To date, the most robust genetic signals identified for both alcohol consumption and dependence have been within ADH1B (across multiple ancestries (Bierut et al., 2012; Clarke et al., 2017; Kranzler et al., 2019; Luczak et al., 2006; Sanchez-Roige et al., 2018; Walters et al., 2018). Recent GWAS of alcohol consumption (Jorgenson et al., 2017; Liu et al., 2019; Schumann et al., 2011, 2016) have implicated loci in AUTS2, KLB, GCKR and other genes; however, evidence for their involvement in the genetics of alcohol dependence remains limited (Sanchez-Roige et al., 2018), although a recent preprint implicated GCKR in a large GWAS of AUD (Kranzler et al., 2019). The protective allele of rs1229984, the missense SNP within ADH1B that affects the conversion of ethanol to acetaldehyde, exerts one of the largest single-variant effects on a polygenic trait, with up to a 3-fold decrease in risk for alcohol dependence (Edenberg, 2007; Edenberg & McClintick, 2018). Thus, studies that examine the polygenic overlap between consumption and dependence should account for the role of ADH1B in aggregated genomic propensity.
