGTCCGTCTGACGTGGTGGGCCGTGTGCCGAGACTCCGTGTAC TACACCATC

TCTGTCATCGTGCTCATCGTGTTCATATATGATGAACAAATTGTGTGGTGGGAAGGC CTGGTGCTCA

TCATCTTGTATGTGTTTTATATTCTGATCATGAAGTACAATGTGAAGATGCAAGCCT TTTTCACAGTCA

AACAAAAGAGCATTGCAAACGGTAACCCGGTCAACAGTGAGCTGGAGGCTGGTAATG ATTTCTATGA

CGGTAGCTATGATGACCCTTCCGTGCCATTGCTGGGGCAAGTGAAGGAGAAGCCACA GTATGGCAA

GAACCCCGTGGTGATGGTGGACGAGATTATGAGCTCCAGCCCTCCCAAGTTCACCTT CCCTGAAGC

AGGCTTACGAATCATGATCACCAATAAGTTTGGACCCAGGACCCGACTACGGATGGC CAGCAGGAT

CATCATTAATGAGCGGCAGAGACTGATCAACTCGGCCAATGGTGTGAGCAGTAAGCC GCTTCAAAAC

GGGAGGCACGAGAACATTGAGAACGGGAATGTTCCTGTGGAAAACCCCGAAGACCCT CAGCAGAAT

CAGGAGCAGCAGCCGCCGCCACAGCCACCACCGCCAGAGCCAGAGCCGGTGGAGGCT GACTTCCT

GTCCCCCTTCTCCGTGCCGGAGGCCAGAGGGGACAAGGTCAAGTGGGTGTTCACCTG GCCCCTCA

TCTTCCTCCTGTGCGTCACCATTCCCAACTGCAGCAAGCCCCGCTGGGAGAAGTTCT TCATGGTCAC

CTTCATCACCGCCACGCTGTGGATCGCTGTGTTCTCCTACATCATGGTGTGGCTGGT GACTATTATC

GGATACACACTTGGGATCCCGGATGTCATCATGGGCATTACTTTCCTGGCAGCAGGG ACAAGTGTTC

CAGACTGCATGGCCAGCCTAATTGTGGCGAGACAAGGCCTTGGGGACATGGCAGTCT CCAACACCA

TAGGAAGCAACGTGTTTGACATCCTGGTAGGACTTGGTGTACCGTGGGGCCTGCAGA CCATGGTTG

TTAATTATGGATCAACAGTGAAGATCAACAGCCGGGGGCTGGTCTATTCCGTGGTCC TGTTGCTGGG

CTCTGTCGCTCTCACCGTCCTCGGCATCCACCTAAACAAGTGGCGACTGGACCGGAA GCTGGGTGT

CTACGTGCTGGTTCTCTACGCCATCTTCTTGTGCTTCTCCATAATGATAGAGTTTAA CGTCTTTACCTT

CGTCAACTTGCCGATGTGCCGGGAAGACGATTAGCGCTGAGTCGCGGCCCCTGGGAG CTGATCTG

GACACCCTGTGACACTGGCGTTCTCCTCTCCCCTCCTTCCCCCACCACAGGTCTCTC CTGCATAGGC

AGCCACTGTCCGTTCTTTCACACACTGGAAGGAAGAGCCATCGTGGTCTTTGTCTGG CCACAGGCCA

GGCTGCTGGGCATCCTCCTCCTCCTTGGAGTTCCGCCCCTGCAAGGCTGGATTTGGG GGCCATTAT

CTGAGCAGCTTCAAAGACCCCTGAGCTGCCAACCACGGAGATGTGCCAAGCATCTCA TCTCTCCTG

CACACTTTAGTCAGAAGGACTTCTGCATGCAGTTTGTCTTTCTGTTCTGCAGGCAGC TTCAGAATTGA

GGTCATTTGTGAGCACAAGATCTCATAGGGCAGGTGCAAAATAGGAATGTTGTTCTC AAGTGTCACC

TCCAGCCCAGAGGTGGTTCCTTAGGCAGCATGTGCTCCTGGGAGCCTCTGACTTTTG CTGGAAGCA

GCCACAGTTTGGAAGGGGCAAGACCTCAACCTGTTGGGGTTTAGGGCCCATGATGGC AGACATTCT

ACCCCTTTTCCT GG AAAAACTGGAAG AAT GAAAAT AATTTTTTT CTGTGGAAG AG AG AAAAT G AGTG A

AT ATT CTTCT C ACTTTT ATT GAT GC ATT C AG AG AAT AAGC AAT G AAAT ATT AAAAAAT G AAAC AT CAT AT

AGGTC AT CAT ACTT G AAAATT AT C ATTCC AT AT G AAAG GAT CAT GAT AC AC AC C AAAAAAGTAAT G ATC

GTAAAGACACAAATCCTCTGTATGCCATCTTGCATTGGCACTGAGGTGTTTGGTTTG GAATAGGGAA

AAAG GT AAG AG ACT AAC GT GG AAAG GTGCTAACT C AG AG ACT G GAG ATT AT AGTTT AC AG CTGTACT

TTCCAGATCTTCTATGTGACACAATGCACTGTCCTTGTGGGTTTGTCATTTATTGGT TAATGCTCTAGT

TTCAAAACCACCCTGTTGAAAGTTCCAGTTATTTATATGCCCAACAAATTTCATAGC CTGCTGAACTGA

ACT G AGT GT GT CAG AAGT GCTGGTTAAT GACGAG AAG AGATT GCCT GAAAAACAACAAACT GCTTTC

TGGTTAGCTGAAGGCAAGTGTGAAAATCAGAATTTAGAATATTTAGAGCTAAGCTTC TGGAACCACGT

AGTTTCTACACGTGGCAGGCCAAGAATGGGAGGCTGACTCAAAACTAGATAGAAAAA TATAAAATAAT CTTCG ACC ACTT GAT AG CTCT C AAAT AT AT ATTT AAAAG ATTT AT G AAT AC AAACC ATTT AT G GTTT AT G

ATTT CT AAAAAG AAAGC AC AATT AATTTT AT AG AG AGGTTTTTT ATTTTTTT AAT ATTT CT ATT G C AAAAG

TCTATCCGATTTGATGCACTTTGAATATTGAGATATTTTGCACGGATGAATGTATGG GAACTACCCAT

GAT GAT GT AAG AGGAAAGAAC ATTTTTTTGTGATT CAC CAGACATC ACTTTAAACTT GGTG AT GAGTTT

AAATCCAGTAGCTAATCCCTTCCTGAGACTCAAAGATCGTGACGCTGGTTGGAATTT CTGACTGTGC

CCTTTAGGGCCTCCTGAGTTTCAAAAGGAGGAAGTGTTCGTGCTTGTGTCCCTGAAG TTCCCTGTTG

CATGAGCCTGCGACAGGACCTCACCCCCACCACCAGGCTTCTATTTGGGATTCACAT CAGTATTAGT

ATCGTAGCTACACCAAGTTCAGGCTTCTCTTTTTGTTTTTTTACCTAGAAATTGGGC TCAGTGGTCTTC

AACTTGAGGACGAGGGTGATTTTCCTAAGAAATCAGCAAAGAGGGAAGGCAGGGCCC CTGTAGATT

CACCAGTATAAACTTCAGCTGCAGGGATTCCAGAGCCCTCGGGACCACTCTGTCACC TTAATAGCCA

AGTTCTCCTGGTTCCTCCGATCTTACAGGCTCATCCAGGTTCCAAAGTGCTTCTGTC TCTGTTTTGAT

TCTCCAAACTGCTCTGTGATGTATGTAGGGATTATTCTCCCCACTTAACAGAAAGTA GTGTCTTGGAG

AGGTCAAGGGTCTCTAGTTCAATGGCCAGTCATAGCAGAAGGGAGGCCAAGCACCAG TCCATCACC

CCTCCCAGGCCAGCCTCTGTAAGTTGGCCACACTTGGGGAGTGAGTGTGGGTATGAC TTTACCCTC

CTGGTTGGTTCTTACTGTTTGAGTCAAAACCTCATCAATATATCATTGACTCCTGGG TTCCTCAGGTC

ATTTCCTAATATCTGTCCCTATCCAATGCCTCTATTTTATCTTGAAAAAAGGACCAA AAATTATTTTTAG

CTATGGCAAGGCACAGGCCACATGGCCCCTGATGGCGTCCCTGCTGGTTTTCAATTC TCTGAAGCCT

TGTGTAGCTTTCAGAGCACACGTATCCTAATTACCCTCCTCTTCCTCAGCAGAACCC ATTTGAGATTC

TAAATGAATACTCTTAGTCTCTAAAGTTGCAGTTAGAAACTAAAATAATGTTTTTTA ATATGTAATATGC

TCCTCTTGGCTAATTTTCTTTTGACTTTAATGTGCCAATGTAACTTCCTTTAAAGGA TCTATGCATTTAT

T AAAT CTG G AAAACT ATATGT AC ACT GT AG GT GG AAAATT CT CTTTTTT AACT AAAT ATTTTTCC AT CAC

AAATTTAAAGAATTGCATGATTAATTAGGCTTTCATTTTTAAATTACGCTTTCATCA CTACGCAGGATTA

CTTTATTTTATTCCCAAAGCTCATTAGCATGGGATAATTACTCTGCTACAGAAATAG GCAATTTAAAAA

AAT G AATTT AG CTCTTCT C ATT G GG GG C AG AAAAG AAAAAAAAAACC ATT G C ACT C AG AT G G AAAAT G

CCTATAGACACAGGAGCAGGTGGTTCCTGTGGACTTCTGGTTTGGAATTTTGCCTCA CCAGGTCAAG

CGTGGTTAGGGTGGAAGGTGTCCAGTATCTTGAAAACCTGGCCCTGGAGGAAGGTTC TGGGTCAGC

TGCAATGAGAGACTGGTGATTAAGGGCACCGTGGGCAGGACACAGTCCTCGCCTTAC CCACCCCAT

CCTTCCTGTTACCCACAGTCTGCTGGCCTCCATGCCTCTTCCCCTTGTCACTTGTGT CTCCTCCTTAT

GCACAGAGCTGCCTGCCTTTATGAATTTTCTTTTCTTTTTTTTTTGAGACAGCGTCT TGCTGTGTCACC

CAGGCTGGAGTGCAGTGGTGCCATCTTGGCTCACTGCAACCTCCGCCTCCCAGGTTC AAGCAATTC

TTGTGCCTCAGCCTCCTGAGGATTACAGGCGTGCGCCACCACACCCAGCTAATTTTT GTATTTTTAGT

AGAGACGGGTTTTCACCATGTTGGCCAGGCTGGTCTCAAACTCCTGACCTCAGGTGA TCCACCCAC

CTCGGTTTCCCAAAGTGCTGGGATTACAGGTGTGAGCCACCACGCCCAGCCTGCCCT TGTGAATTTT

CACCTGCTCCTTACCCCTCACCTGTTAGGACTGTTTCTTGCTTTTGCCCCTGTCGGT CCCCTGCCTTA

ACAGACCTAAGCAGCTGATAATGCACCAAGCTTCCCTGACCAGGTGGGGTGTGTCTA TCACCCAAG

GGCAGTCCTACAGACCCTGACCAAAGGCCGTTCCTGGGCGGCCCAAGGTCCAGGTTT CTTCCACCT

GCTCTTCCCTGTTTATGGGGATTTGCAAGCCTAATTGCATCAGCAGGAGCCCATCTC TCAGAGAACC

CGGACTCCCCAAGCAGACTGGGATTTTGGGAAGGGTGTGGGGGGTGTCATTGCTGGA TACCCGTCT

TTCTGCCTGTCCTTTCTCCTCTCTGAATCCTGGGGCCCCTCTCCCTCCTTAAAGCTG GAGTGGACAG

AGGGACAGGAGAGGATCAGAGTTCATCCCCCCTGGGAAAGAGCAAGAGCGAATGAAT CCCAGCGC

CAGCGGCTGAGGCTGCCTTCCGTGCCTTCCCTCCATGGGCGACGGGTGAGTGGGGCT TAGGAAAC

T GGAAC AGGG AAGGTT CTGTT ACCACACTTTGGAACTTTCCCCCT GGGATT CAGCAGTT GAG AAGC A GAGACCTTTCTGCCCTGGGTGAATGGGTCCTTGGGGGAGGGGTTGGTCTTTTGTCTCGCA TCCCCA

TCTTTCCTTTCCTTCTGGGCCATGCTCCTCCCTGGCTGGAAAAAGGTGGCTGTGCTG TCCCTGTGAT

CCACTCTCAGCAAATGCGTGTGGCTCAAATAAACAAAGAACTTACCTGTTAGAGTGA AAATCCTCAG

GAGATTGTACCCAAATGCCATGCTCTAAATATTCATGGTCTCTCTAATGCCCTCAAG ACGTGATTTCC

ATGGGAACCATCCTCCCCTGGGGGCAGTTAGCAGGAGTACGTGGGGCACGTGAGGTG GTCCTCCT

TTCAGCACACCGTGCCCATAGAAACTTCTAGAAATTTCTGAAAATGCTCTGTGGGCA GCTCTTGGGT

GGCAGTAAGTCCATCAACCCCCATCTACCCCGGGCCTGAAGCGCTGCGCTTGCTCTC TTTATGTGTG

TGCACCCGAAGGATTTCCTGGTCTCTGTAGCTGATCCTGTGAGCCCCTCAAGCATGA AGCCTCCCTT

GGGGCTTCTCAAAGCATGGAGAGGGGCCCTTCCTGTCCTTTGGGAAAATCTTCCCCA CTGTGTCAGT

TATATGGGAACAAGAGTGATGGGGTCTTTCTCTAGGCCTGTGCCACAGGACAGAGAA CACGGGATT

CTGCTGTTCGCTTTGAGCCACAGCCTTTACCAGCCCGGCTTGTGTGGGGGGCCCCTT CGCCTTGCT

GCAAAGAGCTGTTCCCCAAAGGGCATATCCACAGGGTACAGGTTTTAAAAAGGCTTT TTTTTTTTTTT

TTGAGACAGGGTCTCGCTCTGTCGCCTAGACTCAGTGCAGTGGCGCCATGTTGGCTG GTTGCAACC

TCCACCTCCTGGGTTCAAGTGATTCTCCCACCTCAGCCTCTCTGGTAGCTGGGACTA CAGGCACGC

GCCACCATGCCCAGCTAATTTTTGGATTTTTAGTAGAGAAGGAGTTTCACCATGCTG ACCAGGCTGG

TTTCGAACTCCTGACCTCAAGTGATCCGCCCGCCTGGGCCTCCCAGAGTGCTGAGAT TACAGGCGT

GAGCCACCGCACCTGGCCAAAAAAAGGCATTTTGATTTAGGTTGCTGTGTTTGCTTG TTGATAAAGAA

AACTCAATCGGGACACTAGTTTTGTGCTCAGCTTTAGGCCGGGTAGCTAATGGGAGG ATGTCCAGCC

TGTCACTGTGCTCCCAGCGCAAGGAAATGGGTGCCCACCTGGAATCAGGAGAAGAGG CTTTTCCCT

CCTGTTCTGCAACCAGGGTGGAGCTATCTTTCCAGGGAAGCCAGCTGAGAGGTTTTA GGGCTTTGG

TTATTTTATGGGGGTTTTAAACCTCCTAACTTTTCAATGACAAATGGCTCCCAGGTG CCATAGTCTCT

GTTAAATCCTCAAACATTCACAAGCACACACTGCCAGGGGCACGGGTTGTCTTTCAC CTGCATGTTT

CTAAGGCTCTTTATTCAATCTCACGGTGTCAGTGTCCAGTTGTCAAAGTTATGAATC TTCCTCCTGCT

TCTAAACAGGGCTGACAGTATACTCTCGTCTAGTCTAGGAACATGTCTGCTGCTGGG ATACCCTGGT

ACCAGGATTTGAGGGCCACGGGTGGCATCTCTGAGAGCTGAAAATCCACAGAGTGCC TGTGGGAAA

GCCAAGCCCTTGGCTGTGTGGCTTTTCTATCCCTTGGATTTACAGGTCTGGGAATTG GCTGCTTCTT

AGTTATAACCCCAGTGACAAATGCTGGCTTAAGCCACACCTGTTCCCACTGTTGCTA GAATTCAAACA

GTTGCTTTTTTTTTTTCTTTTTGAGAAAGGGCCTCACTCTGTTGCCCAGGCTGGAGT GCAGTGGCTTG

ATCACAGCTCACGAAAGCCTCAAACTCCTAGGCTCAAGTGATCCTCCTGAAAAGTAG GTAGGACTAC

AGG CAC AT G CC ACC AC AT AC AG CT AATTT GTTTT C ATTTTTTTTTTTTTT AG AG AC AG GATCTCGCTGT

GTTCCCCAGGTAGGTCTTGAACTCCTGGCCTCAAGTGATCCTCCTGCCTTGACCTCC CAAAGTGCTG

GATTACAAGCGTGAGCCCCTGCACCCGGCCCAAGCAGTTGCTTCTTTTTTTCTCTTT TTTTTTTTTTTT

GAGATGGAGCCTCACTCTGTTGCCCAGGCTGGAGTGCAGTGGCGCGATCTCCACTCA CTGCAAGCT

CCGCCTCCCGGGTTCATGCCATTCTCCTGCCTCAGCCTCCCGAGTAGCTGGGACTAC AGGCGCCTG

CCACCACACCCAGCTAATTTTTTGTATTTTTGGTACAGACAGGGTTTCACCGTGTTA GCCAGGATGGT

CTTGATCTCCTGATCTCGTGATCCGCCCACCCCGGCCTCCCAAAGTGCTGGATTACA AGCGTGAGC

CACCGCGCCCCGCCAAGCAGTTGCTTCTTATGCAACATGTTGGTTGGGACTTGTCCA CGGGCCAGG

CCAATAAAATTCTTAATCCTGCAGAGAGTCAGTACCCTCATCACCCCATCACTGGAA AACAAATGTTT

TAAGCTATCAAGAGAGGGAATGTGCAGCTTTTGGTTTCTAGATGCATGGTTTGGTGT GATCTACCTTT

GTGCCT AAAGGGAAT GTCCCAAACAACAG AGCCTT CTTTGCTGTCACTCCAGAATTCT CT AC ACAG A

ATTTCCCAAGTCCATTCAGGACAGACGCGCAGTCCTCTTTCAATGGAAGAAGAGAGG ACTTTTCCCC

TCCT G AAAAAT GACTGGAGTGT G AAC AAG GC AG CTCTG TTTTT CT AAAT AAGTTGTTCTTGT G AGTTT TTTCTGGCCACTGGGCATCTCTGCCCTCACTTTTCATCCCTGCCCTCTAAGCTGCAGACC CCATGAC

CACACTGTCTGCTTCCTTGAGCTTCCCGCACGAGGCTTGGACCTGGGGGACCTGGAG ACCCTGCGG

ACAGAACTGTGGCTGAGCCACTGTGGCCAACTCTTGGGGAGCTCCACAGTGGGGGTT GCTGGTCTG

TGAGGCTGAGTCTCCATTTCAGAGCACACACTCCCTGGCAGGGCGCCTCTGCCTGTG TCTCCTGCC

CAGCAGCCGCCAGCAGGGAATAGTTGCTGGTGTCTGAGCACAAAGAGAGCTTTGATT ACCTAGAGA

GGAAAAAGGCTGTCAGCCAGATGCAGCCAGGCCCAGGGGTAGATACAGGAGTTGCTA AGGAAGGG

GCCGAGCCAGGAGAGGCCAGGCAGATCCACAAAGCCCAAGGGGATGCAGGCTGGGTG TGGTTTCT

G AGGGAACCT ACCAAAT AGCAGGT AG ATGG AAT CAGAGG ACT CTT GT GTCCT G AAAG AACCTCCTT A

AAAACAACTAAAACGAAGAACTTCTGGGGCTGTTCACACATTGTTCAAGTCACCCCA AGATCGTTCTG

GCACGCTGAGCTGAACACCACCATCTTTGTTCATTCTCTCTCTAATGGGCAAAGCAG GATCATCGAG

TTGAAAAGTTGTAAATAATGAGGATATTTATCCCGCTATTTATTTTTTCAATAACTG TGACCTCCTGCA

CTGT G AAT GCTCTGT G AC AT GAG ATT CTT AGTTT AAT AAAACT GT C ATT AAATTT G AAT G AATT GAT AT

T ATT GGTTACT G AAC ACT G GC AT G AGTTT ATTTTT ATTGTG AAG AAAAAAAT CT AC AG C AAT CT AAACT

AAACCTTTCTAAGAAATCTAGCAGTCAGTATTGTAATGCAATATATCAAAATCTGTA CACTGTCAATAA

AAT AAAT GAGCACAAAAAAAAAAAAAA

(SEQ ID NO: 64)

As used herein, the term “SORL1” refers to the gene encoding Sortilin-related receptor. The terms “SORL1” and "Sortilin-related receptor" include wild-type forms of the SORL1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type SORL1 . Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type SORL1 nucleic acid sequence (e.g., SEQ ID NO: 65, ENA accession number Y08110). SEQ ID NO: 65 is a wild-type gene sequence encoding SORL1 protein, and is shown below:

