Table 1.
Top-ranked or replicable nsSNPs associated with alcohol dependence
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p values for associations (risk allele frequency: affected/unaffected) |
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| SNP | CHR | Gene | Amino acid | EA | AA | EAu | Meta | cis-eQTL | Splicing | Damaging effects | Diseases/traits# | Mouse* (RPKM)▲ | Rat* (FPKM)◆ |
| rs3820198• | 1 | APOER2 | D45E | 0.015 (T: .681/.650) | 2.7 × 10−5 (G: .869/.811) | – | 5.9 × 10−5 | 0.013 | Y | benign | 1 | 7.17 | N.A. |
| rs3820678 | 1 | OR10R2 | A190T | 0.008 (A: .223/.195) | – | 0.027 (A: .260/.233) | 7.0 × 10−4 | 0.273 | – | benign | N.A. | N.A. | |
| rs12075 | 1 | DARC | G41D | 0.007 (A: .599/.563) | 0.029 (G: .145/. 131) | – | 7.0 × 10−4 | N.A. | – | benign | 2 | 3.85 | N.A. |
| rs12118628 | 1 | OR10J1 | Mini | 0.002 (G: .894/.867) | – | 0.029 (G: .876A857) | 2.0 × 10−4 | 0.038 | – | benign | 0.00 | N.A. | |
| rs11120301• | 1 | SMYD2 | I429M | 1.1 × 10−5 (G: .010/.003) | 0.280 (G: .005/.002) | N.A. | 9.5 × 10−6 | N.A. | Y | benign | 15.95 | 18.59 | |
| rs3100246 | 2 | RSNL2 | R485L | 0.011 (G: .854/.831) | 0.003 (G: .981/.959) | – | 3.0 × 10−4 | 0.049 | Y | damaging | 4.50 | 0.00 | |
| rs961360• | 2 | R3HDM1 | M269V | 0.441 (T: .838/.822) | 0.311 (T: .802/.784) | 2.5 × 10−5 (T: .904/.872) | 1.0 × 10−4 | N.A. | Y | damaging | 16.80 | 24.46 | |
| rs7627615 | 3 | HTR3E | A85T | – | 0.027 (A: .882/.859) | 0.003 (G: .413/.377) | 3.0 × 10−4 | 0.047 | Y | benign | 3 | N.A. | N.A. |
| rs1052439 | 3 | FAM79B | L3P | 0.045 (T: .673/.647) | 0.038 (T: .659/.617) | 0.006 (T: .700/.669) | 1.0 × 10−4 | 0.087 | Y | unknown | N.A. | N.A. | |
| rs16902872 | 5 | FLJ25422 | A270V | 0.003 (A: .003/.001) | 0.016 (A: .290/.254) | N.A. | 2.0 × 10−4 | N.A. | Y | benign | 4.41 | N.A. | |
| rs846664 | 7 | TAS2R16 | N171K | 0.005 (G: .004/.001) | 0.041 (G: .286/.252) | N.A. | 6.0 × 10−4 | N.A. | – | benign | 0.00 | 0.00 | |
| rs307658 | 9 | UBAP2 | N605S | – | 0.019 (A: .495/.449) | 0.007 (A: .642/.606) | 7.0 × 10−4 | 6.1 × 10−4 | – | benign | N.A. | N.A. | |
| rs1785506 | 9 | UBAP2 | R13Q | – | 0.019 (A: .494/.448) | 0.006 (A: .641/.605) | 6.0 × 10−4 | 6.1 × 10−4 | YY | damaging | 93.98 | 6.79 | |
| rs3750425 | 9 | TRPM6 | VI3921 | – | 0.046 (T: .281/.246) | 2.6 × 10−5 (T: .102/.073) | 3.3 × 10−6 | 0.002 | – | benign | 4 | 0.12 | N.A. |
| rs1200875 | 10 | ANKRD30A | R928C | 0.022 (G: .781/.754) | – | 0.009 (G: .782/.754) | 5.0 × 10−4 | 0.048 | – | damaging | N.A. | N.A. | |
| rs2792751 | 10 | GPAM | I42V | 0.021 (A: .304/.279) | – | 0.012 (A: .287/.261) | 7.0 × 10−4 | 3.7 × 10−4 | Y | benign | 7.53 | 2.99 | |
| rs1541314 | 11 | TOLLIP | G1807S | 0.015 (A: .084/.069) | – | 0.006 (A: .072/.055) | 2.0 × 10−4 | 0.23 | – | benign | 13.14 | 34.80 | |
