Alcohol use disorders (AUD) are modestly heritable, with twin-studies demonstrating that approximately 50% of the phenotypic variance is attributed to genetic factors (1, 2). To date, genetic studies of AUD have identified genes that influence pharmacokinetic (e.g. ADH1B, ADH1C, ALDH2)(3–8), but not pharmacodynamic factors. The difficulty of assembling large, carefully diagnosed cohorts of AUD has stimulated additional studies of non-clinical phenotypes, such as alcohol consumption, in populations not ascertained for alcohol dependence. This approach has allowed for the relatively rapid collection of much larger sample sizes (e.g. >100,000s individuals) and has identified numerous loci associated with both pharmacokinetic and pharmacodynamic factors that influence alcohol consumption, including ADH1B/ADH1C/ADH5 (9–11), KLB (encoding β-klotho)(9, 11, 12) and GCKR, encoding the glucokinase regulatory protein (9, 11). However, the genetic overlap between alcohol consumption (units per week) and DSM-IV diagnosed alcohol dependence is moderate (rg = 0.38)(13), reinforcing the notion that alcohol consumption cannot be used as a surrogate for alcohol dependence or AUD.