CCGGCCCAGCGGCTCTCCTGGCCTCGCGCTGCACATTCTCTCCTGGCGGCGGCGCCA CCT

GCAGTAGCGTTCGCCCGAACATGGCGACACGGAGCAGCAGGAGGGAGTCGCGACTCC CGT

TCCTATTCACCCTGGTCGCACTGCTGCCGCCCGGAGCTCTCTGCGAAGTCTGGACGC AGA

GGCTGCACGGCGGCAGCGCGCCCTTGCCCCAGGACCGGGGCTTCCTCGTGGTGCAGG GCG

ACCCGCGCGAGCTGCGGCTGTGGGCGCGCGGGGATGCCAGGGGGGCGAGCCGCGCGG ACG

AGAAGCCGCTCCGGAGGAAACGGAGCGCTGCCCTGCAGCCCGAGCCCATCAAGGTGT ACG

GACAGGTTAGTCTGAATGATTCCCACAATCAGATGGTGGTGCACTGGGCTGGAGAGA AAA

GCAACGTGATCGTGGCCTTGGCCCGAGATAGCCTGGCATTGGCGAGGCCCAAGAGCA GTG

ATGTGTACGTGTCTTACGACTATGGAAAATCATTCAAGAAAATTTCAGACAAGTTAA ACT

TTGGCTTGGGAAATAGGAGTGAAGCTGTTATCGCCCAGTTCTACCACAGCCCTGCGG ACA

ACAAGCGGTACATCTTTGCAGACGCTTATGCCCAGTACCTCTGGATCACGTTTGACT TCT

GCAACACTCTTCAAGGCTTTTCCATCCCATTTCGGGCAGCTGATCTCCTCCTACACA GTA

AGGCCTCCAACCTTCTCTTGGGCTTTGACAGGTCCCACCCCAACAAGCAGCTGTGGA AGT

CAGATGACTTTGGCCAGACCTGGATCATGATTCAGGAACATGTCAAGTCCTTTTCTT GGG

G AATT G ATCCCT AT G ACAAACCAAAT ACC AT CTACATT GAACG ACACG AACCCT CTGGCT

ACTCCACTGTCTTCCGAAGTACAGATTTCTTCCAGTCCCGGGAAAACCAGGAAGTGA TCC TTGAGGAAGTGAGAGATTTTCAGCTTCGGGACAAGTACATGTTTGCTACAAAGGTGGTGC

ATCTCTTGGGCAGTGAACAGCAGTCTTCTGTCCAGCTCTGGGTCTCCTTTGGCCGGA AGC

CCATGAGAGCAGCCCAGTTTGTCACAAGACATCCTATTAATGAATATTACATCGCAG ATG

CCTCCG AGGACCAGGTGTTT GTGTGTGTCAGCCACAGT AACAACCG CACCAATTTATACA

TCTCAGAGGCAGAGGGGCTGAAGTTCTCCCTGTCCTTGGAGAACGTGCTCTATTACA GCC

CAGGAGGGGCCGGCAGTGACACCTTGGTGAGGTATTTTGCAAATGAACCATTTGCTG ACT

TCCACCGAGTGGAAGGATTGCAAGGAGTCTACATTGCTACTCTGATTAATGGTTCTA TGA

ATGAGGAGAACATGAGATCGGTCATCACCTTTGACAAAGGGGGAACCTGGGAGTTTC TTC

AGGCTCCAGCCTTCACGGGATATGGAGAGAAAATCAATTGTGAGCTTTCCCAGGGCT GTT

CCCTTCATCTGGCTCAGCGCCTCAGTCAGCTCCTCAACCTCCAGCTCCGGAGAATGC CCA

TCCTGTCCAAGGAGTCGGCTCCAGGCCTCATCATCGCCACTGGCTCAGTGGGAAAGA ACT

TGGCTAGCAAGACAAACGTGTACATCTCTAGCAGTGCTGGAGCCAGGTGGCGAGAGG CAC

TTCCTGGACCTCACTACTACACATGGGGAGACCACGGCGGAATCATCACGGCCATTG CCC

AGGGCATGGAAACCAACGAGCTAAAATACAGTACCAATGAAGGGGAGACCTGGAAAA CAT

TCATCTTCTCTGAGAAGCCAGTGTTTGTGTATGGCCTCCTCACAGAACCTGGGGAGA AGA

GCACTGTCTTCACCATCTTTGGCTCGAACAAAGAGAATGTCCACAGCTGGCTGATCC TCC

AGGTCAATGCCACGGATGCCTTGGGAGTTCCCTGCACAGAGAATGACTACAAGCTGT GGT

CACCATCTGATGAGCGGGGGAATGAGTGTTTGCTGGGACACAAGACTGTTTTCAAAC GGC

GGACCCCCCATGCCACATGCTTCAATGGAGAGGACTTTGACAGGCCGGTGGTCGTGT CCA

ACTGCTCCTGCACCCGGGAGGACTATGAGTGTGACTTCGGTTTCAAGATGAGTGAAG ATT

TGTCATTAGAGGTTTGTGTTCCAGATCCGGAATTTTCTGGAAAGTCATACTCCCCTC CTG

TGCCTTGCCCTGTGGGTTCTACTTACAGGAGAACGAGAGGCTACCGGAAGATTTCTG GGG

ACACTTGTAGCGGAGGAGATGTTGAAGCGCGACTGGAAGGAGAGCTGGTCCCCTGTC CCC

TGGCAGAAGAGAACGAGTTCATTCTGTATGCTGTGAGGAAATCCATCTACCGCTATG ACC

TGGCCTCGGGAGCCACCGAGCAGTTGCCTCTCACCGGGCTACGGGCAGCAGTGGCCC TGG

ACTTTGACTATGAGCACAACTGTTTGTATTGGTCCGACCTGGCCTTGGACGTCATCC AGC

GCCTCTGTTTGAATGGAAGCACAGGGCAAGAGGTGATCATCAATTCTGGCCTGGAGA CAG

T AG AAGCTTT GGCTTTT G AACCCCT CAGCCAGCTGCTTT ACT GGGT AG AT GCAGGCTT CA

AAAAGATTGAGGTAGCTAATCCAGATGGCGACTTCCGACTCACAATCGTCAATTCCT CTG

TGCTTGATCGTCCCAGGGCTCTGGTCCTCGTGCCCCAAGAGGGGGTGATGTTCTGGA CAG

ACTGGGGAGACCTGAAGCCTGGGATTTATCGGAGCAATATGGATGGTTCTGCTGCCT ATC

ACCTGGTGTCTGAGGATGTGAAGTGGCCCAATGGCATCTCTGTGGACGACCAGTGGA TTT

ACTGGACGGATGCCTACCTGGAGTGCATAGAGCGGATCACGTTCAGTGGCCAGCAGC GCT

CTGTCATTCTGGACAACCTCCCGCACCCCTATGCCATTGCTGTCTTTAAGAATGAAA TCT

ACTGGGATGACTGGTCACAGCTCAGCATATTCCGAGCTTCCAAATACAGTGGGTCCC AGA

TGGAGATTCTGGCAAACCAGCTCACGGGGCTCATGGACATGAAGATTTTCTACAAGG GGA

AGAACACT GGAAGCAAT GCCT GT GTGCCCAGGCCAT GCAGCCT GCTGTGCCT GCCCAAGG

CCAACAACAGTAGAAGCT GCAGGTGTCCAGAGGAT GT GTCCAGCAGT GT GCTTCCATCAG

GGGACCTGATGTGTGACTGCCCTCAGGGCTATCAGCTCAAGAACAATACCTGTGTCA AAG

AAGAGAACACCTGTCTTCGCAACCAGTATCGCTGCAGCAACGGGAACTGTATCAACA GCA

TTTGGT GGTGTGACTTT GACAACG ACTGTGG AG ACAT GAGCG AT G AG AG AAACTGCCCT A

CCACCATCTGTGACCTGGACACCCAGTTTCGTTGCCAGGAGTCTGGGACTTGTATCC CAC TGTCCT AT AAATGTG ACCTT GAGG AT GACTGTGG AGACAAC AGTG AT GAAAGTCATT GT G

AAATGCACCAGTGCCGGAGTGACGAGTACAACTGCAGTTCCGGCATGTGCATCCGCT CCT

CCTGGGTATGTGACGGGGACAACGACTGCAGGGACTGGTCTGATGAAGCCAACTGTA CCG

CCATCTATCACACCTGTGAGGCCTCCAACTTCCAGTGCCGAAACGGGCACTGCATCC CCC

AGCGGTGGGCGTGTGACGGGGATACGGACTGCCAGGATGGTTCCGATGAGGATCCAG TCA

ACTGTGAGAAGAAGTGCAATGGATTCCGCTGCCCAAACGGCACTTGCATCCCATCCA GCA

AACATTGTGATGGTCTGCGTGATTGCTCTGATGGCTCCGATGAACAGCACTGCGAGC CCC

TCTGTACGCACTTCATGGACTTTGTGTGTAAGAACCGCCAGCAGTGCCTGTTCCACT CCA

TGGTCTGTGACGGAATCATCCAGTGCCGCGACGGGTCCGATGAGGATGCGGCGTTTG CAG

GAT GCTCCCAAGATCCT GAGTTCCACAAGGTAT GT GATGAGTTCGGTTTCCAGT GTCAGA

ATGGAGTGTGCATCAGTTTGATTTGGAAGTGCGACGGGATGGATGATTGCGGCGATT ATT

CTGATGAAGCCAACTGCGAAAACCCCACAGAAGCCCCAAACTGCTCCCGCTACTTCC AGT

TTCGGTGTG AG AATGGCCACTGCATCCCCAAC AG ATGGAAAT GT GACAGGG AG AACG ACT

GTGGGGACTGGTCTGATGAGAAGGATTGTGGAGATTCACATATTCTTCCCTTCTCGA CTC

CT GGGCCCTCCACGT GTCT GCCCAATTACTACCGCT GCAGCAGT GGGACCTGCGT GATGG

ACACCTGGGTGTGCGACGGGTACCGAGATTGTGCAGATGGCTCTGACGAGGAAGCCT GCC

CCTTGCTTGCAAACGTCACTGCTGCCTCCACTCCCACCCAACTTGGGCGATGTGACC GAT

TTGAGTTCGAATGCCACCAACCGAAGACGTGTATTCCCAACTGGAAGCGCTGTGACG GCC

ACCAAGATTGCCAGGATGGCCGGGACGAGGCCAATTGCCCCACACACAGCACCTTGA CTT

GCATGAGCAGGGAGTTCCAGTGCGAGGACGGGGAGGCCTGCATTGTGCTCTCGGAGC GCT

GCGACGGCTTCCTGGACTGCTCGGACGAGAGCGATGAAAAGGCCTGCAGTGATGAGT TGA

CTGTGTACAAAGTACAGAATCTTCAGTGGACAGCTGACTTCTCTGGGGATGTGACTT TGA

CCTGGATGAGGCCCAAAAAAATGCCCTCTGCATCTTGTGTATATAATGTCTACTACA GGG

TGGTTGGAGAGAGCATATGGAAGACTCTGGAGACCCACAGCAATAAGACAAACACTG TAT

TAAAAGTCTTGAAACCAGATACCACGTATCAGGTTAAAGTACAGGTTCAGTGTCTCA GCA

AGGCACACAACACCAATGACTTTGTGACCCTGAGGACCCCAGAGGGATTGCCAGATG CCC

CTCGAAATCTCCAGCTGTCACTCCCCAGGGAAGCAGAAGGTGTGATTGTAGGCCACT GGG

CTCCTCCCATCCACACCCATGGCCTCATCCGTGAGTACATTGTAGAATACAGCAGGA GTG

GTTCCAAGATGTGGGCCTCCCAGAGGGCTGCTAGTAACTTTACAGAAATCAAGAACT TAT

TGGTCAACACTCTATACACCGTCAGAGTGGCTGCGGTGACTAGTCGTGGAATAGGAA ACT

GGAGCGATTCTAAATCCATTACCACCATAAAAGGAAAAGTGATCCCACCACCAGATA TCC

ACATTGACAGCTATGGTGAAAATTATCTAAGCTTCACCCTGACCATGGAGAGTGATA TCA

AGGTGAATGGCTATGTGGTGAACCTTTTCTGGGCATTTGACACCCACAAGCAAGAGA GGA

G AACTTT GAACTTCCG AGG AAGCAT ATT GT CAC ACAAAGTTGGCAAT CT G ACAGCTCAT A

CATCCTATGAGATTTCTGCCTGGGCCAAGACTGACTTGGGGGATAGCCCTCTGGCAT TTG

AGCATGTTATGACCAGAGGGGTTCGCCCACCTGCACCTAGCCTCAAGGCCAAAGCCA TCA

ACCAGACTGCAGTGGAATGTACCTGGACCGGCCCCCGGAATGTGGTTTATGGTATTT TCT

ATGCCACGTCCTTT CTT GACCT CT ATCGCAACCCG AAG AGCTT GACTACTTCACTCCAC A

ACAAGACGGTCATTGTCAGTAAGGATGAGCAGTATTTGTTTCTGGTCCGTGTAGTGG TAC

CCTACCAGGGGCCATCCTCTGACTACGTTGTAGTGAAGATGATCCCGGACAGCAGGC TTC

CACCCCGTCACCTGCATGTGGTTCATACGGGCAAAACCTCCGTGGTCATCAAGTGGG AAT

CACCGTATGACTCTCCTGACCAGGACTTGTTGTATGCAATTGCAGTCAAAGATCTCA TAA G AAAGACT G ACAGG AGCTACAAAGT AAAATCCCGTAACAGC ACT GT GG AAT ACACCCTT A

ACAAGTTGGAGCCTGGCGGGAAATACCACATCATTGTCCAACTGGGGAACATGAGCA AAG

ATTCCAGCATAAAAATTACCACAGTTTCATTATCAGCACCTGATGCCTTAAAAATCA TAA

CAGAAAATGATCATGTTCTTCTGTTTTGGAAAAGCCTGGCTTTAAAGGAAAAGCATT TTA

ATGAAAGCAGGGGCTATGAGATACACATGTTTGATAGTGCCATGAATATCACAGCTT ACC

TTGG G AAT ACTACT G AC AATTT CTTT AAAATTTCC AAC CT G AAG AT G GGTC AT AATT AC A

CGTTCACCGTCCAAGCAAGATGCCTTTTTGGCAACCAGATCTGTGGGGAGCCTGCCA TCC

TGCTGTACGATGAGCTGGGGTCTGGTGCAGATGCATCTGCAACGCAGGCTGCCAGAT CTA

CGGATGTTGCTGCTGTGGTGGTGCCCATCTTATTCCTGATACTGCTGAGCCTGGGGG TGG

GGTTTGCCATCCTGTACACGAAGCACCGGAGGCTGCAGAGCAGCTTCACCGCCTTCG CCA

ACAGCCACTACAGCTCCAGGCTGGGGTCCGCAATCTTCTCCTCTGGGGATGACCTGG GGG

AAG AT GAT G AAG ATGCCCCTAT GAT AACT GG ATTTTCAGAT G ACGTCCCCAT GGTGATAG

CCT GAAAGAGCTTTCCT CACT AG AAACC AAATGGT GT AAAT ATTTT ATTT GAT AAAG AT A

GTTGATGGTTTATTTTAAAAGATGCACTTTGAGTTGCAATATGTTATTTTTATATGG GCC

(SEQ ID NO: 65)

As used herein, the term “SPM” refers to the gene encoding Transcription factor PU.1 . The terms “SPIT’ and "Transcription factor PU.1" include wild-type forms of the SPI1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type SPIT Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type SPI1 nucleic acid sequence (e.g., SEQ ID NO: 66, ENA accession number X52056). SEQ ID NO: 66 is a wild-type gene sequence encoding SPI1 protein, and is shown below:

AAAATCAGGAACTTGTGCTGGCCCTGCAATGTCAAGGGAGGGGGCTCACCCAGGGCT CCT

GTAGCTCAGGGGGCAGGCCTGAGCCCTGCACCCGCCCCACGACCGTCCAGCCCCTGA CGG

GCACCCCATCCTGAGGGGCTCTGCATTGGCCCCCACCGAGGCAGGGGATCTGACCGA CTC

GGAGCCCGGCTGGATGTTACAGGCGTGCAAAATGGAAGGGTTTCCCCTCGTCCCCCC TCC

ATCAGAAGACCTGGTGCCCTATGACACGGATCTATACCAACGCCAAACGCACGAGTA TTA

CCCCTATCTCAGCAGTGATGGGGAGAGCCATAGCGACCATTACTGGGACTTCCACCC CCA

CCACGTGCACAGCGAGTTCGAGAGCTTCGCCGAGAACAACTTCACGGAGCTCCAGAG CGT

GCAGCCCCCGCAGCTGCAGCAGCTCTACCGCCACATGGAGCTGGAGCAGATGCACGT CCT

CGATACCCCCATGGTGCCACCCCATCCCAGTCTTGGCCACCAGGTCTCCTACCTGCC CCG

GATGTGCCTCCAGTACCCATCCCTGTCCCCAGCCCAGCCCAGCTCAGATGAGGAGGA GGG

CGAGCGGCAGAGCCCCCCACTGGAGGTGTCTGACGGCGAGGCGGATGGCCTGGAGCC CGG

GCCTGGGCTCCTGCCTGGGGAGACAGGCAGCAAGAAGAAGATCCGCCTGTACCAGTT CCT

GTTGGACCTGCTCCGCAGCGGCGACATGAAGGACAGCATCTGGTGGGTGGACAAGGA CAA

GGGCACCTTCCAGTTCTCGTCCAAGCACAAGGAGGCGCTGGCGCACCGCTGGGGCAT CCA

GAAGGGCAACCGCAAGAAGATGACCTACCAGAAGATGGCGCGCGCGCTGCGCAACTA CGG

CAAGACGGGCGAGGTCAAGAAGGTGAAGAAGAAGCTCACCTACCAGTTCAGCGGCGA AGT

GCTGGGCCGCGGGGGCCTGGCCGAGCGGCGCCACCCGCCCCACTGAGCCCGCAGCCC CCG CCGGCCCCGCCAGGCCTCCCCGCTGGCCATAGCATTAAGCCCTCGCCCGGCCCGGACACA

GGGAGGACGCTCCCGGGGCCCAGAGGCAGGACTGTGGCGGGCCGGGCTCCGTCACCC GCC

CCTCCCCCCACTCCAGGCCCCCTCCACATCCCGCTTCGCCTCCCTCCAGGACTCCAC CCC

GGCTCCCGACGCCAGCTGGGCGTCAGACCCACCGGCAACCTTGCAGAGGACGACCCG GGG

TACTGCCTTGGGAGTCTCAAGTCCGTATGTAAATCAGATCTCCCCTCTCACCCCTCC CAC

CCATTAACCTCCTCCCAAAAAACAAGTAAAGTTATTCTCAATCC

(SEQ ID NO: 66)

As used herein, the term “SPP1” refers to the gene encoding Secreted Phosphoprotein 1 . The terms “SPP1” and "Secreted Phosphoprotein 1" include wild-type forms of the SPP1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type SPP1. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type SPP1 nucleic acid sequence (e.g., SEQ ID NO: 67, NCBI Reference Sequence: NM_001040058.1). SEQ ID NO: 67 is a wild-type gene sequence encoding SPP1 protein, and is shown below:

CTCCCTGTGTTGGTGGAGGATGTCTGCAGCAGCATTTAAATTCTGGGAGGGCTTGGT TGTCAGCAG

CAGCAGGAGGAGGCAGAGCACAGCATCGTCGGGACCAGACTCGTCTCAGGCCAGTTG CAGCCTTC

TCAGCCAAACGCCGACCAAGGAAAACTCACTACCATGAGAATTGCAGTGATTTGCTT TTGCCTCCTA

GGCATCACCTGTGCCATACCAGTTAAACAGGCTGATTCTGGAAGTTCTGAGGAAAAG CAGCTTTACA

ACAAATACCCAGATGCTGTGGCCACATGGCTAAACCCTGACCCATCTCAGAAGCAGA ATCTCCTAGC

CCCACAGAAT GCT GT GTCCTCT G AAG AAACCAAT G ACTTT AAACAAG AGACCCTTCCAAGTAAGTCC

AACG AAAGCC AT GACCACATGGAT GAT ATGG AT GAT GAAG AT GAT GAT G ACCAT GT GG ACAGCCAG

GACTCCATTGACTCGAACGACTCTGATGATGTAGATGACACTGATGATTCTCACCAG TCTGATGAGT

CT CACC ATT CT GAT GAAT CT GAT GAACT GGTCACT GATTTTCCCACGG ACCT GCCAGCAACCG AAGT

TTTCACTCCAGTTGTCCCCACAGTAGACACATATGATGGCCGAGGTGATAGTGTGGT TTATGGACTG

AGGTCAAAATCTAAGAAGTTTCGCAGACCTGACATCCAGTACCCTGATGCTACAGAC GAGGACATCA

CCTCACACATGGAAAGCGAGGAGTTGAATGGTGCATACAAGGCCATCCCCGTTGCCC AGGACCTGA

ACGCGCCTTCT GATT GGGACAGCCGT GGGAAGGACAGTTAT GAAACGAGTCAGCT GGAT GACCAGA

GTGCT GAAACCCACAGCCAC AAGC AGTCCAGATT ATAT AAGCGGAAAGCCAAT GAT G AG AGCAAT G A

GCATTCCGATGTGATTGATAGTCAGGAACTTTCCAAAGTCAGCCGTGAATTCCACAG CCATGAATTTC

ACAGCCAT GAAGAT ATGCTGGTT GT AG ACCCC AAAAGTAAGG AAG AAGAT AAACACCT G AAATTTCG

T ATTT CT CAT G AATT AG AT AGT GC AT CTTCT G AGGTC AATT AAAAG G AG AAAAAAT AC AATTT CTC ACT

TTGCATTTAGT CAAAAGAAAAAATGCTTT AT AGCAAAAT GAAAGAG AAC AT GAAAT GCTTCTTTCT CAG

TTTATTGGTTGAATGTGTATCTATTTGAGTCTGGAAATAACTAATGTGTTTGATAAT TAGTTTAGTTTGT

GGCTTCATGGAAACTCCCTGTAAACTAAAAGCTTCAGGGTTATGTCTATGTTCATTC TATAGAAGAAA

T GC AAACT ATC ACTGT ATTTT AAT ATTT GTT ATT CTCT CAT GAAT AG AAATTT AT GTAG AAG C AAAC AAA

ATACTTTTACCCACTTAAAAAGAGAATATAACATTTTATGTCACTATAATCTTTTGT TTTTTAAGTTAGT

GTATATTTTGTTGTGATTATCTTTTTGTGGTGTGAATAAATCTTTTATCTTGAATGT AATAAGAATTTGG

TGGTGTCAATTGCTTATTTGTTTTCCCACGGTTGTCCAGCAATTAATAAAACATAAC CTTTTTTACTGC

CT AAAAAAAAAAAAAAAAA (SEQ ID NO: 67)