| rs2273549 | 11 | TCP11L1 | K177R | 0.037 (A: .835/.815) | – | 0.005 (A: .834/.806) | 5.0 × 10−4 | 0.025 | – | benign | 7.37 | N.A. | |
| rs7927370 | 11 | OR4A15 | A286V | 0.044 (C: .952/.939) | 0.044 (C: .993/.984) | 0.035 (C: .948/.933) | 7.0 × 10−4 | 0.413 | – | benign | 0.00 | 0.00 | |
| rs11630901 | 15 | RPAP1 | R581G | 0.005 (T: .830/.804) | 0.023 (T: .972/.957) | – | 4.0 × 10−4 | 0.123 | Y | damaging | 1.77 | 3.18 | |
| rs1139897 | 16 | RHOT2 | R244Q | – | 0.007 (G: .945/.921) | 0.009 (G: .783/.753) | 6.0 × 10−4 | 0.016 | Y | benign | N.A. | 9.91 | |
| rs1800309 | 17 | GAA | E688K | 0.008 (G: .971/.957) | 0.002 (G: .986/.967) | N.A. | 2.0 × 10−4 | N.A. | Y | benign | 33.61 | N.A. | |
| rs4806163 | 19 | ZD52F10 | V90A | – | 0.012 (A: .054/.031) | 0.008 (A: .232/.204) | 6.0 × 10−4 | 0.016 | – | benign | 0.63 | 0.50 | |
| rs2125579 | 19 | ZNF235 | H295P | 0.008 (G: .559/.529) | 0.060 (T: .808/.780) | 0.044 (G: .549/.522) | 2.0 × 10−4 | 0.031 | – | benign | N.A. | N.A. | |
These three single-nucleotide polymorphisms (SNPs) are top-ranked SNPs in three samples, respectively; two of them are not replicable. Risk allele = the allele having higher frequency in cases/transmitted than controls/untransmitted; EA = European Americans; AA = African Americans; EAu = European Australians; cis-eQTL = minimal p values for exon-level cis-acting expression regulation in human brain; Y = located at exon-splicing enhancer (ESE) or exon-splicing silencer (ESS); YY = located at ESE or ESS that can abolish protein domain.
These diseases/traits are associated with nsSNPs: (1) Parkinson’s disease, plasma cholesterol levels as well as size and composition of low-density lipoprotein particles; (2) Inflammation, white blood cell count, circulating concentrations of monocyte chemoattractant protein-1; (3) Schizophrenia; (4) Type 2 diabetes.
Transcript-level RNA expression in mouse and rat brains; raw and processed data are available at http://phenogen.ucdenver.edu; expression of all genes with RPKM > 0 listed in this table could be distinguished above background (p < .0001) in whole brain samples of all mice and rats examined using the Affymetrix Mouse (Rat) Exon 1.0 ST array.
RPKM = reads per kilobase of transcript per million mapped reads; these RPKM values were calculated from the RNA-Seq data generated from ribosomal depleted total RNA from six mouse brains using the Helicos Helisphere single molecule sequencing system.
FPKM = fragments per kilobase of transcript per million mapped reads; these FPKM values were calculated from the RNA-Seq data generated from polyA+ selected RNA from three rat brains using the Illumina HiSeq2000. “–”, p > .05; N.A. = not available.