Genome-wide search for replicable risk gene regions in alcohol and nicotine co-dependence

The present study searched for replicable risk genomic regions for alcohol and nicotine co-dependence using a genome-wide association strategy. The data contained a total of 3,143 subjects including 818 European-American (EA) cases with alcohol and nicotine co-dependence, 1,396 EA controls, 449 African-American (AA) cases, and 480 AA controls. We performed separate genome-wide association analyses in EAs and AAs and a meta-analysis to derive combined P-values, and calculated the genome-wide false discovery rate (FDR) for each SNP. Regions with P < 5 × 10(-7) together with FDR < 0.05 in the meta-analysis were examined to detect all replicable risk SNPs across EAs, AAs, and meta-analysis. These SNPs were followed with a series of functional expression quantitative trait locus (eQTL) analyses. We found a unique genome-wide significant gene region--SH3BP5-NR2C2--that was enriched with 11 replicable risk SNPs for alcohol and nicotine co-dependence. The distributions of -log(P) values for all SNP-disease associations within this region were consistent across EAs, AAs, and meta-analysis (0.315 ≤ r ≤ 0.868; 8.1 × 10(-52) ≤ P ≤ 3.6 × 10(-5)). In the meta-analysis, this region was the only association peak throughout chromosome 3 at P < 0.0001. All replicable risk markers available for eQTL analysis had nominal cis- and trans-acting regulatory effects on gene expression. The transcript expression of the genes in this region was regulated partly by several nicotine dependence (ND)-related genes and significantly correlated with transcript expression of many alcohol dependence- and ND-related genes. We concluded that the SH3BP5-NR2C2 region on Chromosome 3 might harbor causal loci for alcohol and nicotine co-dependence.