As used herein, the term “SPPL2A” refers to the gene encoding Signal Peptide Peptidase Like 2A. The terms “SPPL2A” and "Signal Peptide Peptidase Like 2A" include wild-type forms of the SPPL2A gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type SPPL2A. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type SPPL2A nucleic acid sequence (e.g., SEQ ID NO: 68, NCBI Reference Sequence: NM_001040058.1). SEQ ID NO: 68 is a wild-type gene sequence encoding SPPL2A protein, and is shown below:

AAGAGGAAGTCGCGCTGCTGTGGCGGCCGCTGTAGCAGCGGCGGTCCAGTCGTAGCC CGGCCGC

CCGCGCCTGTCCGGTCCGGTCCGGCCACGGAGGCAGCGCAGCGGCGGGACTCCGAGC CTACCCC

GCCGAGTGAGCTGCGCCGCACCGTGCCGTCCCACCCGGCACCCACCAGTCCGATGGG GCCGCAG

CGGCGGCTGTCCCCTGCCGGGGCCGCCCTACTCTGGGGCTTCCTGCTCCAGCTGACA GCCGCTCA

GGAAGCAATCTTGCATGCGTCTGGAAATGGCACAACCAAGGACTACTGCATGCTTTA TAACCCTTATT

GGACAGCT CTTCCAAGTACCCT AGAAAAT GCAACTTCCATTAGTTT GAT G AATCT GACTTCCACACCA

CTATGCAACCTTTCTGATATTCCTCCTGTTGGCATAAAGAGCAAAGCAGTTGTGGTT CCATGGGGAA

GCTGCCATTTT CTT GAAAAAGCCAGAATT GCACAG AAAGG AGGTGCT G AAGC AATGTT AGTTGTCAA

T AACAGTGTCCT ATTTCCTCCCT CAGGT AAC AG AT CT GAATTTCCT GAT GT GAAAAT ACT GATT GCATT

TATAAGCT AC AAAG ACTTT AG AG AT AT G AAC C AG ACT CT AGG AG AT AAC ATT ACTGT G AAAATGTATT

CTCCATCGTGGCCTAACTTTGATTATACTATGGTGGTTATTTTTGTAATTGCGGTGT TCACTGTGGCA

TT AG GTGG ATACT GG AGTG G ACT AGTT G AATT GG AAAACTT G AAAG C AGT G AC AACT G AAG AT AG AG

AAAT G AGG AAAAAG AAG G AAG AAT ATTT AACTTTT AGTCCTCTT AC AGTT GT AAT ATTTGTG GT CAT CT

GCTGTGTTATGATGGTCTTACTTTATTTCTTCTACAAATGGTTGGTTTATGTTATGA TAGCAATTTTCTG

CATAGCATCAGCAATGAGTCTGTACAACTGTCTTGCTGCACTAATTCATAAGATACC ATATGGACAAT

GCACGATTGCATGTCGTGGCAAAAACATGGAAGTGAGACTTATTTTTCTCTCTGGAC TGTGCATAGC

AGTAGCTGTTGTTTGGGCTGTGTTTCGAAATGAAGACAGGTGGGCTTGGATTTTACA GGATATCTTG

GGGATTGCTTTCTGTCTGAATTTAATTAAAACACTGAAGTTGCCCAACTTCAAGTCA TGTGTGATACTT

CT AGGCCTT CTCCTCCT CTAT G ATGTATTTTTT GTTTT CAT AACACCATT CAT CACAAAG AAT GGTG AG

AGTATCATGGTTGAACTCGCAGCTGGACCTTTTGGAAATAATGAAAAGTTGCCAGTA GTCATCAGAGT

ACCAAAACTGATCTATTTCTCAGTAATGAGTGTGTGCCTCATGCCTGTTTCAATATT GGGTTTTGGAG

ACATT ATT GT ACC AGGCCTGTT G ATTGCAT ACT GT AGAAGATTT GATGTT CAG ACT GGTT CTT CTT AC A

TATACTATGTTTCGTCTACAGTTGCCTATGCTATTGGCATGATACTTACATTTGTTG TTCTGGTGCTGA

TGAAAAAGGGGCAACCTGCTCTCCTCTATTTAGTACCTTGCACACTTATTACTGCCT CAGTTGTTGCC

TGGAGACGTAAGGAAATGAAAAAGTTCTGGAAAGGTAACAGCTATCAGATGATGGAC CATTTGGATT

GTGCAACAAATGAAGAAAACCCTGTGATATCTGGTGAACAGATTGTCCAGCAATAAT ATTATGTGGAA

CTGCTAT AATGTGTC ATT G ATTTT CT AC AAAT AG ACTTCG ACTTTTT AAATT G ACTTTT G AATT G AC AAT

CT GAAAGAGT CTT CAAT GAT AT GCTT GCAAAAAT ATATTTTT AT GAGCT GGTACT G ACAGTT ACATC AT

AAAT AACT AAAAC GCTTT GCTTTT AAT GTT AAAGTT GTGCCTT C AC ATT AAAT AAAAC AT ATGGTCTGT

GTAGTTTCCG AG AT GTACTATAT AC AGTAT ATTTTT CT AAAAAAAAA

(SEQ ID NO: 68) As used herein, the term “TBK refers to the gene encoding Serine/threonine-protein kinase TBK1. The terms “TBK and "Serine/threonine-protein kinase TBK1" include wild-type forms of the TBK1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type TBK1 . Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type TBK1 nucleic acid sequence (e.g., SEQ ID NO: 69, ENA accession number AF191838). SEQ ID NO: 69 is a wild-type gene sequence encoding TBK1 protein, and is shown below:

GCCGGCGGTGGCGCGGCGGAGACCCGGCTGGTATAACAAGAGGATTGCCTGATCCAG CCA

AGATGCAGAGCACTTCTAATCATCTGTGGCTTTTATCTGATATTTTAGGCCAAGGAG CTA

CT GCAAATGTCTTTCGT GGAAG ACAT AAG AAAACTGGT GATTT ATTT GCT AT CAAAGT AT

TTAATAACATAAGCTTCCTTCGTCCAGTGGATGTTCAAATGAGAGAATTTGAAGTGT TGA

AAAAACT C AAT C AC AAAAAT ATTGTC AAATT ATTT GCT ATT G AAG AG G AG AC AAC AAC AA

G AC AT AAAGT ACTT ATT AT G G AATTTT GTCC AT GT G GG AGTTT AT AC ACT GTTTT AG AAG

AACCTTCTAATGCCTATGGACTACCAGAATCTGAATTCTTAATTGTTTTGCGAGATG TGG

TGGGTGGAATGAATCATCTACGAGAGAATGGTATAGTGCACCGTGATATCAAGCCAG GAA

ATATCATGCGTGTTATAGGGGAAGATGGACAGTCTGTGTACAAACTCACAGATTTTG GTG

CAGCT AG AG AATTAGAAG AT GAT GAGC AGTTTGTTT CTCT GT AT GGCACAG AAG AAT ATT

TGC ACCCT GAT ATGTAT GAG AG AG C AGTG CT AAG AAAAG AT CAT C AG AAG AAAT AT GG AG

CAACAGTTGATCTTTGGAGCATTGGGGTAACATTTTACCATGCAGCTACTGGATCAC TGC

CATTTAGACCCTTTGAAGGGCCTCGTAGGAATAAAGAAGTGATGTATAAAATAATTA CAG

GAAAGCCTTCTGGTGCAATATCTGGAGTACAGAAAGCAGAAAATGGACCAATTGACT GGA

GTGGAGACATGCCTGTTTCTTGCAGTCTTTCTCGGGGTCTTCAGGTTCTACTTACCC CTG

TTCTTGCAAACATCCTTGAAGCAGATCAGGAAAAGTGTTGGGGTTTTGACCAGTTTT TTG

CAGAAACTAGTGATATACTTCACCGAATGGTAATTCATGTTTTTTCGCTACAACAAA TGA

CAGCT CAT AAG ATTT AT ATT CAT AG CTAT AAT ACTGCTACTAT ATTT CAT GAACTGGTAT

ATAAACAAACCAAAATTATTTCTTCAAATCAAGAACTTATCTACGAAGGGCGACGCT TAG

TCTTAGAACCTGGAAGGCTGGCACAACATTTCCCTAAAACTACTGAGGAAAACCCTA TAT

TTGTAGTAAGCCGGGAACCTCTGAATACCATAGGATTAATATATGAAAAAATTTCCC TCC

CTAAAGTACATCCACGTTATGATTTAGACGGGGATGCTAGCATGGCTAAGGCAATAA CAG

GGGTTGTGTGTTATGCCTGCAGAATTGCCAGTACCTTACTGCTTTATCAGGAATTAA TGC

G AAAGGGGATACG AT GGCT GATT GAATT AATT AAAGAT G ATTAC AAT G AAACT GTT CACA

AAAAG AC AGAAGTTGTG AT CAC ATTGG ATTT CTGTAT CAG AAACATT GAAAAAACTGTG A

AAGTATATGAAAAGTTGATGAAGATCAACCTGGAAGCGGCAGAGTTAGGTGAAATTT CAG

ACATACACACCAAATTGTTGAGACTTTCCAGTTCTCAGGGAACAATAGAAACCAGTC TTC

AGGATATCGACAGCAGATTATCTCCAGGTGGATCACTGGCAGACGCATGGGCACATC AAG

AAGGCACTCATCCGAAAGACAGAAATGTAGAAAAACTACAAGTCCTGTTAAATTGCA TGA

CAG AG ATTT ACTAT C AGTT C AAAA AAG AC AAAGC AG AACGT AG ATT AG CTT AT AAT G AAG

AACAAATCCACAAATTTGATAAGCAAAAACTGTATTACCATGCCACAAAAGCTATGA CGC

ACTTTACAGATGAATGTGTTAAAAAGTATGAGGCATTTTTGAATAAGTCAGAAGAAT GGA TAAGAAAGATGCTTCATCTTAGGAAACAGTTATTATCGCTGACTAATCAGTGTTTTGATA

TT G AAG AAG AAGTAT C AAAAT AT C AAG AAT ATACT A AT G AGTT AC AAG AAACTCTG CCT C

AGAAAATGTTTACAGCTTCCAGTGGAATCAAACATACCATGACCCCAATTTATCCAA GTT

CT AAC AC ATT AGT AG AAAT G ACTCTTG GTAT G AAG AAATT AAAG G AAG AG AT GG AAGG GG

TGGTTAAAGAACTTGCTGAAAATAACCACATTTTAGAAAGGTTTGGCTCTTTAACCA TGG

ATGGTGGCCTTCGCAACGTTGACTGTCTTTAGCTTTCTAATAGAAGTTTAAGAAAAG TTT

CCGTTTGCACAAGAAAATAACGCTTGGGCATTAAATGAATGCCTTTATAGATAGTCA CTT

GTTTCTACAATTCAGTATTTGATGTGGTCGTGTAAATATGTACAATATTGTAAATAC ATA

AAAAAT AT AC AAATTTTT GGCTGCTGT G AAG AT GT AATTTT AT CTTTT AAC ATTT AT AAT

T ATAT G AGG AAATTT G ACCTCAGT GAT CACGAG AAG AAAGCCAT G ACCG ACCAAT ATGTT

GACATACTGATCCTCTACTCTGAGTGGGGCTAAATAAGTTATTTTCTCTGACCGCCT ACT

GGAAATATTTTTAAGTGGAACCAAAATAGGCATCCTTACAAATCAGGAAGACTGACT TGA

CACGTTTGTAAATGGTAGAACGGTGGCTACTGTGAGTGGGGAGCAGAACCGCACCAC TGT

TATACTGGGATAACAATTTTTTTGAGAAGGATAAAGTGGCATTATTTTATTTTACAA GGT

GCCCAGATCCCAGTT ATCCTT GT ATCCAT GT AATTTCAG AT GAATT ATT AAGC AAACATT

TTAAAGT

(SEQ ID NO: 69)

As used herein, the term “TNF” refers to the gene encoding Tumor necrosis factor. The terms “TNF” and "Tumor necrosis factor" include wild-type forms of the TNF gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type TNF. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%,

81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type TNF nucleic acid sequence (e.g., SEQ ID NO: 70, ENA accession number X01394). SEQ ID NO: 70 is a wild-type gene sequence encoding TNF protein, and is shown below:

GCAGAGGACCAGCTAAGAGGGAGAGAAGCAACTACAGACCCCCCCTGAAAACAACCC TCA

GACGCCACATCCCCTGACAAGCTGCCAGGCAGGTTCTCTTCCTCTCACATACTGACC CAC

GGCTCCACCCTCTCTCCCCTGGAAAGGACACCATGAGCACTGAAAGCATGATCCGGG ACG

TGGAGCTGGCCGAGGAGGCGCTCCCCAAGAAGACAGGGGGGCCCCAGGGCTCCAGGC GGT

GCTTGTTCCTCAGCCTCTTCTCCTTCCTGATCGTGGCAGGCGCCACCACGCTCTTCT GCC

TGCTGCACTTTGGAGTGATCGGCCCCCAGAGGGAAGAGTTCCCCAGGGACCTCTCTC TAA

TCAGCCCTCTGGCCCAGGCAGTCAGATCATCTTCTCGAACCCCGAGTGACAAGCCTG TAG

CCCATGTTGTAGCAAACCCTCAAGCTGAGGGGCAGCTCCAGTGGCTGAACCGCCGGG CCA

ATGCCCTCCTGGCCAATGGCGTGGAGCTGAGAGATAACCAGCTGGTGGTGCCATCAG AGG

GCCTGTACCTCATCTACTCCCAGGTCCTCTTCAAGGGCCAAGGCTGCCCCTCCACCC ATG

TGCTCCTCACCCACACCATCAGCCGCATCGCCGTCTCCTACCAGACCAAGGTCAACC TCC

TCTCTGCCATCAAGAGCCCCTGCCAGAGGGAGACCCCAGAGGGGGCTGAGGCCAAGC CCT

GGTATGAGCCCATCTATCTGGGAGGGGTCTTCCAGCTGGAGAAGGGTGACCGACTCA GCG

CTGAGATCAATCGGCCCGACTATCTCGACTTTGCCGAGTCTGGGCAGGTCTACTTTG GGA

TCATTGCCCTGTGAGGAGGACGAACATCCAACCTTCCCAAACGCCTCCCCTGCCCCA ATC CCTTTATTACCCCCTCCTTCAGACACCCTCAACCTCTTCTGGCTCAAAAAGAGAATTGGG

GGCTTAGGGTCGGAACCCAAGCTTAGAACTTTAAGCAACAAGACCACCACTTCGAAA CCT

GGGATTCAGGAATGTGTGGCCTGCACAGTGAATTGCTGGCAACCACTAAGAATTCAA ACT

GGGGCCTCCAGAACTCACTGGGGCCTACAGCTTTGATCCCTGACATCTGGAATCTGG AGA

CCAGGGAGCCTTTGGTTCTGGCCAGAATGCTGCAGGACTTGAGAAGACCTCACCTAG AAA

TTGACACAAGTGGACCTTAGGCCTTCCTCTCTCCAGATGTTTCCAGACTTCCTTGAG ACA

CGGAGCCCAGCCCTCCCCATGGAGCCAGCTCCCTCTATTTATGTTTGCACTTGTGAT TAT

TT ATT ATTT ATTT ATT ATTT ATTT ATTT AC AG AT GAAT GT ATTT ATTT G GG AG AC CGG GG

TATCCTGGGGGACCCAATGTAGGAGCTGCCTTGGCTCAGACATGTTTTCCGTGAAAA CGG

AGCTGAACAATAGGCTGTTCCCATGTAGCCCCCTGGCCTCTGTGCCTTCTTTTGATT ATG

TTTTTT AAAAT ATTT ATCT GATT AAGTTGTCTAAACAAT GCT GATTTGGTG ACC AACTGT

CACTCATTGCTGAGCCTCTGCTCCCCAGGGGAGTTGTGTCTGTAATCGCCCTACTAT TCA

GTGGCGAGAAAT AAAGTTTGCTT

(SEQ ID NO: 70)

As used herein, the term “TREM2” refers to the gene encoding Triggering receptor expressed on myeloid cells 2. The terms “TREM2” and "Triggering receptor expressed on myeloid cells 2" include wild- type forms of the TREM2 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type TREM2. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type TREM2 nucleic acid sequence (e.g., SEQ ID NO: 71 , ENA accession number AF213457). SEQ ID NO: 71 is a wild-type gene sequence encoding TREM2 protein, and is shown below:

TGACATGCCTGATCCTCTCTTTTCTGCAGTTCAAGGGAAAGACGAGATCTTGCACAA GGC

ACTCTGCTTCTGCCCTTGGCTGGGGAAGGGTGGCATGGAGCCTCTCCGGCTGCTCAT CTT

ACTCTTTGTCACAGAGCTGTCCGGAGCCCACAACACCACAGTGTTCCAGGGCGTGGC GGG

CCAGTCCCTGCAGGTGTCTTGCCCCTATGACTCCATGAAGCACTGGGGGAGGCGCAA GGC

CTGGTGCCGCCAGCTGGGAGAGAAGGGCCCATGCCAGCGTGTGGTCAGCACGCACAA CTT

GTGGCTGCTGTCCTTCCTGAGGAGGTGGAATGGGAGCACAGCCATCACAGACGATAC CCT

GGGTGGCACTCTCACCATTACGCTGCGGAATCTACAACCCCATGATGCGGGTCTCTA CCA

GTGCCAGAGCCTCCATGGCAGTGAGGCTGACACCCTCAGGAAGGTCCTGGTGGAGGT GCT

GGCAGACCCCCTGGATCACCGGGATGCTGGAGATCTCTGGTTCCCCGGGGAGTCTGA GAG

CTTCGAGGATGCCCATGTGGAGCACAGCATCTCCAGGAGCCTCTTGGAAGGAGAAAT CCC

CTTCCCACCCACTTCCATCCTTCTCCTCCTGGCCTGCATCTTTCTCATCAAGATTCT AGC

AGCCAGCGCCCTCTGGGCTGCAGCCTGGCATGGACAGAAGCCAGGGACACATCCACC CAG

TGAACTGGACTGTGGCCATGACCCAGGGTATCAGCTCCAAACTCTGCCAGGGCTGAG AGA

CACGTGAAGGAAGATGATGGGAGGAAAAGCCCAGGAGAAGTCCCACCAGGGACCAGC CCA

GCCTGCATACTTGCCACTTGGCCACCAGGACTCCTTGTTCTGCTCTGGCAAGAGACT ACT

CTGCCTGAACACTGCTTCTCCTGGACCCTGGAAGCAGGGACTGGTTGAGGGAGTGGG GAG

GTGGTAAG AACACCT GACAACTTCT GAAT ATT GG ACATTTT AAACACTT ACAAATAAAT C

C AAG ACT GT CAT ATTT AAAAA (SEQ ID NO: 71)

As used herein, the term “TREML2” refers to the gene encoding Triggering Receptor Expressed on Myeloid Cells Like 2. The terms “TREML2” and "Triggering Receptor Expressed on Myeloid Cells Like 2" include wild-type forms of the TREML2 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type TREML2. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type TREML2 nucleic acid sequence (e.g., SEQ ID NO: 72, NCBI Reference Sequence: NM_024807.3). SEQ ID NO: 72 is a wild-type gene sequence encoding TREML2 protein, and is shown below:

