The contribution of heritable factors to alcoholism has been documented in twin studies for over two decades (e.g., Jardine and Martin, 1984; Kaprio et al., 1987), but identification of the specific genetic variants that influence alcohol use disorder (AUD) has proven challenging. AUD is a complex and heterogeneous disorder that involves multiple biological pathways, including alcohol metabolism, GABA receptor activity, and serotonin and dopamine signaling, and as such, involves a large number of genes with diverse functions. The individual contribution of a given genetic variant is modest, typically accounting for less than 1% of genetic variance in alcohol phenotypes, and the sum of the individual contributions of known variants does not approach the 50–60% heritability estimate from twin studies (Reed et al., 1996, True et al., 1996, van den Bree et al., 1998). The so-called missing heritability problem (Maher, 2008) may be due in part to inflation in heritability estimates from twin studies, in which gene–environment correlation and interaction effects are subsumed under additive genetic effects. Thus, investigating gene–environment interplay in alcohol-related outcomes is critical to the development of valid etiological models of alcohol use and misuse.
