Although, AUD-associated genetic variants have been identified by genome-wide association studies (GWAS),5–10 they only explain a small proportion of the genetic variance for AUDs.11,12 While more variance will surely be explained when larger GWAS samples are collected or aggregated, the presently unexplained genetic variance may also be attributable in part to epigenetic events (such as DNA methylation, histone modifications, chromatin remodeling, and noncoding RNA regulations), rare or copy number variants, epistasis, or the interplay of genes and environment. Environmental factors alone (eg, chronic alcohol consumption) may also lead to alcohol tolerance or dependence through neuroadaptations. Increasing evidence suggests that drugs of abuse and drug-associated cues can alter gene expression in neurons, and this process may be mediated by epigenetic modifications (eg, DNA methylation).13 Thus, the development of AUDs over time may be influenced by neuroadaptations involving epigenetic modifications after long-term alcohol consumption.14