CAATGAATCCCTGCGGTTGGCTGGGGGCAGTGGGTCCCACACTGCCTCACTTCCCTA AATGGGCAG

CTTCACTTTTAGAACCCCGGGTCCTTCCCTGGCAGGCCCAGGTGGCACATCCTGTGT CGGGTGGGC

CCTCACCTTGGATCTCCAGGCCTGACACTGCCCAGCTGGATGGAACCATGGCCCCAG CCTTCCTGC

TGCTGCTGCTGCTGTGGCCACAGGGTTGCGTCTCAGGCCCCTCTGCTGACAGTGTAT ACACAAAAG

TGAGGCTCCTTGAAGGGGAGACTCTGTCTGTGCAGTGCTCCTATAAGGGCTACAAAA ACCGCGTGG

AGGGCAAGGTTTGGTGCAAAATCAGGAAGAAGAAGTGTGAGCCTGGCTTTGCCCGAG TCTGGGTGA

AAGGGCCCCGCTACTTGCTGCAGGACGATGCCCAGGCCAAGGTGGTCAACATCACCA TGGTGGCC

CTCAAGCTCCAGGACTCAGGCCGATACTGGTGCATGCGCAACACCTCTGGGATCCTG TACCCCTTG

ATGGGCTTCCAGCT GG AT GT GT CTCCAGCTCCCC AAACT G AG AGG AACATTCCTTT CAC ACAT CTGG

ACAACATCCTCAAGAGTGGAACTGTCACAACTGGCCAAGCCCCTACCTCAGGCCCTG ATGCCCCTTT

TACCACTGGTGTGATGGTGTTCACCCCAGGACTCATCACCTTGCCTAGGCTCTTAGC CTCCACCAGA

CCTGCCTCCAAGACAGGCTACAGCTTCACTGCTACCAGCACCACCAGCCAGGGACCC AGGAGGACC

ATGGGGTCCCAGACAGTGACCGCGTCTCCCAGCAATGCCAGGGACTCCTCTGCTGGC CCAGAATCC

ATCTCCACTAAGTCTGGGGACCTCAGCACCAGATCGCCCACCACAGGGCTCTGCCTC ACCAGCAGA

TCTCTCCTCAACAGACTACCCTCCATGCCCTCCATCAGGCACCAGGATGTTTACTCC ACTGTGCTTG

GGGTGGTGCTGACCCTCCTGGTGCTGATGCTGATCATGGTCTATGGGTTTTGGAAGA AGAGACACA

TGGCAAGCTACAGCATGTGCAGCGATCCTTCTACACGTGACCCACCTGGAAGACCAG AGCCCTATG

TGGAAGTCTACTTGATCTGAGGCCACTTAAGCATGGGGTGGGGAGCTTCTCCCAGAG TGGCCCCAG

GGGGTTAGAGGAGGGGTGAAGATTGGGGCCAGTATCGATCTTATGAAGCTGGAGGAC TTGTGCAGT

GCTGGACTCACCCAGGACTTCCCAAACCCAGAGGCTGCCATCCTAAGCAGCCCCACA GCCCAGTGT

TCTCCTTGGGGGCAGGAACCTGGGGAGGGGCCCAGAGCAAAGGGCATCAGGGAGAAA GTCCCGAG

GAAATGTGACCAGTGGTTTCTGCTCGGAGCTGCAGACCCCAGGGCTCTTGGTGGAGG CAGGGGAA

CCCTGAGAGTGCTGTTTACAGAGAACCTCAGCTCCCGTCTGCCTCAGAAACCCTATT GGGCTGAGCT

GCCCTCCCCACCAGGGCCACTGTGTCCTCTGCTTCCCTCCGTTCTGCTTCAGCTTCC CCTAAGGTTA

GGGAAGAAAGAATCGGGCTCACGAATGCCAGAGGCAGTGATGTCCCATCCTGGAGGA GAGGAAAC

AGTGACTAAAAGCTGGGGACCCACAGAGGGGTTGGCAGCTTCTCTTGTCGGGACAGG TGTCCTTTG

CTGGGCCTCTGGATGGCCCTGCCCTGACTGGGGCTGCTCCTCCCTCCTGTCCTGGGA CCGCGCAG

AGCCCACGCTCTCACTGCTGCCTCCTGCTGGCCGCTGCCTCCTTAGAAAGCTGTGAC CAGGCAGCT

AAGAGCCTCT GGGCT GCAGGGTCAGCCTCTCCCAAGACT GAAGT GCAGAGGCTGGACTT GGGGCT

CTCTCCCCCAGCTTCTACACCTGGGCTCCAAGTCTGAGTTCCCACAGGGGACCCAGC AGCCTCCAG GAAGTCCATACCCTGGGGTGGCTGAGACCTTGGCTCTGTATGGAGGCTGCTCACCCCACA GACACT

GGTGGGGAGACCATGGCTCAGAGGAAGGGTGGAGCAACCCTCCTCCTACCCCTCAGG ATAGAGAG

AGAAGACACACTTGGGACACAGTGAAGACAGTAACTTGGAACTGACCACGGCCTGGA GGACTGGCC

CAGGCAGGGGGACAGGGAAAATGGAGCCCAAGTAGCCTCTGGCCAGGGACCCAATGT CCCGAGGA

ATCTGCCTCCCACCCACTGACTCAGGGCTCAGACTCAGCCTCTATTGTCCAGAGCAC TGGCTTGGC

GTCCAGCAATGAAGGCTGGAGAATGCAGCCTGGATTCCCCTACACACACACACACAC ACACACACA

C AC AC AC AC AC AC AC AC AC AC AC AC AC AG GT GTCTACT GACCT GGAGT GACT GGAATAGCACCTGG

GGATAAATGTGACAACTGTGCATTGAACCCTGGGTCAGGGACGTTCCAATGGCCAAG AGAGTGACA

CAGCCAGGACCCTGGTGGACAGCCAGAGGGGCCACTTCAGGATGGATGTGGGGAGAG TGGAAGAG

GCAGGGAGTAATCCTGGGGGACAGCAGGGAGGAGGCACTTCTTCCCTATGTCCAGGA GAGGGCAA

TAGAGGGAAGACTGAGGCTGAAGAATTGACGGCTCTGGACCCAGGACAGACAGACAG ACAGACAGA

CAGACAGACAGACAGACACGCACACACACCCATCTCTGTCTAGCAAGCAGCCTCCTA AGATAGCTGT

TCTCCCTATCATGACGGTGTAGCCACCATCCTGTTGTATACTAGGAGAGAACTTAAC CCACCTGGGG

GAAAATAGCTCCCCAAGAGCTGGCACCAGTACCACTGATGGCCCTGCTTCCTCTGAG TGAGATGCC

CAGGAGGAGGAGCCCTAGGGAAGAAGTCAGGGACAGGGACCAGGATACCACTCTGTC ACTGTGTG

ACCCTCAGCAAGTCACTAACCCTTGGCCTCATTTTTCCTGTCTTGTGAAAGAGGACA ATAATTCCTAC

TTCTCAAGATTGTTTTCAAGATAAAATAACATTAGCATTGTACAATGATGCAAATGC CTCATTACCATT

ATTCCTTAAGTTGTTTTCCAGCTCTAATGTTGTTTCCAACATTACATTTAAGACCTT AGGATTCTGTTTC

TTGCTTTTGTCATATCTCTTCCCAAGTGTCATCACTATATGGATGTTGAGGGCCCCC GATGACAGTCC

CTTTGGTAAGGTCCTCTTTTGAGGAGGGGAGGGTACAGGGTGGACTCATCTCAGTGT GAACTTGGC

AAGTCACTGTCCCTCTCTGATCTTGTTTCCTCATCTGGAGAAGGAGTGAGAGAGGAG AAAGGAAGAA

ACCAGTCAGGCAGGCAGTTAGGGTGGGTTCTCGGTAGAATTCTTTTAAACAAAAGAA CAGCCTGAAA

AATCAAGCTGCAGGCACAGATATGGGAACTTGCACAGGGGGGCTTGCCTAAGACATG CCCACAGCC

T CATAG AT AAG AC AG ACT ACACAGGT GACTTGCCCAAAC AT GCCT GCAATGG AAAATTT CATCCCCT

GACATGTGCAGTAAGGGGAACAAAGCAATATGGAGTAAGTAACTCAAGCCAAGGGCC CACATGTAC

ATTAGAAGGACAGCAGGGAGCTACCAGAAATTCATGCCTTATGCAGATGAGCTGCCC AGTCCTCATC

GGTTTCTTATAAAAGCCTTTACATTCAACTGTAAAAATGGCAACCCTCTTTCAGGCC TCCTCTCCACA

G C AG AG AGCTTT CTTCTCTCACT C ATT AAACTTT C ACTCC AAC CT C AAAAAAAAAAAAAAAAAA

(SEQ ID NO: 72)

As used herein, the term “TYROBP” refers to the gene encoding TYRO protein tyrosine kinasebinding protein. The terms “TYROBP” and "TYRO protein tyrosine kinase-binding protein" include wild- type forms of the TYROBP gene, as well as variants (e.g., splice variants and polymorphisms) of wild- type TYROBP. Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild- type TYROBP nucleic acid sequence (e.g., SEQ ID NO: 73, ENA accession number AF019562). SEQ ID NO: 73 is a wild-type gene sequence encoding TYROBP protein, and is shown below:

CCACGCGTCCGCGCTGCGCCACATCCCACCGGCCCTTACACTGTGGTGTCCAGCAGC ATC

CGGCTTCATGGGGGGACTTGAACCCTGCAGCAGGCTCCTGCTCCTGCCTCTCCTGCT GGC

TGTAAGTGGTCTCCGTCCTGTCCAGGCCCAGGCCCAGAGCGATTGCAGTTGCTCTAC GGT GAGCCCGGGCGT GCT GGCAGGGATCGTGAT GGGAGACCT GGTGCTGACAGT GCTCATT GC CCTGGCCGTGTACTTCCTGGGCCGGCTGGTCCCTCGGGGGCGAGGGGCTGCGGAGGCAGC GACCCGGAAACAGCGTATCACTGAGACCGAGTCGCCTTATCAGGAGCTCCAGGGTCAGAG GTCGGATGTCTACAGCGACCTCAACACACAGAGGCCGTATTACAAATGAGCCCGAATCAT GACAGTCAGCAACATGATACCTGGATCCAGCCATTCCTGAAGCCCACCCTGCACCTCATT CCAACTCCTACCGCGATACAGACCCACAGAGTGCCATCCCTGAGAGACCAGACCGCTCCC C AAT ACTCTCCT AAAAT AAAC AT G AAG C AC AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA (SEQ ID NO: 73)

As used herein, the term “ZCWPW1” refers to the gene encoding Zinc finger CW-type PVWVP domain protein 1 . The terms “ZCWPW1” and " Zinc finger CW-type PWWP domain protein 1" include wild-type forms of the ZCWPW1 gene, as well as variants (e.g., splice variants and polymorphisms) of wild-type ZCWPW1 . Examples of such variants are nucleic acids having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to a wild-type ZCWPW1 nucleic acid sequence (e.g., SEQ ID NO: 74, ENA accession number AL136735). SEQ ID NO: 74 is a wild-type gene sequence encoding ZCWPW1 protein, and is shown below:

CGCCGTTTTCCCGGGGAGATGCGCCGCCCGGTCTCCCTGCCAGCGGAGTGCTGGGCC GAG

GACAGGGCGGCAGGGGTGACAGTGGGGTCCAGGAGAGTCTCAAAATCCTAAGCTTTC AGT

ATTTGTTATTGTGAAAGAAGTTAATTCACCTGAAACAGAGGAGGGGCAACCTGAGTT ATC

AGAAAGTGACTTCCTGGCCTTCCCTTCTTTACTGATCAGAGGCACACAAAGCGTAGT TTC

T AAGCT G AAT GAT G ACAACGTT GCAG AAT AAAG AAG AAT GT GGAAAGGG ACCAAAGAG AA

TCTTTGCCCCACCTGCACAAAAATCTTACAGCCTGTTACCTTGTAGCCCTAACTCCC CTA

AGGAGGAGACCCCGGGGATCAGTTCCCCAGAGACAGAGGCCAGGATAAGCCTGCCAA AGG

CCAGTTTAAAGAAGAAAGAGGAAAAAGCAACCATGAAGAATGTTCCAAGCAGGGAAC AGG

AGAAAAAAAGAAAGGCACAAATCAACAAGCAAGCAGAGAAGAAAGAAAAGGAAAAAT CAA

GTCTTACCAATGCAGAATTTGAGGAGATTGTCCAGATTGTTCTGCAGAAGTCCCTTC AGG

AGT GCTT GGGG AT GGG AT CTGGCCTT G ATTTT GCAGAGACTT CTT GTGCCCAGCCCGT AG

TATCT ACC C AAT C AG AC AAGG AG CC AGG AATT ACTGCTTCTGCTACT GAT ACTG AT AAT G

CT AATGG AG AGG AGGT ACCAC AT ACT CAAG AG ATTTCAGT GT CTTGGGAAGGTG AAGCT G

CCCCT GAG AT AAGG AC ATCT AAGTT AGGCCAGCC AG ATCCTGCACCCTCT AAGAAGAAAT

CCAATAGACTCACCTTAAGCAAAAGAAAGAAGGAAGCTCATGAGAAGGTGGAGAAAA CTC

AAG GTG G AC AT GAG C AC AG AC AGG AAG ACCG ACT AAAG AAAAC AGTT C AGG AT C ATT CTC

AGATCAGGGACCAGCAAAAAGGAGAGATAAGTGGTTTTGGTCAATGTCTGGTCTGGG TCC

AGTGTTCCTTCCCAAACTGTGGGAAATGGAGGCGGCTGTGTGGGAACATTGACCCCT CAG

TTCTCCCAGATAATTGGTCCTGTGATCAGAACACAGATGTGCAGTATAATCGCTGTG ATA

TTCCTGAGGAGACCTGGACAGGGCTTGAGAGTGATGTGGCCTATGCCTCCTACATCC CAG

GATCCATCATCTGGGCCAAGCAATACGGTTACCCCTGGTGGCCAGGCATGATAGAAT CTG

ATCCTGACTTAGGGGAATATTTTCTTTTTACTTCCCATCTTGATTCCCTGCCGTCTA AGT

ACCATGTGACGTTTTTTGGAGAAACAGTTTCTCGTGCATGGATCCCAGTCAACATGC TAA

AGAACTTCCAGGAGCTGTCCCTGGAGCTATCAGTCATGAAAAAGCGCAGAAATGACT GCA GCCAGAAACTGGGGGTGGCCCTGATGATGGCTCAAGAGGCAGAACAGATCAGCATTCAGG

AACGGGTTAACTTGTTTGGTTTCTGGAGCCGATTCAACGGATCTAACAGTAATGGGG AAA

GAAAAGACTTACAGCTCTCTGGTTTGAACAGCCCAGGATCCTGCTTAGAGAAAAAGG AGA

AAGAGGAAGAGTTGGAAAAGGAGGAAGGAGAGAAAACAGACCCAATTTTGCCCATTC GTA

AGCGAGTCAAAATACAGACCCAAAAAAACCAAGCCAAGAGGGCTTGGGGGTGATGCA GGC

ACAGCAGATGGCCGAGGCAGGACACTGCAGAGGAAGATAATGAAGAGATCTCTAGGC AGG

AAATCCACAGCTCCTCCTGCACCCAGAATGGGAAGGAAAGAAGGCCAAGGGAATTCA GAT

TCTGACCAGCCAGGCCCTAAGAAAAAATTTAAAGCTCCCCAGAGCAAGGCCTTGGCA GCC

AGCTTTTCAGAGGGAAAAGAAGTTAGAACAGTGCCAAAGAACCTGGGCCTATCAGCG TGT

AAGGGGGCCTGCCCCTCATCTGCGAAAGAAGAGCCCAGACACCGGGAACCCCTGACC CAG

GAGGCTGGAAGTGTCCCCCTTGAGGACGAAGCCTCCAGTGACCTGGACCTGGAGCAA CTC

ATGGAAGATGTTGGGAGAGAGCTGGGGCAGAGCGGGGAGCTGCAGCACAGCAACAGT GAT

GGCGAGGACTTCCCCGTGGCGCTGTTTGGGAAGTAGCTGGTGCTCCTCTGCTCCCTC TTT

TTCTCCCTTCTCTGGGGCGCAGGAGGGAGAAGTTGCTAAGTGCTGGGTCTGTTCATT GGC

TATGAGGTTCAAATGTGTGTGGTGCAGTTTCTGTGTTAATAAAGCAGGTTACAGTCG AAA

AAAAAAAAAAAAAAAAA

(SEQ ID NO: 74)

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides new forms of siRNA, including single- and double-stranded short interfering RNA (ds-siRNA), and methods for their use in treating a patient in need of microglial gene silencing (e.g., a patient having dysregulated microglial gene expression, such as a patient with, e.g., Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, frontotemporal dementia, Huntington’s disease, multiple sclerosis, or progressive supranuclear palsy). The branched siRNA in the present invention has shown a surprising ability to permeate the cell. The branched compositions described herein may employ a variety of modifications known and previously unknown in the art. The siRNA of the invention may contain an antisense strand including a region that is represented by Formula IX:

Z-((A-P-)n(B-P-)m)q;

(IX) wherein Z is a 5’ phosphorus stabilizing moiety; each A is, independently, a 2'-modified-ribonucleoside of a first type; each B is, independently, a 2'-modified-ribonucleoside of a second type; each P is, independently, an internucleoside linkage selected from a phosphodiester linkage and a phosphorothioate linkage; n is an integer from 1 to 5; m is an integer from 1 to 5; and q is an integer between 1 and 15. The embodiments of each part of Formula IX and the methods of use for the molecules Formula IX represents are described herein.

In some embodiments, the siRNA of the invention may have a sense strand represented by Formula X:

Y-((A-P-)n(B-P-)m)qL-((B-P-)m(A-P-)n)q; (X) wherein Y is a hydrophobic moiety (e.g., cholesterol, vitamin D, or tocopherol); L is a linker; each A is, independently, a 2'-modified-ribonucleoside of a first type; each B is, independently, a 2'-modified- ribonucleoside of a second type; each P is, independently, an internucleoside linkage selected from a phosphodiester linkage and a phosphorothioate linkage; n is an integer from 1 to 5; m is an integer from 1 to 5; and q is an integer between 1 and 15. The embodiments of each part of Formula X and the methods of use for the molecules Formula X represents are described herein. siRNA Structure

The simplest siRNAs consist of a ribonucleic acid comprising a single- or double-stranded structure, formed by a first strand, and in the case of a double-stranded siRNA, a second strand. The first strand comprises a stretch of contiguous nucleotides that is at least partially complementary to a target nucleic acid. The second strand also comprises a stretch of contiguous nucleotides where the second stretch is at least partially identical to a target nucleic acid. The first strand and said second strand may be hybridized to each other to form a double-stranded structure. The hybridization typically occurs by Watson Crick base pairing.

Depending on the sequence of the first and second strand, the hybridization or base pairing is not necessarily complete or perfect, which means that the first and second strand are not 100% base-paired due to mismatches. One or more mismatches may also be present within the duplex without necessarily impacting the siRNA activity.

The first strand contains a stretch of contiguous nucleotides which is essentially complementary to a target nucleic acid. Typically, the target nucleic acid sequence is, in accordance with the mode of action of interfering ribonucleic acids, a single-stranded RNA, preferably an mRNA. Such hybridization occurs most likely through Watson Crick base pairing but is not necessarily limited thereto. The extent to which the first strand has a complementary stretch of contiguous nucleotides to a target nucleic acid sequence can be between 80% and 100%, e.g., 80%, 85%, 90%, 95%, or 100% complementary. siRNAs described herein may employ modifications to the nucleobase, phosphate backbone, ribose core, 5'- and 3'-ends, and branching, wherein multiple strands of siRNA may be covalently linked.

Length of siRNA molecules

It is within the scope of the invention that any length, known and previously unknown in the art, may be employed for the current invention. As described herein, potential lengths for an antisense strand of the branched siRNA of the present invention is between 10 and 30 nucleotides (e.g., 10 nucleotides,

11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, or 30 nucleotides), 15 and 25 nucleotides (e.g., 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, or 25 nucleotides), or 18 and 23 nucleotides (e.g., 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, or 30 nucleotides). In some embodiments, the antisense strand is 21 nucleotides. In some embodiments, the antisense strand is 22 nucleotides. In some embodiments, the antisense strand is 23 nucleotides. In some embodiments, the antisense strand is 24 nucleotides. In some embodiments, the antisense strand is 25 nucleotides. In some embodiments, the antisense strand is 26 nucleotides. In some embodiments, the antisense strand is 27 nucleotides. In some embodiments, the antisense strand is 28 nucleotides. In some embodiments, the antisense strand is 29 nucleotides. In some embodiments, the antisense strand is 30 nucleotides.

In some embodiments, the sense strand of the branched siRNA of the present invention is between 12 and 30 nucleotides (e.g., 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, or 30 nucleotides), or 14 and 18 nucleotides (e.g., 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, or 18 nucleotides). In some embodiments, the sense strand is 16 nucleotides. In some embodiments, the sense strand is 17 nucleotides. In some embodiments, the sense strand is 18 nucleotides. In some embodiments, the sense strand is 19 nucleotides. In some embodiments, the sense strand is 20 nucleotides. In some embodiments, the sense strand is 21 nucleotides. In some embodiments, the sense strand is 22 nucleotides. In some embodiments, the sense strand is 23 nucleotides. In some embodiments, the sense strand is 24 nucleotides. In some embodiments, the sense strand is 25 nucleotides. In some embodiments, the sense strand is 26 nucleotides. In some embodiments, the sense strand is 27 nucleotides. In some embodiments, the sense strand is 28 nucleotides. In some embodiments, the sense strand is 29 nucleotides. In some embodiments, the sense strand is 30 nucleotides.

