Table 3. Top candidate genes for alcoholism.
| Gene symbol/name | Discovery GWAS1 best P-value SNP | Internal score nominally significant SNPs/total SNPs tested (% significant) | Human genetic evidence | Human post-mortem brain expression evidence | Human peripheral expression evidence | Animal model genetic evidence | Animal model brain expression evidence | Animal model peripheral (blood) expression evidence | CFG score | DBP stress4 | DBP stress DHA5 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| SNCA, synuclein alpha (non A4 component of amyloid precursor) | 0.02363 rs17015982 | 2 4/68 (5.89%) | Association7,8 | (D) PFC8, 9, 10 (I) FC11 | (I) Blood12 (I) Blood13 (I) Serum14 DNA hypermethylation15 | QTL16 | (D) FC, CP17 (I) HIP P1 AMY P33 | (I) Blood male adult cynomolgus monkeys18 | 13 | (D) AMY, blood | (I) Blood |
| GFAP, glial fibrillary acidic protein | 0.01052 rs744281 | 3 4/12 (33.34%) | Linkage19 | (D) FC9,11,20 | (I) FC21 HIP, NAC, PFC P13 | 9.5 | (I) AMY | ||||
| DRD2, dopamine receptor D2 | 0.03652 rs4938019 | 2 2/46 (4.35%) | Association22, 23, 24, 25, 26 | (D) FC, CP27 (D)28 | (Transgenic) alcohol aversion decreased alcohol consumption29 | 9 | (D) PFC | (I) AMY | |||
| GRM3, glutamate receptor, metabotropic 3 | 0.001126 rs41440 | 2 15/133 (11.28%) | Linkage30,31 | (D) HIP32 | (I) NAC33 (D) FC34 (D) CP P23 | 9 | (I) AMY | ||||
| MBP, myelin basic protein | 0.006503 rs1124941 | 2 16/109 (14.68%) | (D) FC11 | (I) PFC35 (D) cerebellum36 delayed expression37 | (D) CG-4 glial cells rat brain38 | 8.5 | (D) PFC (I) AMY | (D) Blood (I) HIP | |||
| MOBP, myelin-associated oligodendrocyte basic protein | 0.01231 rs562545 | 2 2/43 (4.66%) | (D) FC11 | QTL39 | (I) PFC35 (D) NAC40 (I) whole brain41 (I) PFC P13 | 8.5 | (D) PFC (I) AMY | (D) Blood (I) HIP | |||
| GNAI1, guanine nucleotide binding protein (G protein), alpha-inhibiting activity polypeptide 1 | 0.00059 rs12706724 | 2 11/66 (16.67%) | Linkage42,43 | (D) HIP32 | (D) NAC P33 | 8 | (D) PFC | ||||
| MOG, myelin oligodendrocyte glycoprotein | 0.01429 rs3117292 | 2 3/19 (15.79%) | (D) FC, HIP11,32 | (D) VTA44 (I) PFC35 (I) PFC P13 | 8 | (D) PFC | (I) HIP | ||||
| RXRG, retinoid X receptor, gamma | 0.005815 rs10800098 | 2 1/37 (2.71%) | Linkage45 | (D) FC11 | (I) CP P33 | 8 | (D) PFC | ||||
| SYT1, synaptotagmin I | 0.04139 rs1245810 | 2 7/117 (5.99%) | (D) NAC46 | (D) FC34 (D) HIP47 | (I) Cultured neurons48 (I) Cortical neurons49 | 8 | (D) PFC | (D) AMY | |||
| TIMP2, TIMP metallopeptidase inhibitor 2 | 0.04309 rs7502935 | 2 1/25 (4%) | Linkage45 | (D) FC, HIP, NAC32,46,50 | (I) VTA44 | 8 | (D) PFC | (D) Blood |
Abbreviations: AMY, amygdala; Association, association evidence; CFG, convergent functional genomics; CP, caudate–putamen; D, decreased in expression; DBP, D-box-binding protein; DHA, docosahexaenoic acid; GWAS, genome-wide association study; HIP, hippocampus; I, increased; Linkage, linkage evidence; NAC, nucleus accumbens; P1, paradigm 1; P2, Paradigm 2; P3, paradigm 3 in the Rodd et al;3 PFC, prefrontal cortex; QTL, quantitative trait loci; SNP, single-nucleotide length polymorphism; TG, transgenic; VT, ventral tegmentum; VTA, ventral tegmental area.
Top genes with a CFG score of 8 and above that overlapped with top genes from the stress-reactive animal model are shown (n=11; Figure 4). Best P-value SNP within the gene or flanking regions is depicted. A more complete list of genes with CFG score of 8 and above (n=135) is available in the Supplementary Information section (Supplementary Table S1). Underlined gene symbol represents means gene is a blood biomarker candidate. Bold P-values <0.001.