In contrast to the consistent evidence for the heritability of alcohol use and problems, no robust associations have been detected in genome-wide association studies (GWAS) to date. This is the case, in part, because the small samples typically used in alcohol research are underpowered to detect the very modest individual effect sizes that are generally observed in GWAS of complex behavioral outcomes. Large meta- and mega-analyses pooling across many studies are needed to obtain robust results in the substance use area [11]; only now are these studies underway for alcohol use and alcohol problems. In candidate gene studies, a few compelling associations have emerged within biologically plausible pathways. For example, polymorphisms in ADH1B and ALDH2 genes, which code for alcohol-metabolizing enzymes, have well-replicated associations with alcohol dependence [12,13,14,15]. In another example, independent groups have found evidence that the α2 encoding subunit of the GABA-A receptor (GABRA2) is associated with alcohol dependence [16,17]. Likewise, despite consistent evidence from twin samples that environmental factors moderate latent genetic influences, measured gene-by-environment moderation effects for behavioral outcomes have been widely criticized on the grounds that they are underpowered and likely reflect Type I statistical error [18].