2' modifications

The present invention includes single- and double-stranded compositions comprising at least one alternating motif. Alternating motifs of the present invention may have the formula ((A-P-) _n (B-P-) _m )q where A is a nucleoside of a first type, B is a nucleoside of a second type, n is from 1 to 5, m is from 1 to 5, and q is from 1 to 15, and P is an internucleoside linkage. The result may include a regular or irregular pattern of alternating nucleosides of the first and second types. Each of the types of nucleosides may be identical with the exception that at least the 2’-substituent groups are different.

Possible 2'-modifications comprise all possible orientations of OH; F; 0-, S-, or N-alkyl; 0-, S-, or N-alkenyl; 0-, S- or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted C1 to C10 alkyl or C2 to C10 alkenyl and alkynyl. In some embodiments, the modification includes a 2’-0-methyl (2’-0-Me) modification. Some embodiments use 0[(CH ₂ )n0] _m CH3, 0(CH ₂ )n0CH ₃ , 0(CH ₂ ) _n NH ₂ , 0(CH ₂ ) _n CH ₃ , 0(CH ₂ ) _n 0NH ₂ , and 0(CH ₂ )n0N[(CH ₂ ) _n CH ₃ ] ₂ , where n and m are from 1 to about 10. Other potential sugar substituent groups include: C1 to C10 lower alkyl, substituted lower alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH ₃ , OCN, Cl, Br,

CN, CF ₃ , OCF ₃ , SOCH ₃ , S0 ₂ CH ₃ , 0N0 ₂ , N0 ₂ , N ₃ , NH ₂ , heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide, and other substituents having similar properties. In some embodiments, the modification includes 2' methoxyethoxy (2'-0-CH ₂ CH ₂ 0CH ₃ , also known as 2'-0-(2-methoxyethyl) or2'-MOE). In some embodiments, the modification includes 2'-dimethylaminooxyethoxy, i.e. , a 0(CH ₂ ) ₂ 0N(CH ₃ ) ₂ group, also known as 2'-DMAOE, and 2'-dimethylaminoethoxyethoxy (also known in the art as 2'-0-dimethylamino- ethoxy-ethyl or2'-DMAEOE), i.e., 2'-0-CH ₂ 0CH ₂ N(CH3) ₂ . Other potential sugar substituent groups include aminopropoxy (-OCH2CH2CH2NH2), allyl (-CH ₂ -CH=CH ₂ ), -O-allyl (-0-CH ₂ -CH=CH ₂ ) and fluoro (F). 2'-sugar substituent groups may be in the arabino (up) position or ribo (down) position. In some embodiments, the 2'-arabino modification is 2'-F. Similar modifications may also be made at other positions on the oligomeric compound, particularly the 3' position of the sugar on the 3' terminal nucleoside or in 2'-5' linked oligonucleotides and the 5' position of 5' terminal nucleotide.

Oligonucleotides may also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar.

Nucleobase modifications

Oligomeric compounds may also include nucleosides or other surrogate or mimetic monomeric subunits that include a nucleobase (often referred to in the art simply as "base" or "heterocyclic base moiety"). The nucleobase is another moiety that has been extensively modified or substituted and such modified and or substituted nucleobases are amenable to the present invention. As used herein, "unmodified" or "natural" nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified nucleobases also referred herein as heterocyclic base moieties include other synthetic and natural nucleobases such as 5-methylcytosine (5- me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2- thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl (-C=C-CH3) uracil and cytosine and other alkynyl derivatives of pyrimidine bases, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 2-F-adenine, 2-amino-adenine, 8-azaguanine and 8- azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. Nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobases include those disclosed in United States Patent No. 3,687,808, those disclosed in The Concise Encyclopedia of Polymer Science and Engineering, pages 858-859, Kroschwitz, J.I., ed. John Wiley & Sons, 1990, those disclosed by Englisch et al., Angewandte Chemie, International Edition, 1991 , 30, 613, and those disclosed by Sanghvi, Y.S., Chapter 15, Antisense Research and , Applications, pages 289-302, Crooke, S.T. and Lebleu, B., ed., CRC Press, 1993. Oligomeric compounds of the present invention can also include polycyclic heterocyclic compounds in place of one or more heterocyclic base moieties. A number of tricyclic heterocyclic compounds have been previously reported. These compounds are routinely used in antisense applications to increase the binding properties of the modified strand to a target strand.

Representative cytosine analogs that make 3 hydrogen bonds with a guanosine in a second strand include 1 ,3-diazaphenoxazine-2-one (Kurchavov, et al., Nucleosides and Nucleotides, 1997, 16, 1837-1846), 1 ,3-diazaphenothiazine-2-one (Lin, K.-Y.; Jones, R. J.; Matteucci, M.J. Am. Chem. Soc.

1995, 117, 3873-3874), and 6,7,8,9-tetrafluoro-l,3-diazaphenoxazine-2-one (Wang, J.; Lin, K.-Y., Matteucci, M. Tetrahedron Lett. 1998, 39, 8385-8388). Incorporated into oligonucleotides these base modifications were shown to hybridize with complementary guanine and the latter was also shown to hybridize with adenine and to enhance helical thermal stability by extended stacking interactions (also see U.S. Patent Application entitled "Modified Peptide Nucleic Acids" filed May 24, 2002, Serial number 10/155,920; and U.S. Patent Application entitled "Nuclease Resistant Chimeric Oligonucleotides" filed May 24, 2002, Serial number 10/013,295, both of which are herein incorporated by reference in their entirety). Further helix-stabilizing properties have been observed when a cytosine analog/substitute has an aminoethoxy moiety attached to the rigid 1 ,3-diazaphenoxazine-2-one scaffold (Lin, K.-Y.; Matteucci, M. J.25 Am. Chem. Soc. 1998, 120, 8531-8532).

Internucleoside linkage modifications

Another variable in the design of the present invention are the internucleoside linkages making up the phosphate backbone. Although the natural RNA phosphate backbone may be employed here, derivatives thereof, known and yet unknown in the art, may be used which enhance desirable characteristics of a siRNA. Although not limiting, of particular importance in the present invention is protecting parts, or the whole, of the siRNA from hydrolysis. One example of a modification that decreases the rate of hydrolysis is phosphorothioates. Any portion or the whole of the backbone may contain phosphate substitutions (e.g., phosphorothioates, phosphodiesters, etc.). For instance, the internucleoside linkages may be between 0 and 100% phosphorothioate, e.g., between 0 and 100%, 10 and 100%, 20 and 100%, 30 and 100%, 40 and 100%, 50 and 100%, 60 and 100% 70 and 100%, 80 and 100%, 90 and 100%, 0 and 90%, 0 and 80%, 0 and 70%, 0 and 60%, 0 and 50%, 0 and 40%, 0 and 30%, 0 and 20%, 0 and 10%, 10 and 90%, 20 and 80%, 30 and 70% 40 and 60%, 10 and 40%, 20 and 50%,

30 and 60%, 40 and 70%, 50 and 80%, or 60 and 90% phosphorothioate linkages. Similarly, the internucleoside linkages may be between 0 and 100% phosphodiester linkages, e.g., between 0 and 100%, 10 and 100%, 20 and 100%, 30 and 100%, 40 and 100%, 50 and 100%, 60 and 100% 70 and 100%, 80 and 100%, 90 and 100%, 0 and 90%, 0 and 80%, 0 and 70%, 0 and 60%, 0 and 50%, 0 and 40%, 0 and 30%, 0 and 20%, 0 and 10%, 10 and 90%, 20 and 80%, 30 and 70%, 40 and 60%, 10 and 40%, 20 and 50%, 30 and 60%, 40 and 70%, 50 and 80%, or 60 and 90% phosphodiester linkages.

Specific examples of some potential oligomeric compounds useful in this invention include oligonucleotides containing modified e.g. non-naturally occurring internucleoside linkages. As defined in this specification, oligonucleotides having modified internucleoside linkages include internucleoside linkages that retain a phosphorus atom and internucleoside linkages that do not have a phosphorus atom. For the purposes of this specification, and as sometimes referenced in the art, modified oligonucleotides that do not have a phosphorus atom in their internucleoside backbone can also be considered to be oligonucleosides. In the C.elegans system, modification of the internucleotide linkage (phosphorothioate) did not significantly interfere with RNAi activity. Based on this observation, it is suggested that some compositions of the invention can also have one or more modified internucleoside linkages. A preferred phosphorus containing modified internucleoside linkage is the phosphorothioate internucleoside linkage.

In some embodiments, the modified oligonucleotide backbones containing a phosphorus atom therein include, for example, phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates, 5'- alkylene phosphonates, phosphinates, phosphoramidates including 3'-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, selenophosphates, and boranophosphates having normal 3'-5' linkages, 2'-5' linked analogs of these, and those having inverted polarity wherein one or more internucleotide linkages is a 3' to 3', 5' to 5' or 2' to 2' linkage. In some embodiments, the modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; riboacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH2 component parts. siRNA Patterning

Nucleosides used in the invention tolerate a range of modifications in the nucleobase and sugar.

A complete siRNA, single-stranded or double-stranded, may have 1 , 2, 3, 4, 5, or more different nucleosides that each appear in the siRNA strand or strands once or more. The nucleosides may appear in a repeating pattern (e.g., alternating between two modified nucleosides) or may be a strand of one type of nucleoside with substitutions of a second type of nucleoside. Similarly, internucleoside linkages may be of one or more type appearing in a single- or double-stranded siRNA in a repeating pattern (e.g., alternating between two internucleoside linkages) or may be a strand of one type of internucleoside linkage with substitutions of a second type of internucleoside linkage. Though the siRNAs of the invention tolerate a range of substitution patterns, the following exemplify some preferred patterns in which A and B represent nucleosides of two types, and T and P represent internucleoside linkages of two types:

Pattern 1 :

A-T-B-T-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-B-T-A -T-A-T-A-T-A-T-A-T-A-T

A-T-A-T-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-T-A -T

Pattern 2:

A-T-A-T-A-P-B-P-B-P-B-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-B-T-A -T-A-T-A-T-A-T-A-T-A-T

A-T-A-T-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-T-A -T

Pattern 3:

A-T-B-T-A-P-B-P-B-P-B-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-B-T-A -T-A-T-A-T-A-T-A-T-A-T

A-T-A-T-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-T-A -T

Pattern 4:

A-T-B-T-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-B-T-A -T-A-T-A-T-A-T-A-T-A-T

A-T-A-T-A-P-A-P-A-P-A-P-B-P-A-P-A-P-B-P-B-P-A-P-A-P-A-T-A -T Pattern 5:

A-T-B-T-A-P-A-P-A-P-B-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-B-T-A -T-B-T-A-T-A-T-A-T-A-T

A-T-A-T-A-P-A-P-A-P-A-P-B-P-A-P-B-P-B-P-B-P-A-P-A-P-A-T-A -T.

In some embodiments, T represents phosphorothioate, and P represents phosphodiester.

In some embodiments, the siRNA molecule of the disclosure features any one of the siRNA nucleotide modification patterns and/or internucleoside linkage modification patterns described in International Patent Application Publication Nos. WO 2016/161388 and WO 2020/041769, the disclosures of which are incorporated in their entirety herein.

In some embodiments of the disclosure, the siRNA may contain an antisense strand including a region represented by Formula A-l, wherein Formula A-l is, in the 5’-to-3’ direction

A-B-(A’)j-C-P ² -D-P ¹ -(C’-P ¹ ) _k -C’

Formula A-l; wherein A is represented by the formula C-P ¹ -D-P ¹ ; each A’ is represented by the formula C-P ² -D-P ² ; B is represented by the formula C-P ² -D-P ² -D-P ² -D-P ² ; each C is a 2’-0-methyl (2’-0-Me) ribonucleoside; each C’, independently, is a 2’-0-Me ribonucleoside or a 2’-fluoro (2’-F) ribonucleoside; each D is a 2’-F ribonucleoside; each P ¹ is a phosphorothioate internucleoside linkage; each P ² is a phosphodiester internucleoside linkage; j is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); and k is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7). In some embodiments, j is 4. In some embodiments, k is 4. In some embodiments, j is 4 and k is 4. The antisense is complementary (e.g., fully or partially complementary) to a target nucleic acid sequence.

In some embodiments, the antisense strand includes a structure represented by Formula A1 , wherein Formula A1 is, in the 5’-to-3’ direction:

A-S-B-S-A-O-B-O-B-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A -O-B-S-A-S-A-S-A-S-B-S-A

Formula A1; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments of the disclosure, the siRNA may contain an antisense strand including a region represented by Formula A-ll, wherein Formula A-ll is, in the 5’-to-3’ direction:

A-B-(A’)j-C-P ² -D-P ¹ -(C-P ¹ ) _k -C’

Formula A-ll; wherein A is represented by the formula C-P ¹ -D-P ¹ ; each A’ is represented by the formula C-P ² -D-P ² ; B is represented by the formula C-P ² -D-P ² -D-P ² -D-P ² ; each C is a 2’-0-methyl (2’-0-Me) ribonucleoside; each C’, independently, is a 2’-0-Me ribonucleoside or a 2’-fluoro (2’-F) ribonucleoside; each D is a 2’-F ribonucleoside; each P ¹ is a phosphorothioate internucleoside linkage; each P ² is a phosphodiester internucleoside linkage; j is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); and k is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7). In some embodiments, j is 4. In some embodiments, k is 4. In some embodiments, j is 4 and k is 4. The antisense is complementary (e.g., fully or partially complementary) to a target nucleic acid sequence.

In some embodiments of the disclosure, the antisense strand includes a structure represented by Formula A2, wherein Formula A2 is, in the 5’-to-3’ direction:

A-S-B-S-A-O-B-O-B-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A -O-B-S-A-S-A-S-A-S-A-S-A

Formula A2; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments of the disclosure, the sense strand includes a structure represented by Formula S-lll, wherein Formula S-lll is, in the 5’-to-3’ direction:

E-(A’)m-F

Formula S-lll; wherein E is represented by the formula (C-P ¹ )2; F is represented by the formula (C-P ² )3-D-P ¹ -C-P ¹ -C, (C- P ² ) ₃ -D-P ² -C-P ² -C, (C-P ² ) ₃ -D-P ¹ -C-P ¹ -D, or (C-P ² ) ₃ -D-P ² -C-P ² -D; A’, C, D, P ¹ , and P ² are as defined in Formula I; and m is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7). In some embodiments, m is 4. The sense strand is complementary (e.g., fully or partially complementary) to the antisense strand.

In some embodiments of the disclosure, the sense strand includes a structure represented by Formula S1 , wherein Formula S1 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-A-O-A-O-B-S-A -S-A

Formula S1; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage. In some embodiments of the disclosure, the sense strand includes a structure represented by Formula S2, wherein Formula S2 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-A-O-A-O-B-O-A -O-A

Formula S2; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments of the disclosure, the sense strand includes a structure represented by Formula S3, wherein Formula S3 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-A-O-A-O-B-S-A -S-B

Formula S3; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments of the disclosure, the sense strand includes a structure represented by Formula S4, wherein Formula S4 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-A-O-A-O-B-O-A -O-B

Formula S4; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments of the disclosure, the siRNA may contain an antisense strand including a region represented by Formula A-IV, wherein Formula A-IV is, in the 5’-to-3’ direction:

A-(A’)j-C-P ² -B-(C-P ¹ ) _k -C’

Formula A-IV; wherein A is represented by the formula C-P ¹ -D-P ¹ ; each A’ is represented by the formula C-P ² -D-P ² ; B is represented by the formula D-P ¹ -C-P ¹ -D-P ¹ ; each C is a 2’-0-Me ribonucleoside; each C’, independently, is a 2’-0-Me ribonucleoside or a 2’-F ribonucleoside; each D is a 2’-F ribonucleoside; each P ¹ is a phosphorothioate internucleoside linkage; each P ² is a phosphodiester internucleoside linkage; j is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); and k is an integer from 1 to7 (e.g., 1 , 2, 3, 4, 5, 6, or 7). In some embodiments, j is 6. In some embodiments, k is 4. In some embodiments, j is 6 and k is 4. The antisense strand is complementary (e.g., fully or partially complementary) to a target nucleic acid. In some embodiments of the disclosure, the antisense strand includes a structure represented by Formula A3, wherein Formula A3 is, in the 5’-to-3’ direction:

A-S-B-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A -O-B-S-A-S-B-S-A-S-A-S-A

Formula A3; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments of the disclosure, the siRNA of the disclosure may have a sense strand represented by Formula S-V, wherein Formula S-V is, in the 5’-to-3’ direction:

E-(A’) _m -C-P ² -F

Formula S-V; wherein E is represented by the formula (C-P ¹ )2; F is represented by the formula D-P ¹ -C-P ¹ -C, D-P ² -C-P ² - C, D-P ¹ -C-P ¹ -D, or D-P ² -C-P ² -D; A’, C, D, P ¹ , and P ² are as defined in Formula IV; and m is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7). In some embodiments, m is 5. The sense strand is complementary (e.g., fully or partially complementary) to the antisense strand.

In some embodiments of the disclosure, the sense strand includes a structure represented by Formula S5, wherein Formula S5 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-S-A -S-A

Formula S5; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments of the disclosure, the sense strand includes a structure represented by Formula S6, wherein Formula S6 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A -O-A

Formula S6; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage. In some embodiments of the disclosure, the sense strand includes a structure represented by Formula S7, wherein Formula S7 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-S-A -S-B

Formula S7; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments of the disclosure, the sense strand includes a structure represented by Formula S8, wherein Formula S8 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A-O-B-O-A -O-B

Formula S8; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments of the disclosure, the siRNA may contain an antisense strand including a region represented by Formula A-VI, wherein Formula A-VI is, in the 5’-to-3’ direction:

A-Bj-E-B _k -E-F-Gi-D-P ¹ -C’

Formula A-VI; wherein A is represented by the formula C-P ¹ -D-P ¹ ; each B is represented by the formula C-P ² ; each C is a 2’-0-Me ribonucleoside; each C’, independently, is a 2’-0-Me ribonucleoside or a 2’-F ribonucleoside; each D is a 2’-F ribonucleoside; each E is represented by the formula D-P ² -C-P ² ; F is represented by the formula D-P ¹ -C-P ¹ ; each G is represented by the formula C-P ¹ ; each P ¹ is a phosphorothioate internucleoside linkage; each P ² is a phosphodiester internucleoside linkage; j is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); k is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); and I is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7). In some embodiments, j is 3. In some embodiments, k is 6. In some embodiments, I is 2. In some embodiments, j is 3, k is 6, and I is 2. The antisense strand is complementary (e.g., fully or partially complementary) to a target nucleic acid.

In some embodiments of the disclosure, the antisense strand includes a structure represented by Formula A4, wherein Formula A4 is, in the 5’-to-3’ direction:

A-S-B-S-A-O-A-O-A-O-B-O-A-O-A-O-A-O-A-O-A-O-A-O-A-O-B-O-A -O-B-S-A-S-A-S-A-S-B-S-A

Formula A4; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage. In some embodiments of the disclosure, the siRNA may contain a sense strand including a region represented by Formula S-VII, wherein Formula S-VII is, in the 5’-to-3’ direction:

H-Bm-ln-A’-Bo-H-C

Formula S-VII; wherein A’ is represented by the formula C-P ² -D-P ² ; each H is represented by the formula (C-P ¹ )2; each I is represented by the formula (D-P ² ); B, C, D, P ¹ , and P ² are as defined in Formula VI; m is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); n is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7); and o is an integer from 1 to 7 (e.g., 1 , 2, 3, 4, 5, 6, or 7). In some embodiments, m is 3. In some embodiments, n is 3. In some embodiments, o is 3. In some embodiments, m is 3, n is 3, and o is 3. The sense strand is complementary (e.g., fully or partially complementary) to the antisense strand.

In some embodiments of the disclosure, the sense strand includes a structure represented by Formula S9, wherein Formula S9 is, in the 5’-to-3’ direction:

A-S-A-S-A-O-A-O-A-O-B-O-B-O-B-O-A-O-B-O-A-O-A-O-A-O-A-S-A -S-A

Formula S9; wherein A represents a 2’-0-Me ribonucleoside, B represents a 2’-F ribonucleoside, O represents a phosphodiester internucleoside linkage, and S represents a phosphorothioate internucleoside linkage.

In some embodiments of the disclosure, the siRNA may contain an antisense strand including a region that is represented by Formula VIII:

5' phosphorus stabilizing moiety

To further protect the siRNA from degradation a 5'-phosphorus stabilizing moiety may be employed. A 5'-phosphorus stabilizing moiety replaces the 5'-phosphate to prevent hydrolysis of the phosphate. Hydrolysis of the 5'-phosphate prevents binding to RISC, a necessary step in gene silencing. Any replacement for phosphate that does not impede binding to RISC is contemplated in this disclosure.

In some embodiments, the replacement for the 5'-phosphate is also stable to in vivo hydrolysis. Each siRNA strand may independently and optionally employ any suitable 5'-phosphorus stabilizing moiety.

