Alcohol use disorder (AUD) is a complex trait that is about 50% heritable (1). However, with the exception of genetic variants in ADH1B, few variants contributing to the risk of the disorder have been identified. The relatively small sample size of most published genome-wide association studies (GWASs) of AUD has provided limited statistical power to identify the many variants of small effect that likely contribute to the disorder. Linkage and candidate gene studies, and more recently GWASs, have consistently identified risk loci at the genes encoding several of the alcohol-metabolizing enzymes (2). In a discovery and replication sample of 16,087 subjects (3), we confirmed previously identified risk loci mapped to the alcohol-metabolizing enzyme genes ADH1B in African Americans (AAs; Arg369Cys or rs2066702, P = 6.33 × 10−17) and European Americans (EAs; Arg48His or rs1229984, P = 1.17 × 10−31) and identified numerous novel additional associations across the ADH region on chromosome 4. Despite the presence of AUD risk loci in the ADH gene region and elsewhere, these account for only a small percentage of the estimated heritability of the disorder.
