GWAS, when well powered, can serve as a powerful tool for uncovering common variation associated with addiction phenotypes. For instance, in the largest of the aforementioned meta-analyses of CPD, an aggregate sample size > 140,000 resulted in an association signal for rs1051730 in CHRNA3 on the order of magnitude of 10-73 [53••]. Despite the high degree of statistical significance, the effect size was small with each risk allele only associated with one extra CPD. Such weak penetrance likely limits the ability of individual GWAS to produce replication. There have now been nine GWAS on DSM-IV alcohol dependence [76-83] and of these, only three report genomewide significant signals. The first two report signals in PECR (Peroxisomal Trans-2-Enoyl-CoA Reductase) [82] and ADH1C (alcohol dehydrogenase 1C) [83], however none of the other studies have replicated these associations. The most recent of these is perhaps the most promising, convincingly demonstrating association between a symptom count of alcohol dependence and SNPs in ADH1B, including rs1229984 (p=1.2E-31) in European- and rs2066702 (p=6.3E-17) in African-American subjects [41••]. One meta-analysis has also identified a significant association between daily typical alcohol intake and a variant (rs6943555) within the autism susceptibility candidate 2 (AUTS2) gene (P=4.1E-9) [84].