Some exemplary endcaps are demonstrated in Formula l-VIII. Nuc in Formula l-VIII represents a nucleobase or nucleobase derivative or replacement as described herein. X in Formula l-VIII represents a 2’-modification as described herein. Some embodiments employ hydroxy as in Formula I, phosphate as in Formula II, vinylphosphonates as in Formula III, and VI, 5’-methylsubstitued phosphates as in Formula IV, VI, and VIII, or methylenephosphonates as in Formula VII, vinyl 5'-vinylphosphonate as a 5'- phosphorus stabilizing moiety as demonstrated in Formula III. siRNA Branching

Branching of the siRNA molecules is a key feature in the present invention. The siRNA molecule may not be branched, or may be dibranched, tribranched, or tetrabranched, connected through a linker. Each main branch may be further branched to allow for 2, 3, 4, 5, 6, 7, or 8 separate RNA single- or double-strands. The branch points on the linker may stem from the same atom, or separate atoms along the linker. Some exemplary embodiments are listed in Table 1 , where L represent a linker, and X represents any atom suitable to the siRNA molecule branch points:

Table 1 : Branched siRNA structures

Linkers

Multiple strands of siRNA described herein may be covalently attached by way of a linker. The effect of this branching improves, inter alia, cell permeability allowing better access into microglia in the CNS. Any linking moiety may be employed which is not incompatible with the siRNAs of the present invention. Exemplary linkers include ethylene glycol chains of 2 to 10 subunits (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 subunits), alkyl chains, carbohydrate chains, block copolymers, peptides, RNA, DNA, and others.

In some embodiments, any carbon or oxygen atom of the linker is optionally replaced with a nitrogen atom, bears a hydroxyl substituent, or bears an oxo substituent. In some embodiments, the linker is a poly-ethylene glycol (PEG) linker. The PEG linkers suitable for use with the disclosed compositions and methods include linear or non-linear PEG linkers. Examples of non-linear PEG linkers include branched PEGs, linear forked PEGs, or branched forked PEGs.

PEG linkers of various weights may be used with the disclosed compositions and methods. For example, the PEG linker may have a weight that is between 5 and 500 Daltons. In some embodiments, a PEG linker having a weight that is between 500 and 1 ,000 Dalton may be used. In some embodiments, a PEG linker having a weight that is between 1 ,000 and 10,000 Dalton may be used. In some embodiments, a PEG linker having a weight that is between 200 and 20,000 Dalton may be used. In some embodiments, the linker is covalently attached to a sense strand of the siRNA. In some embodiments, the linker is covalently attached to an antisense strand of the siRNA. In some embodiments, the PEG linker is a triethylene glycol (TrEG) linker. In some embodiments, the PEG linker is a tetraethylene linker (TEG).

In some embodiments, the linker is an alkyl chain linker. In some embodiments, the linker is a peptide linker. In some embodiments, the linker is a RNA linker. In some embodiments, the linker is a DNA linker.

Linkers may covalently link 2, 3, 4, or 5 unique siRNA strands. The linker may covalently bind to any part of the siRNA oligomer. In some embodiments, the linker attaches to the 3' end of nucleosides of each siRNA strand. In some embodiments, the linker attaches to the 5' end of nucleosides of each siRNA strand. In some embodiments, the linker attaches to a nucleoside of an siRNA strand (e.g., sense or antisense strand) by way of a covalent bond-forming moiety. In some embodiments, the covalent-bond- forming moiety is selected from the group consisting of an alkyl, ester, amide, carbonate, carbamate, triazole, urea, formacetal, phosphonate, phosphate, and phosphate derivative (e.g., phosphorothioate, phosphoramidate, etc.).

In some embodiments, the linker has a structure of Formula L1 , as is shown below:

(Formula L1)

In some embodiments, the linker has a structure of Formula L2, as is shown below:

(Formula L2)

In some embodiments, the linker has a structure of Formula L3, as is shown below:

(Formula L3)

In some embodiments, the linker has a structure of Formula L4, as is shown below:

(Formula L4)

In some embodiments, the linker has a structure of Formula L5, as is shown below:

(Formula L5) In some embodiments, the linker has a structure of Formula L6, as is shown below:

(Formula L6)

In some embodiments, the linker has a structure of Formula L7, as is shown below:

(Formula L7)

In some embodiments, the linker has a structure of Formula L8, as is shown below:

(Formula L8)

In some embodiments, the linker has a structure of Formula L9, as is shown below:

(Formula L9)

In some embodiments, the selection of a linker for use with one or more of the branched siRNA molecules disclosed herein may be based on the hydrophobicity of the linker, such that, e.g., desirable hydrophobicity is achieved for the one or more branched siRNA molecules of the disclosure. For example, a linker containing an alkyl chain may be used to increase the hydrophobicity of the branched siRNA molecule as compared to a branched siRNA molecule having a less hydrophobic linker or a hydrophilic linker.

Methods of Treatment

The invention provides methods of treating a subject in need of gene silencing. The gene silencing may be performed in order to silence defective or overactive microglial genes, silence negative regulators of microglial genes with reduced expression and/or activity, silence wild type microglial genes with an activating role in a pathway(s) that increases expression and/or activity of a disease driver gene, silence splice isoforms of a microglial gene(s) that, when selectively knocked down, may elevate total expression and/or activity of the gene(s), among other reasons, so long as the goal is to restore genetic and biochemical pathway activity from a disease state towards a healthy state. The active compound can be administered in any suitable dose. The actual dosage amount of a composition of the present invention administered to a patient can be determined by physical and physiological factors such as body weight, severity of condition, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. Depending upon the dosage and the route of administration, the number of administrations of a preferred dosage and/or an effective amount may vary according to the response of the subject. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject. Administration may occur any suitable number of times per day, and for as long as necessary. Subjects may be adult or pediatric humans, with or without comorbid diseases.

Diseases

The methods of the invention feature delivering a branched siRNA molecule to a microglial cell in a subject in need of microglial gene silencing. Subjects in need of microglial gene silencing may be suffering from neurodegenerative diseases in which neuroinflammation is a primary component of the disease pathology (e.g., Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, frontotemporal dementia, Huntington’s disease, multiple sclerosis, or progressive supranuclear palsy).

Alzheimer’s disease

Alzheimer’s disease (AD) is a late-onset neurodegenerative disorder responsible for the majority of dementia cases in the elderly. AD patients suffer from a progressive cognitive decline characterized by symptoms including an insidious loss of short- and long-term memory, attention deficits, language- specific problems, disorientation, impulse control, social withdrawal, anhedonia, and other symptoms. Distinguishing neuropathological features of AD are extracellular aggregates of amyloid-b plaques and neurofibrillary tangles composed of hyperphosphorylated microtubule-associated tau proteins. Accumulation of these aggregates is associated with neuronal loss and atrophy in a number of brain regions including the frontal, temporal, and parietal lobes of the cerebral cortex as well as subcortical structures like the basal forebrain cholinergic system and the locus coeruleus within the brainstem. AD is also associated with increased neuroinflammation characterized by reactive gliosis and elevated levels of pro-inflammatory cytokines.

Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a fast-progressing fatal neurodegenerative disease that affects motor neurons both in the brain and spinal cord, consequently resulting in paralysis of voluntary muscles at later stages of disease. ALS affects about 6 persons per 100,000 people and typically leads to death within 3 to 5 years after the onset of symptoms, with no cure yet available. ALS leads to muscle weakness, atrophy, and muscle spasms as a result of degeneration of upper and lower motor neurons. Cognitive and behavioral dysfunction (e.g., language dysfunction, executive dysfunction, social cognition, and verbal memory dysfunction), and frontotemporal dementia are all possible symptoms of ALS. Parkinson’s disease

PD is a progressive disorder that affects movement, and it is recognized as the second most common neurodegenerative disease after Alzheimer’s disease. Common symptoms of PD include resting tremor, rigidity, and bradykinesia, and non-motor symptoms, such as depression, constipation, pain, sleep disorders, genitourinary problems, cognitive decline, and olfactory dysfunction, are also increasingly being associated with PD. A key feature of PD is the death of dopaminergic neurons in the substantia nigra pars compacta, and, for that reason, most current treatments for PD focus on increasing dopamine. Another well-known neuropathological hallmark of PD is the presence of Lewy bodies containing a-synuclein in brain regions affected by PD, which are thought to contribute to the disease.

PD is thought to result from a combination of genetic and environmental risk factors. There is no single gene responsible for all Parkinson’s disease cases, and the vast majority of PD cases seem to be sporadic and not directly inherited. Mutations in the genes encoding parkin, PTEN-induced putative kinase 1 (PINK1), leucine-rich repeat kinase 2 (LRRK2), and Parkinsonism-associated deglycase (DJ-1) have been found to be associated with PD, but they represent only a small subset of the total number of PD cases. Occupational exposure to some pesticides and herbicides has also been proposed as a risk factor for PD. The synthetic neurotoxin MPTP can cause Parkinsonism, but its use is extremely rare.

Frontotemporal dementia

Frontotemporal dementia (FTD; also known as frontotemporal lobar degeneration (FTLD)) is a clinical syndrome characterized by progressive neurodegeneration in the frontal and temporal lobes of the cerebral cortex. The manifestation of FTD is complex and heterogeneous, and may present as one of three clinically distinct variants including: 1) behavioral-variant frontotemporal dementia (BVFTD), characterized by changes in behavior and personality, apathy, social withdrawal, perseverative behaviors, attentional deficits, disinhibition, and a pronounced degeneration of the frontal lobe; 2) semantic dementia (SD), characterized by fluent, anomic aphasia, progressive loss of semantic knowledge of words, objects, and concepts and a pronounced degeneration of the anterior temporal lobes. Furthermore, SD variant of FTD exhibit a flat affect, social deficits, perseverative behaviors, and disinhibition; or 3) progressive nonfluent aphasia; characterized by motor deficits in speech production, reduced language expression, and pronounced degeneration of the perisylvian cortex. Neuronal loss in brains of FTD patients is associated with one of three distinct neuropathologies: 1) the presence of tau-positive neuronal and glial inclusions; 2) ubiquitin (ub)-positive and TAR DNA-binding protein 43 (TDP43)-positive, but tau-negative inclusions; or 3) ub and fused in sarcoma (FUS)-positive, but tau and TDP-43-negative inclusions. These neuropathologies are considered to be important in the etiology of FTD.

Nearly half of FTD patients have a first-degree family member with dementia, ALS, or Parkinson’s disease, suggesting a strong genetic link to the cause of the disease. A number of mutations in chromosome 17q21 have been linked to FTD presentation.

Huntington’s disease

Huntington's Disease (HD) is an example of a trinucleotide repeat expansion disorder. This class of disorders involve the localized expansion of unstable repeats of sets of three nucleotides and can result in loss of function of a gene in which the expanded repeat is found, a gain of toxic function, or both. Trinucleotide repeats can be located in any part of the gene, including coding and non-coding regions.

Ί 3 Repeats located within coding regions typically involve a repeated glutamine encoding triplet (CAG) or an alanine encoding triplet (CGA). Expanded repeat regions within non-coding sequences can lead to aberrant expression of the gene, while expanded repeats within coding regions (also known as codon reiteration disorders) may cause protein mis-folding and aggregation. Typically, regions of wild-type genes contain a variable number of repeat sequences in the normal population, but in the afflicted populations, the number of repeats can increase from a doubling to a log order increase in the number of repeats. In HD, repeats are inserted within the N-terminal coding region of the large cytosolic protein Huntingtin (Htt). Normal Htt alleles contain 15-20 CAG repeats, while alleles containing 35 or more repeats can be considered to confer a risk for developing the disease. Alleles containing 36-39 repeats are considered incompletely penetrant, and those individuals harboring those alleles may or may not develop the disease (or exhibit delayed presentation later in life), while alleles containing 40 repeats or more are considered completely penetrant. Those individuals with juvenile onset HD (<21 years of age) are often found to have 60 or more CAG repeats.

Multiple sclerosis

Multiple sclerosis (MS) is the most common demyelinating disease of the CNS affecting young adults (disease onset between 20 to 40 years of age) and is the third leading cause for disability after trauma and rheumatic diseases in the US.

MS patients present with destruction of myelin, death of oligodendrocytes, and axonal loss. The main pathologic finding in MS is the presence of infiltrating mononuclear cells, predominantly T lymphocytes and macrophages, which breach the blood brain barrier and induce active inflammation within the CNS. The neurological symptoms that characterize MS include complete or partial vision loss, diplopia, sensory symptoms, motor weakness that can progress to complete paralysis, bladder dysfunction, and cognitive deficits. The associated inflammatory foci lead to myelin destruction, plaques of demyelination, gliosis, and axonal loss within the brain and spinal cord and are the primary drivers of the clinical manifestations of neurological disability.

The etiology of MS is not fully understood. The disease develops in genetically predisposed subjects exposed to yet undefined environmental factors and the pathogenesis involves autoimmune mechanisms associated with autoreactive T cells against myelin antigens. It is well established that not one dominant gene determines genetic susceptibility to develop MS, but rather many genes, each with different influence, are involved. The detailed molecular mechanisms underlying MS etiology are still to be elucidated.

Progressive supranuclear palsy

Progressive supranuclear palsy (PSP), a progressive and fatal tauopathy, represents ~10% of all Parkinsonian cases in the US. PSP patients have a variety of motor disorders, including postural instability, falls, abnormalities in gait, bradykinesia, vertical gaze paralysis, pseudobulbar paralysis, and axial stiffness without limb stiffness, in addition to cognitive impairments such as apathy, loss of executive function, and reduced fluency. Neuropathology of PSP is characterized by an accumulation oftau protein, which is associated with abnormal intracellular microtubules, resulting in insoluble filament deposits. The neuropathological presentation of PSP neurodegeneration is located in the subcortical regions, including substantia nigra, globus pallidus ,and subthalamic nucleus. PSP neurodegeneration is characterized by the destruction of tissues and cytokine profiles of activated microglia and astrocytes.

There are currently no disease-modifying treatments for PSP. The current standard of care is palliative. Patients in the advanced stages of the disease often have feeding tubes inserted to avoid choking hazards and to provide nutrition. Although therapies are available to decrease some symptoms of PSP, none protect the brain from neurodegeneration. Current medications to treat symptoms of PSP include dopamine agonists, tricyclic antidepressants, methysergide, onabotulinumtoxin A (to treat muscle stiffness in the face). However, as the disease progresses and symptoms worsen, medications may fail to adequately decrease symptoms.

Gene targets

The methods of the invention feature delivering a branched siRNA molecule to a microglial cell in a subject in need of microglial gene silencing. Patients in need of microglial gene silencing may have dysregulated expression and/or activity of a gene selected from the group consisting of ABCA7, ABI3, ADAM10, APOC1 , APOE, AXL, BIN1 , C1QA, C3, C90RF72, CASS4, CCL5, CD2AP, CD33, CD68, CLPTM1 , CLU, CR1 , CSF1 , CST7, CTSB, CTSD, CTSL, CXCL10, CXCL13, DSG2, ECHDC3, EPHA1 , FABP5, FERMT2, FTH1 , GNAS, GRN, HBEGF, HLA-DRB1 , HLA-DRB5, IFIT1 , IFIT3, IFITM3, IFNAR1 , IFNAR2, IGF1 , IL10RA, IL1A, IL1B, IL1RAP, INPP5D, ITGAM, ITGAX, LILRB4, LPL, MEF2C, MMP12, MS4A4A, MS4A6A, NLRP3, NME8, NOS2, PICALM, PILRA, PLCG2, PTK2B, SCIMP, SLC24A4,

SORL1 , SPI1 , SPP1 , SPPL2A, TBK1 , TNF, TREM2, TREML2, TYROBP, and ZCWPW1 gene.

In some embodiments, the patient in need of microglial gene silencing may require silencing of any one of the genes selected from the group consisting of APOE, BIN1 , C1QA, C3, C90RF72, CCL5, CD33, CLU/APOJ, CR1 , CXCL10, CXCL13, IFIT1 , IFIT3, IFITM3, IFNAR1 , IFNAR2, IL10RA, IL1A, IL1B, IL1RAP, INPP5D, ITGAM, MEF2C, MMP12, NLRP3, NOS2, PILRA, PLCG2, PTK2B, SLC24A4, TBK1 , and TNF.

Pharmaceutical compositions

The branched siRNA molecules in the present invention can be formulated into a pharmaceutical composition for administration to a subject in a biologically compatible form suitable for administration in vivo. Accordingly, in one aspect, the present invention provides a pharmaceutical composition containing a branched siRNA in admixture with a suitable diluent, carrier, or excipient. The siRNA can be administered, for example, orally or by intravenous injection.

Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy (2012, 22 ^nd ed.) and in The United States Pharmacopeia: The National Formulary (2015, USP 38 NF 33).

Under ordinary conditions of storage and use, a pharmaceutical composition may contain a preservative, e.g., to prevent the growth of microorganisms. Pharmaceutical compositions may include sterile aqueous solutions, dispersions, or powders, e.g., for the extemporaneous preparation of sterile solutions or dispersions. In all cases the form may be sterilized using techniques known in the art and may be fluidized to the extent that may be easily administered to a subject in need of treatment.

A pharmaceutical composition may be administered to a subject, e.g., a human subject, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which may be determined by the solubility and/or chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.

Regimens

A physician having ordinary skill in the art can readily determine an effective amount of siRNA for administration to a mammalian subject (e.g., a human) in need thereof. For example, a physician could start prescribing doses of a siRNA of the invention at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. Alternatively, a physician may begin a treatment regimen by administering a siRNA at a high dose and subsequently administer progressively lower doses until a therapeutic effect is achieved (e.g., a reduction in expression of a target gene sequence). In general, a suitable daily dose of a siRNA of the invention will be an amount of the siRNA which is the lowest dose effective to produce a therapeutic effect. A single-strand or double-strand siRNA of the invention may be administered by injection, e.g., intrathecally, intracerebroventricularly, or intrastriatally . A daily dose of a therapeutic composition of a siRNA of the invention may be administered as a single dose or as two, three, four, five, six or more doses administered separately at appropriate intervals throughout the day, week, month, or year, optionally, in unit dosage forms. While it is possible for a siRNA of the invention to be administered alone, it may also be administered as a pharmaceutical formulation in combination with excipients, carriers, and optionally, additional therapeutic agents.

Routes of administration

The method of the invention contemplates any route of administration tolerated by the therapeutic composition. Some embodiments of the method include injection intrathecally, intracerebroventricularly, or intrastriatally.

Intrathecal injection is the direct injection into the spinal column or subarachnoid space. By injecting directly into the CSF of the spinal column the siRNA molecule of the invention has direct access to microglia in the spinal column and a route to access the microglia in the brain by bypassing the blood brain barrier.

Intracerebroventricular (ICV) injection is a method to directly inject into the CSF of the cerebral ventricles. Similar to intrathecal injection, ICV is a method of injection which bypasses the blood brain barrier. Using ICV allows the advantage of access to the microglia of the brain and spinal column without the danger of the therapeutic being degraded in the blood.

Intrastriatal injection is the direct injection into the striatum, or corpus striatum. The striatum is an area in the subcortical basal ganglia in the brain. Injecting into the striatum bypasses the blood brain barrier and the pharmacokinetic challenges of injection into the blood stream and allows for direct access to the microglia of the brain and spinal column.

EXAMPLES

Example 1. Protocol for Uptake of di-siRNA in Microglia of Non-Human Primates

The experiments described in this example were conducted to assess the ability of branched siRNA molecules to permeate the central nervous system and internalize within microglial cells. To this end, a branched siRNA compound targeting the huntingtin (HTT) gene and conjugated to a fluorescent dye (Cy3) was first injected into the cerebrospinal fluid via intrathecal injection into non-human primates (NHP; cynomolgus macaque). Central nervous system tissue samples were later obtained from the animals. To assess the extent to which the branched siRNA molecules were internalized by microglial cells, the tissue samples were stained using fluorescent-labeled antibodies that are specific for markers expressed in certain cell types (e.g., microglia). Fluorescence microscopy was then utilized to determine the degree of colocalization of the Cy3-labeled branched siRNA molecules and antibody-labeled microglial cells, which served as an indicator of microglial uptake. These experiments, and their results, are described in further detail below:

Paraffin embedded CNS tissue slides were tested. A dose of fluorescent labeled branched siRNA was administered to a NHP (cynomolgus macaque) via intrathecal injection. 48 hours after injection a distribution study was done. The control was an uninjected NHP. NHP tissues for imaging were post-fixed for 48-72 hours in 4% PFA at 5±3°C, and then transferred to PBS. All tissues were paraffin-embedded and sliced into 4 pm sections and mounted on slides for immunofluorescence staining. Subsequently, sections were deparaffinized and subjected to antigen retrieval. Samples were deparaffanized by two changes of xylene, 5 minutes each, then 50% xylene+50% ethanol (100%) for 5 minutes. Samples were hydrated by two changes of 100% ethanol for 3 minutes each, 90%, 80%, 70% and then 50% ethanol for 3 minutes each, followed by distilled water rinse. Antigen retrieval was carried out using 150 ml_ of Tris-EDTA buffer (pH9), placing the staining dish in a pressure cooker (containing 1200 ml_ DDH2O) for 10 minutes, allowing the slides to cool to room temperature, followed by section- wise rinsing with H2O and TBST. Sections were blocked with Background Terminator Blocking Reagent and the slides were then incubated with the primary antibody against the microglial-specific gene, lba-1 , for 1.5 hours at room temperature, followed by treatment with a secondary antibody labeled with Alexa Flour 488 (Alexa-488). Alexa-488 was used to visualize lba-1 antibody. DAPI was used to visualize cell nuclei. Tissues were washed three times for 5 min with TBS-Tween 20. Fluoromount-G was used to place glass coverslips, and slides were left to dry at 4°C overnight protected from light. Olympus VS200 slide scanner was used to acquire immunofluorescent images of brain and spinal cord (20* objective). Images within each imaging channel were acquired under the same settings for light intensity and exposure times.

Colocalization of DAPI stained nuclei, Alexa-488-labeled lba-1 antibody, and Cy3-labeled siRNA was observed across all tested brain and spinal cord tissues of cynomolgus macaques, indicating microglial cell penetration and/or uptake of the branched di-siRNA. Control experiments included uninjected NHP control (no Cy3-siRNA), non-specific primary antibody (isotype antibody control), and no secondary antibody (no Alexa Fluor 488 reagent). Robust colocalization was observed in the cortex (FIG. 1A), hippocampus (FIG. 1 B), caudate nucleus (FIG. 1C), and spinal cord (FIG. 1 D). Controls showed no co-localization of Cy3 and Alexa Fluor 488 signals, indicating specificity of detection of microglial uptake (not shown).

These results demonstrate that the ds-siRNA agents of the present disclosure are capable of being internalized by microglial cells of CNS tissues, including brain and spinal cord, and support the use of such agents for treatment of neurological conditions, such as Alzheimer’s disease or amyotrophic lateral sclerosis. Example 2. Method of Treating a Patient with Alzheimer’s Disease

A subject diagnosed with Alzheimer’s disease is treated with a dose and frequency determined by a practitioner (e.g., three times daily, twice daily, once daily, once weekly, once monthly, bi-monthly, once every 4 months, once every 5 months, once every 6 months, once every 7 months, once every 8 months, once every 9 months, once every 10 months, once every 11 months, or annually). Dosage and frequency are determined based on the subject’s height, weight, age, sex, and other disorders.

The branched siRNA is selected by the practitioner for compatibility with the disease and subject. Single- or double-stranded branched siRNA are available for selection. The siRNA chosen has an antisense strand, and in the case of double-stranded siRNA, a sense strand with a sequence and RNA modifications (e.g., natural and non-natural internucleoside linkages, modified sugars, and 5'-phosphorus stabilizing moieties) best suited to the patient and the disease being targeted (e.g.,

PS M- A-T - B-T -A- P- B- P- A- P- B- P- A- P- B- P- A- P- B- P- A- P- B- P- A- P- B-T - A-T - B-T - A-T - B-T - A-T - B-T B-T-A-T-B-P-A-P-B-P-A-P-B-P-A-P-B-P-A-P-B-P-A-P-B-P-A-T-B-T where A and B are different nucleosides, T is phosphorothioate, P is a phosphodiester, and PSM is a 5'- phosphorus stabilizing moiety).

The branched siRNA is delivered by the route best suited the patient and condition (e.g., intrathecally, intracerebroventricularly, or intrastriatally), at a rate tolerable to the patient until the subject has reached a maximum tolerated dose, or until the symptoms of the disease are ameliorated satisfactorily.

Example 3. Method of Treating a Patient with Amyotrophic Lateral Sclerosis

A subject diagnosed with Amyotrophic Lateral Sclerosis is treated with a dose and frequency determined by a practitioner (e.g., three times daily, twice daily, once daily, once weekly, once monthly bimonthly, once every 4 months, once every 5 months, once every 6 months, once every 7 months, once every 8 months, once every 9 months, once every 10 months, once every 11 months, or annually). Dosage and frequency are determined based on the subject’s height, weight, age, sex, and other disorders.

The branched siRNA is selected by the practitioner for compatibility with the disease and subject. Single- or double-stranded branched siRNA are available for selection. The siRNA chosen has an antisense strand, and in the case of double-stranded siRNA, a sense strand with a sequence and RNA modifications (e.g., natural and non-natural internucleoside linkages, modified sugars, and 5'-phosphorus stabilizing moieties) best suited to the patient and the disease being targeted (e.g.,

PS M- A-T - B-T -A- P- B- P- A- P- B- P- A- P- B- P- A- P- B- P- A- P- B- P- A- P- B-T -A-T - B-T -A-T - B-T -A-T - B-T B-T-A-T-B-P-A-P-B-P-A-P-B-P-A-P-B-P-A-P-B-P-A-P-B-P-A-T-B-T where A and B are different nucleosides, T is phosphorothioate, P is a phosphodiester, and PSM is a 5'- phosphorus stabilizing moiety).

The branched siRNA is delivered by the route best suited the patient and condition (e.g., intrathecally, intracerebroventricularly, or intrastriatally), at a rate tolerable to the patient until the subject has reached a maximum tolerated dose, or until the symptoms of the disease are ameliorated satisfactorily. SPECIFIC EMBODIMENTS

Some specific embodiments are listed below. The below enumerated embodiments should not be construed to limit the scope of the invention, rather, the below are presented as some examples of the utility of the invention.

E1. A method of delivering a branched small interfering RNA (siRNA) molecule to a microglial cell in a subject in need of microglial gene silencing, the method comprising administering the branched siRNA molecule to the central nervous system of the subject.

E2. The method of E1 , wherein the subject has been diagnosed as having a disease associated with expression of a dysregulated microglial gene ordysregulated microglial gene network.

E3. The method of E2, wherein the dysregulated microglial gene exhibits increased expression and/or activity in microglial cells of the subject as compared to the expression and/or activity of the microglial gene in microglial cells of a reference subject.

E4. The method of E2, wherein the dysregulated microglial gene exhibits reduced expression and/or activity in microglial cells of the subject as compared to the expression and/or activity of the microglial gene in microglial cells of a reference subject.

E5. The method of any one of E1 -E4, wherein the delivering of the branched siRNA molecule to the subject results in silencing of a gene in the subject.

E6. The method of any one of E1 -E5, wherein the siRNA includes (i) an antisense strand having complementarity to a portion of a gene encoding a positive regulator of a gene for which increased expression and/or activity (relative, e.g., to the level of expression and/or activity observed in a reference subject) is associated with a disease state.

E7. The method of any one of E1 -E5, wherein the siRNA includes (i) an antisense strand having complementarity to a portion of a gene encoding a negative regulator of a gene for which decreased expression and/or activity (relative, e.g., to the level of expression and/or activity observed in a reference subject) is associated with a disease state.

E8. The method of any one of E1 -E5, wherein the siRNA includes (i) an antisense strand having complementarity to a splice isoform of a gene for which overexpression of the splice isoform relative to the expression of the splice isoform in a reference subject is associated with a disease state.

E9. The method of any one of E6-E8, wherein the siRNA includes (ii) a sense strand having complementarity to the antisense strand.

E10. The method of any one of any one of E1 -E9, wherein the silencing of the microglial gene in the subject treats a disease state in the subject.

E11. The method of any one of E1 -E10, wherein the disease is a neuroinflammatory or neurodegenerative disease.

E12. The method of any one of E2-E10, wherein the dysregulated gene is selected from the group consisting of ABCA7, ABI3, ADAM10, APOC1 , APOE, AXL, BIN1 , C1QA, C3, C90RF72, CASS4, CCL5, CD2AP, CD33, CD68, CLPTM1 , CLU, CR1 , CSF1 , CST7, CTSB, CTSD, CTSL, CXCL10, CXCL13, DSG2, ECHDC3, EPHA1 , FABP5, FERMT2, FTH1 , GNAS, GRN, HBEGF, HLA-DRB1 , HLA-DRB5, IFIT1 , IFIT3, IFITM3, IFNAR1 , IFNAR2, IGF1 , IL10RA, IL1A, IL1 B, IL1 RAP, INPP5D, ITGAM, ITGAX, LILRB4, LPL, MEF2C, MMP12, MS4A4A, MS4A6A, NLRP3, NME8, NOS2, PICALM, PILRA, PLCG2, PTK2B, SCIMP, SLC24A4, SORL1 , SPI1 , SPP1 , SPPL2A, TBK1 , TNF, TREM2, TREML2, TYROBP, and ZCWPW1 or negative regulator, positive regulator, or splice isoform thereof.

E13. The method of any one of E1-E12, wherein the subject is a mammal, e.g., a human.

E14. The method of any one of E1 -E13, wherein the branched siRNA is administered to the subject intrathecally, intracerebroventricularly, or intrastriatally.

E15. The method of any one of E1 -E14, wherein the branched siRNA is administered to the subject intrathecally.

E16. The method of any one of E1 -E14, wherein the branched siRNA is administered to the subject intracerebroventricularly.

E17. The method of any one of E1 -E14, wherein the branched siRNA is administered to the subject intrastriatally.

E18. The method of any one of E1-17, wherein the siRNA molecule is di-branched.

E19. The method of any one of E1-17, wherein the siRNA molecule is tri-branched.

E20. The method of any one of E1-17, wherein the siRNA molecule is tetra-branched.

E21 . The method of any one of E1 -20, wherein the siRNA comprises (i) an antisense strand having complementarity to one or more of genes selected from the group consisting of APOE, BIN1 , C1QA, C3, C90RF72, CCL5, CD33, CLU/APOJ, CR1 , CXCL10, CXCL13, IFIT1 , IFIT3, IFITM3, IFNAR1 , IFNAR2, IL10RA, IL1A, IL1 B, IL1 RAP, INPP5D, ITGAM, MEF2C, MMP12, NLRP3, NOS2, PILRA, PLCG2, PTK2B, SLC24A4, TBK1 , and TNF and (ii) a sense strand having complementarity to the antisense strand.

E22. The method of E21 , wherein the antisense strand has the following formula, in the 5'-to-3' direction:

Z-((A-P-)n(B-P-)m)q; wherein Z is a 5’ phosphorus stabilizing moiety; each A is, independently, a 2’-0-methyl (2'-0-Me) ribonucleoside; each B is, independently, a 2'-fluoro-ribonucleoside; each P is, independently, an internucleoside linkage selected from a phosphodiester linkage and a phosphorothioate linkage; n is an integer from 1 to 5; m is an integer from 1 to 5; and q is an integer between 1 and 15. E23. The method of E22, wherein Z is represented in any one of Formula I- VIII: wherein Nuc represents a nucleobase, such as adenine, uracil, guanine, thymine, or cytosine, and R represents optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl (e.g., optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl), phenyl, benzyl, hydroxy, or hydrogen.

E24. The method of E22 or E23, wherein Z is (E)-vinylphosphonate represented in Formula III. E25. The method of any one of E22-E24, wherein n is from 1 to 4. E26. The method of any one of E22-E25, wherein n is from 1 to 3. E27. The method of any one of E22-E26, wherein n is from 1 to 2. E28. The method of any one of E22-E27, wherein n is 1 . E29. The method of any one of E22-E28, wherein m is from 1 to 4. E30. The method of any one of E22-E29, wherein m is from 1 to 3. E31 . The method of any one of E22-E30, wherein m is from 1 to 2. E32. The method of any one of E22-E31 , wherein m is 1 . E33. The method of any one of E22-E32, wherein n and m are each 1 . E34. The method of any one of E22-E33, wherein 10% or less of the ribonucleosides are 2'-0-Me ribonucleoside.

E35. The method of any one of E22-E34, wherein at least 10% of the ribonucleosides are 2'-0-Me ribonucleoside.

E36. The method of any one of E22-E35, wherein at least 20% of the ribonucleosides are 2'-0-Me ribonucleoside.

E37. The method of any one of E22-E36, wherein at least 30% of the ribonucleosides are 2'-0-Me ribonucleoside.

E38. The method of any one of E22-E37, wherein at least 40% of the ribonucleosides are 2'-0-Me ribonucleoside.

E39. The method of any one of E22-E38, wherein at least 50% of the ribonucleosides are 2'-0-Me ribonucleoside. E40. The method of any one of E22-E39, wherein at least 60% of the ribonucleosides are 2'-0-Me ribonucleoside.

E41 . The method of any one of E22-E40, wherein at least 70% of the ribonucleosides are 2'-0-Me ribonucleoside.

E42. The method of any one of E22-E41 , wherein at least 80% of the ribonucleosides are 2'-0-Me ribonucleoside.

E43. The method of any one of E22-E42, wherein at least 90% of the ribonucleosides are 2'-0-Me ribonucleoside.

E44. The method of any one of E22-E43, wherein 10% or less of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E45. The method of any one of E22-E44, wherein at least 10% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E46. The method of any one of E22-E45, wherein at least 20% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E47. The method of any one of E22-E46, wherein at least 30% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E48. The method of any one of E22-E47, wherein at least 40% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E49. The method of any one of E22-E48, wherein at least 50% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E50. The method of any one of E22-E49, wherein at least 60% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E51 . The method of any one of E22-E50, wherein at least 70% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E52. The method of any one of E22-E51 , wherein at least 80% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E53. The method of any one of E22-E52, wherein at least 90% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E54. The method of any one of E22-E53, wherein 100% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E55. The method of any one of E22-E54, wherein 9 internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E56. The method of any one of E22-E55, wherein the length of the antisense strand is between 10 and 30 nucleotides.

E57. The method of any one of E22-E56, wherein the length of the antisense strand is between 15 and 25 nucleotides.

E58. The method of any one of E22-E57, wherein the length of the antisense strand is between 18 and 23 nucleotides.

E59. The method of any one of E22-E58, wherein the length of the antisense strand is 18 nucleotides.

E60. The method of any one of E22-E56, wherein the length of the antisense strand is 19 nucleotides.

E61 . The method of any one of E22-E56, wherein the length of the antisense strand is 20 nucleotides.

E62. The method of any one of E22-E56, wherein the length of the antisense strand is 21 nucleotides. E63. The method of any one of E22-E56, wherein the length of the antisense strand is 22 nucleotides.

E64. The method of any one of E22-E56, wherein the length of the antisense strand is 23 nucleotides.

E65. The method of any one of E22-E56, wherein the length of the antisense strand is 24 nucleotides.

E66. The method of any one of E22-E56, wherein the length of the antisense strand is 25 nucleotides.

E67. The method of any one of E22-E56, wherein the length of the antisense strand is 26 nucleotides.

E68. The method of any one of E22-E56, wherein the length of the antisense strand is 27 nucleotides.

E69. The method of any one of E22-E56, wherein the length of the antisense strand is 28 nucleotides.

E70. The method of any one of E22-E56, wherein the length of the antisense strand is 29 nucleotides.

E71. The method of any one of E22-E56, wherein the length of the antisense strand is 30 nucleotides.

E72. The method of E22, wherein the antisense strand includes a structure of Formula A1 , wherein Formula A1 is:

A-T-B-T-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-B-T-A -T-A-T-A-T-A-T-A-T-A-T

Formula A1; wherein A represents a 2’-0-methyl ribonucleoside, B represents a 2’-F ribonucleoside, T represents a phosphorothioate internucleoside linkage, and P represents a phosphodiester internucleoside linkage.

E73. The method of E22, wherein the antisense strand includes a structure of Formula A2, wherein Formula A2 is:

A-T-A-T-A-P-B-P-B-P-B-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-B-T-A -T-A-T-A-T-A-T-A-T-A-T

(Formula A2); wherein A represents a 2’-0-methyl ribonucleoside, B represents a 2’-F ribonucleoside, T represents a phosphorothioate internucleoside linkage, and P represents a phosphodiester internucleoside linkage.

E74. The method of E22, wherein the antisense strand includes a structure of Formula A3, wherein Formula A3 is:

A-T-B-T-A-P-B-P-B-P-B-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-B-T-A -T-A-T-A-T-A-T-A-T-A-T

(Formula A3) wherein A represents a 2’-0-methyl ribonucleoside, B represents a 2’-F ribonucleoside, T represents a phosphorothioate internucleoside linkage, and P represents a phosphodiester internucleoside linkage.

E75. The method of E22, wherein the antisense strand includes a structure of Formula A4, wherein Formula A4 is:

A-T-B-T-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-B-T-A -T-A-T-A-T-A-T-A-T-A-T

(Formula A4) wherein A represents a 2’-0-methyl ribonucleoside, B represents a 2’-F ribonucleoside, T represents a phosphorothioate internucleoside linkage, and P represents a phosphodiester internucleoside linkage.

E76. The method of E22, wherein the antisense strand includes a structure of Formula A5, wherein Formula A5 is:

A-T-B-T-A-P-A-P-A-P-B-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-B-T-A -T-B-T-A-T-A-T-A-T-A-T

(Formula A5) wherein A represents a 2’-0-methyl ribonucleoside, B represents a 2’-F ribonucleoside, T represents a phosphorothioate internucleoside linkage, and P represents a phosphodiester internucleoside linkage.

E77. The method of E22, wherein the sense strand has the following formula in the 5'-to-3' direction:

Y-((A-P-)n(B-P-)m)qL-((B-P-)m(A-P-)n)q; wherein Y is a hydrophobic moiety (e.g., cholesterol, vitamin D, or tocopherol) moiety;

L is a linker; each A is, independently, a 2'-0-Me ribonucleoside; each B is, independently, a 2'-fluoro-ribonucleoside; each P is, independently, an internucleoside linkage selected from a phosphodiester linkage and a phosphorothioate linkage; n is an integer from 1 to 5; m is an integer from 1 to 5; and each q is an integer between 1 and 15.

E78. The method of E77, wherein Y is cholesterol.

E79. The method of E77, wherein Y is tocopherol.

E80. The method of any one of E77-E79, wherein L is an ethylene glycol oligomer.

E81. The method of any one of E77-E80, wherein L is tetraethylene glycol.

E82. The method of any one of E77-E81 , wherein the linker attaches to the sense strand by way of a covalent bond-forming moiety.

E83. The method of E82, wherein the covalent bond-forming moiety is selected from the group consisting of an alkyl, ester, amide, carbamate, phosphonate, phosphate, phosphorothioate, phosphoroamidate, triazole, urea, and formacetal.

E84. The method of E77, wherein L includes a structure of Formula L1 , wherein Formula L1 is:

(Formula L1) E85. The method of E77, wherein L includes a structure of Formula L2, wherein Formula L2 is:

(Formula L2)

E86. The method of E77, wherein L includes a structure of Formula L3, wherein Formula L3 is:

(Formula L3)

E87. The method of E77, wherein L includes a structure of Formula L4, wherein Formula L4 is:

(Formula L4)

E88. The method of E77, wherein L includes a structure of Formula L5, wherein Formula L5 is:

(Formula L5)

E89. The method of E77, wherein L includes a structure of Formula L6, wherein Formula L6 is:

(Formula L6) E90. The method of E77, wherein L includes a structure of Formula L7, wherein Formula L7 is:

(Formula L7)

E91 . The method of E77, wherein L includes a structure of Formula L8, wherein Formula L8 is:

(Formula L8)

E92. The method of E77, wherein L includes a structure of Formula L9, wherein Formula L9 is:

(Formula L9)

E93. The method of any one of E77-E92, wherein each P is independently selected from a phosphodiester linkage and a phosphorothioate linkage.

E94. The method of any one of E77-E93, wherein n is from 1 to 4.

E95. The method of any one of E77-E94, wherein n is from 1 to 3.

E96. The method of any one of E77-E95, wherein n is from 1 to 2.

E97. The method of any one of E77-E96, wherein n is 1 .

E98. The method of any one of E77-E97, wherein m is from 1 to 4.

E99. The method of any one of E77-E98, wherein m is from 1 to 3.

E100. The method of any one of E77-E99, wherein m is from 1 to 2.

E101 . The method of any one of E77-E100, wherein m is 1 .

E102. The method of any one of E77-E101 , wherein n and m are each 1 .

E103. The method of any one of E77-E102, wherein 10% or less of the ribonucleosides are 2'-0-Me ribonucleoside.

E104. The method of any one of E77-E103, wherein at least 10% of the ribonucleosides are 2'-0-Me ribonucleoside.

E105. The method of any one of E77-E104, wherein at least 20% of the ribonucleosides are 2'-0-Me ribonucleoside.

E106. The method of any one of E77-E105, wherein at least 30% of the ribonucleosides are 2'-0-Me ribonucleoside. E107. The method of any one of E77-E106, wherein at least 40% of the ribonucleosides are 2'-0-Me ribonucleoside.

E108. The method of any one of E77-E107, wherein at least 50% of the ribonucleosides are 2'-0-Me ribonucleoside.

E109. The method of any one of E77-E108, wherein at least 60% of the ribonucleosides are 2'-0-Me ribonucleoside.

E110. The method of any one of E77-E109, wherein at least 70% of the ribonucleosides are 2'-0-Me ribonucleoside.

E111 . The method of any one of E77-E110, wherein at least 80% of the ribonucleosides are 2'-0-Me ribonucleoside.

E112. The method of any one of E77-E111 , wherein at least 90% of the ribonucleosides are 2'-0-Me ribonucleoside.

E113. The method of any one of E77-E112, wherein 10% or less of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E114. The method of any one of E77-E113, wherein at least 10% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E115. The method of any one of E77-E114, wherein at least 20% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E116. The method of any one of E77-E115, wherein at least 30% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E117. The method of any one of E77-E116, wherein at least 40% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E118. The method of any one of E77-E117, wherein at least 50% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E119. The method of any one of E77-E118, wherein at least 60% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E120. The method of any one of E77-E119, wherein at least 70% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E121. The method of any one of E77-E120, wherein at least 80% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E122. The method of any one of E77-E121 , wherein at least 90% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E123. The method of any one of E77-E122, wherein 100% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E124. The method of any one of E77-E123, wherein the length of the sense strand is between 12 and 30 nucleotides.

E125. The method of any one of E77-E124, wherein the length of the sense strand is between 14 and 28 nucleotides.

E126. The method of any one of E77-E125, wherein the length of the sense strand is between 16 and 26 nucleotides.

E127. The method of any one of E77-E126, wherein the length of the sense strand is between 18 and 24 nucleotides. E128. The method of any one of E77-E125, wherein the length of the sense strand is 14 nucleotides.

E129. The method of any one of E77-E125, wherein the length of the sense strand is 15 nucleotides.

E130. The method of any one of E77-E125, wherein the length of the sense strand is 16 nucleotides.

E131. The method of any one of E77-E125, wherein the length of the sense strand is 17 nucleotides.

E132. The method of any one of E77-E125, wherein the length of the sense strand is 18 nucleotides.

E133. The method of any one of E77-E125, wherein the length of the sense strand is 19 nucleotides.

E134. The method of any one of E77-E125, wherein the length of the sense strand is 20 nucleotides.

E135. The method of any one of E77-E125, wherein the length of the sense strand is 21 nucleotides.

E136. The method of any one of E77-E125, wherein the length of the sense strand is 22 nucleotides.

E137. The method of any one of E77-E125, wherein the length of the sense strand is 23 nucleotides.

E138. The method of any one of E77-E125, wherein the length of the sense strand is 24 nucleotides.

E139. The method of any one of E77-E125, wherein the length of the sense strand is 25 nucleotides.

E140. The method of any one of E77-E125, wherein the length of the sense strand is 26 nucleotides.

E141. The method of any one of E77-E125, wherein the length of the sense strand is 27 nucleotides.

E142. The method of any one of E77-E125, wherein the length of the sense strand is 28 nucleotides.

E143. The method of any one of E77-E125, wherein the length of the sense strand is 29 nucleotides.

E144. The method of any one of E77-E125, wherein the length of the sense strand is 30 nucleotides.

E145. The method of any one of E77-E144, wherein 4 internucleoside linkages are phosphorothioate linkages.

E146. The method of E77, wherein the sense strand includes a structure of Formula S1 , wherein Formula S1 is:

A-T-A-T-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-P-A-T-A -T

Formula S1; wherein A represents a 2’-0-methyl ribonucleoside, B represents a 2’-F ribonucleoside, T represents a phosphorothioate internucleoside linkage, and P represents a phosphodiester internucleoside linkage.

E147. The method of E77, wherein the sense strand includes a structure of Formula S2, wherein Formula S2 is:

A-T-A-T-A-P-A-P-A-P-A-P-B-P-A-P-A-P-B-P-B-P-A-P-A-P-A-T-A -T

Formula S2; wherein A represents a 2’-0-methyl ribonucleoside, B represents a 2’-F ribonucleoside, T represents a phosphorothioate internucleoside linkage, and P represents a phosphodiester internucleoside linkage.

E148. The method of E77, wherein the sense strand includes a structure of Formula S3, wherein Formula S3 is:

A-T-A-T-A-P-A-P-A-P-A-P-B-P-A-P-B-P-B-P-B-P-A-P-A-P-A-T-A -T

Formula S3; wherein A represents a 2’-0-methyl ribonucleoside, B represents a 2’-F ribonucleoside, T represents a phosphorothioate internucleoside linkage, and P represents a phosphodiester internucleoside linkage.

E149. A branched siRNA molecule comprising a sense strand and an antisense strand, wherein the antisense strand comprises a region having complementarity to a segment of contiguous nucleotides within a gene selected from the group consisting of APOE, BIN1 , C1 QA, C3, C90RF72, CCL5, CD33, CLU/APOJ, CR1 , CXCL10, CXCL13, IFIT1 , IFIT3, IFITM3, IFNAR1 , IFNAR2, IL10RA, IL1A, IL1 B, IL1RAP, INPP5D, ITGAM, MEF2C, MMP12, NLRP3, NOS2, PILRA, PLCG2, PTK2B, SLC24A4, TBK1 , and TNF or a negative regulator, positive regulator, or splice isoform thereof.

E150. The molecule of E149, wherein the siRNA molecule is di-branched.

E151. The molecule of E149, wherein the siRNA molecule is tri-branched.

E152. The molecule of any one of E149, wherein the siRNA molecule is tetra-branched.

E153. The molecule of any one of E149-E152, wherein the antisense strand of the branched siRNA has the following formula in the 5'-to-3' direction:

Z-((A-P-)n(B-P-)m)q; wherein Z is a 5' phosphorus stabilizing moiety; each A is, independently, a 2'-0-Me ribonucleoside; each B is, independently, a 2'-fluoro-ribonucleoside; each P is, independently, an internucleoside linkage selected from a phosphodiester linkage and a phosphorothioate linkage; n is an integer from 1 to 5; m is an integer from 1 to 5; and q is an integer between 1 and 15.

E154. The molecule of E153, wherein Z is represented in any one of Formula l-VIII: v VI VII VIII wherein Nuc represents a nucleobase, such as adenine, uracil, guanine, thymine, or cytosine, and R represents optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl (e.g., optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl), phenyl, benzyl, hydroxy, or hydrogen.

E155. The molecule of E153 or E154, wherein Z is (E)-vinylphosphonate as represented in Formula III.

E156. The molecule of any one of E153-E99, wherein each P is independently selected from phosphodiester and phosphorothioate.

E157. The molecule of any one of E153-E156, wherein n is from 1 to 4.

E158. The molecule of any one of E153-E157, wherein n is from 1 to 3.

E159. The molecule of any one of E153-E158, wherein n is from 1 to 2.

E160. The molecule of any one of E153-E159, wherein n is 1.

E161. The molecule of any one of E153-E160, wherein m is from 1 to 4.

E162. The molecule of any one of E153-E161 , wherein m is from 1 to 3.

E163. The molecule of any one of E153-E162, wherein m is from 1 to 2.

E164. The molecule of any one of E153-E163, wherein m is 1.

E165. The molecule of any one of E153-E164, wherein n and m are each 1.

E166. The molecule of any one of E153-E165, wherein 10% or less of the ribonucleosides are 2'-0-Me ribonucleoside.

E167. The molecule of any one of E153-E166, wherein at least 10% of the ribonucleosides are 2'-0-Me ribonucleoside.

E168. The molecule of any one of E153-E167, wherein at least 20% of the ribonucleosides are 2'-0-Me ribonucleoside.

E169. The molecule of any one of E153-E168, wherein at least 30% of the ribonucleosides are 2'-0-Me ribonucleoside.

E170. The molecule of any one of E153-E169, wherein at least 40% of the ribonucleosides are 2'-0-Me ribonucleoside.

E171. The molecule of any one of E153-E170, wherein at least 50% of the ribonucleosides are 2'-0-Me ribonucleoside.

E172. The molecule of any one of E153-E171 , wherein at least 60% of the ribonucleosides are 2'-0-Me ribonucleoside.

E173. The molecule of any one of E153-E172, wherein at least 70% of the ribonucleosides are 2'-0-Me ribonucleoside.

E174. The molecule of any one of E153-E173, wherein at least 80% of the ribonucleosides are 2'-0-Me ribonucleoside.

E175. The molecule of any one of E153-E174, wherein at least 90% of the ribonucleosides are 2'-0-Me ribonucleoside.

E176. The molecule of any one of E153-E175, wherein 10% or less of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E177. The molecule of any one of E153-E176, wherein at least 10% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E178. The molecule of any one of E153-E177, wherein at least 20% of the internucleoside linkages are phosphodiester linkages or phosphorothioate. E179. The molecule of any one of E153-E178, wherein at least 30% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E180. The molecule of any one of E153-E179, wherein at least 40% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E181. The molecule of any one of E153-E180, wherein at least 50% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E182. The molecule of any one of E153-E181 , wherein at least 60% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E183. The molecule of any one of E153-E182, wherein at least 70% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E184. The molecule of any one of E153-E183, wherein at least 80% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E185. The molecule of any one of E153-E184, wherein at least 90% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E186. The molecule of any one of E153-E185, wherein 100% of the internucleoside linkages are phosphodiester linkages or phosphorothioate.

E187. The molecule of any one of E153-E186, wherein the length of the antisense strand is between 10 and 30 nucleotides.

E188. The molecule of any one of E153-E187, wherein the length of the antisense strand is between 15 and 25 nucleotides.

E189. The molecule of any one of E153-E188, wherein the length of the antisense strand is between 18 and 23 nucleotides.

E190. The molecule of any one of E153-E187, wherein the length of the antisense strand is 18 nucleotides.

E191 . The molecule of any one of E153-E187, wherein the length of the antisense strand is 19 nucleotides.

E192. The molecule of any one of E153-E187, wherein the length of the antisense strand is 20 nucleotides.

E193. The molecule of any one of E153-E187, wherein the length of the antisense strand is 21 nucleotides.

E194. The molecule of any one of E153-E187, wherein the length of the antisense strand is 22 nucleotides.

E195. The molecule of any one of E153-E187, wherein the length of the antisense strand is 23 nucleotides.

E196. The molecule of any one of E153-E187, wherein the length of the antisense strand is 24 nucleotides.

E197. The molecule of any one of E153-E187, wherein the length of the antisense strand is 25 nucleotides.

E198. The molecule of any one of E153-E187, wherein the length of the antisense strand is 26 nucleotides.

E199. The molecule of any one of E153-E187, wherein the length of the antisense strand is 27 nucleotides. E200. The molecule of any one of E153-E187, wherein the length of the antisense strand is 28 nucleotides.

E201. The molecule of any one of E153-E187, wherein the length of the antisense strand is 29 nucleotides.

E202. The molecule of any one of E153-E187, wherein the length of the antisense strand is 30 nucleotides.

E203. The molecule of any one of E149-E202, wherein 9 internucleoside linkages are phosphorothioate.

E204. The molecule of any one of E149-E203, wherein the sense strand of the branched siRNA has the following formula in the 5'-to-3' direction:

Y-((A-P-)n(B-P-)m)qL-((B-P-)m(A-P-)n)q; wherein Y is a hydrophobic moiety (e.g., cholesterol, vitamin D, or tocopherol);

L is a linker; each A is, independently, a 2'-0-Me ribonucleoside; each B is, independently, a 2'-fluoro-ribonucleoside; each P is, independently, an internucleoside linkage selected from a phosphodiester linkage and a phosphorothioate linkage; n is an integer from 1 to 5; m is an integer from 1 to 5; and q is an integer between 1 and 15.

E205. The molecule of E204, wherein Y is cholesterol.

E206. The molecule of E204, wherein Y is tocopherol.

E207. The molecule of any one of E204-E206, wherein L is an ethylene glycol oligomer.

E208. The molecule of E207, wherein L is tetraethylene glycol.

E209. The molecule of any one of E204-E208, wherein L attaches to the sense strand by way of a covalent bond-forming moiety.

E210. The molecule of E209, wherein the covalent bond-forming moiety is selected from the group consisting of an alkyl, ester, amide, carbamate, phosphonate, phosphate, phosphorothioate, phosphoroamidate, triazole, urea, and formacetal.

E211. The molecule of E204, wherein L includes a structure of Formula L1 , wherein Formula L1 is:

(Formula L1)

E212. The molecule of E204, wherein L includes a structure of Formula L2, wherein Formula L2 is:

(Formula L2)

E213. The molecule of E204, wherein L includes a structure of Formula L3, wherein Formula L3 is:

(Formula L3)

E214. The molecule of E204, wherein L includes a structure of Formula L4, wherein Formula L4 is:

(Formula L4)

E215. The molecule of E204, wherein L includes a structure of Formula L5, wherein Formula L5 is:

(Formula L5)

E216. The molecule of E204, wherein L includes a structure of Formula L6, wherein Formula L6 is:

(Formula L6) E217. The molecule of E204, wherein L includes a structure of Formula L7, wherein Formula L7 is:

(Formula L7)

E218. The molecule of E204, wherein L includes a structure of Formula L8, wherein Formula L8 is:

(Formula L8)

E219. The molecule of E204, wherein L includes a structure of Formula L9, wherein Formula L9 is:

(Formula L9)

E220. The molecule of any one of E204-E210, wherein each P is independently selected from phosphodiester and phosphorothioate.

E221. The molecule of any one of E204-E141 , wherein n is from 1 to 4.

E222. The molecule of any one of E204-E142, wherein n is from 1 to 3.

E223. The molecule of any one of E204-E143, wherein n is from 1 to 2.

E224. The molecule of any one of E204-E144, wherein n is 1.

E225. The molecule of any one of E204-E145, wherein m is from 1 to 4.

E226. The molecule of any one of E204-E146, wherein m is from 1 to 3.

E227. The molecule of any one of E204-E147, wherein m is from 1 to 2.

E228. The molecule of any one of E204-E148, wherein m is 1.

E229. The molecule of any one of E204-E149, wherein n and m are each 1.

E230. The molecule of any one of E204-E150, wherein 10% or less of the ribonucleosides are 2'-0-Me ribonucleoside.

E231. The molecule of any one of E204-E151 , wherein at least 10% of the ribonucleosides are 2'-0-Me ribonucleoside.

E232. The molecule of any one of E204-E152, wherein at least 20% of the ribonucleosides are 2'-0-Me ribonucleoside.

E233. The molecule of any one of E204-E153, wherein at least 30% of the ribonucleosides are 2'-0-Me ribonucleoside. E234. The molecule of any one of E204-E154, wherein at least 40% of the ribonucleosides are 2'-0-Me ribonucleoside.

E235. The molecule of any one of E204-E155, wherein at least 50% of the ribonucleosides are 2'-0-Me ribonucleoside.

E236. The molecule of any one of E204-E156, wherein at least 60% of the ribonucleosides are 2'-0-Me ribonucleoside.

E237. The molecule of any one of E204-E157, wherein at least 70% of the ribonucleosides are 2'-0-Me ribonucleoside.

E238. The molecule of any one of E204-E158, wherein at least 80% of the ribonucleosides are 2'-0-Me ribonucleoside.

E239. The molecule of any one of E204-E159, wherein at least 90% of the ribonucleosides are 2'-0-Me ribonucleoside.

E240. The molecule of any one of E204-E160, wherein 10% or less of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E241. The molecule of any one of E204-E161 , wherein at least 10% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E242. The molecule of any one of E204-E162, wherein at least 20% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E243. The molecule of any one of E204-E163, wherein at least 30% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E244. The molecule of any one of E204-E164, wherein at least 40% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E245. The molecule of any one of E204-E165, wherein at least 50% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E246. The molecule of any one of E204-E166, wherein at least 60% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E247. The molecule of any one of E204-E167, wherein at least 70% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E248. The molecule of any one of E204-E168, wherein at least 80% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E249. The molecule of any one of E204-E169, wherein at least 90% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E250. The molecule of any one of E204-E170, wherein 100% of the internucleoside linkages are phosphodiester linkages or phosphorothioate linkages.

E251 . The molecule of any one of E204-E250, wherein the length of the sense strand is between 12 and 30 nucleotides.

E252. The molecule of any one of E204-E251 , wherein the length of the sense strand is between 14 and 28 nucleotides.

E253. The molecule of any one of E204-E252, wherein the length of the sense strand is between 16 and 26 nucleotides.

E254. The molecule of any one of E204-E253, wherein the length of the sense strand is between 18 and 24 nucleotides. E255. The molecule of any one of E204-E251 , wherein the length of the sense strand is 14 nucleotides.

E256. The molecule of any one of E204-E251 , wherein the length of the sense strand is 15 nucleotides.

E257. The molecule of any one of E204-E251 , wherein the length of the sense strand is 16 nucleotides.

E258. The molecule of any one of E204-E251 , wherein the length of the sense strand is 17 nucleotides.

E259. The molecule of any one of E204-E251 , wherein the length of the sense strand is 18 nucleotides.

E260. The molecule of any one of E204-E251 , wherein the length of the sense strand is 19 nucleotides.

E261. The molecule of any one of E204-E251 , wherein the length of the sense strand is 20 nucleotides.

E262. The molecule of any one of E204-E251 , wherein the length of the sense strand is 21 nucleotides.

E263. The molecule of any one of E204-E251 , wherein the length of the sense strand is 22 nucleotides.

E264. The molecule of any one of E204-E251 , wherein the length of the sense strand is 23 nucleotides.

E265. The molecule of any one of E204-E251 , wherein the length of the sense strand is 24 nucleotides.

E266. The molecule of any one of E204-E251 , wherein the length of the sense strand is 25 nucleotides.

E267. The molecule of any one of E204-E251 , wherein the length of the sense strand is 26 nucleotides.

E268. The molecule of any one of E204-E251 , wherein the length of the sense strand is 27 nucleotides.

E269. The molecule of any one of E204-E251 , wherein the length of the sense strand is 28 nucleotides.

E270. The molecule of any one of E204-E251 , wherein the length of the sense strand is 29 nucleotides.

E271. The molecule of any one of E204-E251 , wherein the length of the sense strand is 30 nucleotides.

E272. The molecule of any one of E204-E271 , wherein 4 internucleoside linkages are phosphorothioate.

E273. A method of treating a subject diagnosed as having a disease associated with expression of a dysregulated microglial gene, the method comprising administering to the subject the branched siRNA molecule of any one of E149-E271.

E274. The method of any one of E11 -E148 or E273, wherein the disease is a neuroinflammatory disease.

E275. The method of any one of E11 -E148, E273, or E274, wherein the disease is a neurodegenerative disease.

E276. The method of any one of E11 -E148 or E273-E275, wherein the disease is Alzheimer’s disease.

E277. The method of any one of E11 -E148 or E273-E275, wherein the disease is Amyotrophic Lateral

Sclerosis.

E278. The method of any one of E11 -E148 or E273-E275, wherein the disease is Parkinson’s disease.

E279. The method of any one of E11-E148 or E273-E275, wherein the disease is frontotemporal dementia.

E280. The method of any one of E11 -E148 or E273-E275, wherein the disease is Huntington’s disease.

E281. The method of any one of E11-E148 or E273-E275, wherein the disease is multiple sclerosis.

E282. The method of any one of E11 -E148 or E273-E275, wherein the disease is progressive supranuclear palsy.

E283. The method of any one of E273, wherein the dysregulated microglial gene is selected from the group consisting of ABCA7, ABI3, ADAM10, APOC1 , APOE, AXL, BIN1 , C1 QA, C3, C90RF72, CASS4, CCL5, CD2AP, CD33, CD68, CLPTM1 , CLU, CR1 , CSF1 , CST7, CTSB, CTSD, CTSL, CXCL10, CXCL13, DSG2, ECHDC3, EPHA1 , FABP5, FERMT2, FTH1 , GNAS, GRN, HBEGF, HLA-DRB1 , HLA-DRB5, IFIT1 , IFIT3, IFITM3, IFNAR1 , IFNAR2, IGF1 , IL10RA, IL1A, IL1B, IL1RAP, INPP5D, ITGAM, ITGAX, LILRB4, LPL, MEF2C, MMP12, MS4A4A, MS4A6A, NLRP3, NME8, NOS2, PICALM, PILRA, PLCG2, PTK2B, SCIMP, SLC24A4, SORL1 , SPI1 , SPP1 , SPPL2A, TBK1 , TNF, TREM2, TREML2, TYROBP, and ZCWPW1.

E284. The method of E273, wherein the administering of the branched siRNA molecule to the subject results is silencing of a microglial gene in the subject.

E285. The method of E284, wherein silencing of a microglial gene comprises silencing of any one of the genes selected from group consisting of APOE, BIN1 , C1QA, C3, C90RF72, CCL5, CD33, CLU/APOJ, CR1 , CXCL10, CXCL13, IFIT1 , IFIT3, IFITM3, IFNAR1 , IFNAR2, IL10RA, IL1A, IL1B, IL1RAP, INPP5D, ITGAM, MEF2C, MMP12, NLRP3, NOS2, PILRA, PLCG2, PTK2B, SLC24A4, TBK1 , and TNF.

E286. The method of E273, wherein the microglial gene is an overactive disease driver gene (e.g., a dysregulated microglial gene).

E287. The method of E273, wherein the gene is a positive regulator of a gene for which increased expression and/or activity relative to the level of expression and/or activity observed in a reference subject is associated with a disease state.

E288. The method of E273, wherein the gene is a negative regulator of a gene for which decreased expression and/or activity relative to the level of expression and/or activity observed in a reference subject is associated with a disease state.

E289. The method of E273, wherein the gene is a splice isoform of a gene for which overexpression of the splice isoform relative to the expression of the splice isoform in a reference subject is associated with a disease state.

E290. The method of any one of E273-E289, wherein the subject is a human.

OTHER EMBODIMENTS

Various modifications and variations of the described disclosure will be apparent to those skilled in the art without departing from the scope and spirit of the disclosure. Although the disclosure has been described in connection with specific embodiments, it should be understood that the disclosure as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the disclosure that are obvious to those skilled in the art are intended to be within the scope of the disclosure.

Other embodiments are in the claims.