LAUSR

Background Genetic factors contribute to the risk for developing alcohol use disorder (AUD). Previous studies have estimated the heritability of AUD to be between 40–60% and have explored the role of specific candidate genes, including genes for alcohol-metabolizing enzyme like ADH1B, ALDH2. More recently, Genome-Wide Association Studies (GWAS) have been used to identify risk loci for alcoholism. Methods In collaboration with the genetics company 23andMe, Inc., we performed a GWAS of the Alcohol Use Disorder Identification Test (AUDIT), a screening instrument to assess AUD. Our final sample consisted of 20,328 male and female adult research participants of European ancestry, with a mean age of 53.8 (SD= 16.1), and with low to modest self-reported rates of alcohol use. Results We estimated chip-heritability at 12%, supporting the role for common genetic variation in responses to the AUDIT. One of our top hits was on chromosome 4 near the gene ADH1C (rs141973904; 4.4 × 10−7), which has been previously implicated by GWAS for AUD. We also detected a suggestive association on chromosome 1 (2.1 × 10−7; rs182344113) near the gene KCNJ9, which has been implicated in preclinical models of ethanol sensitivity. We used polygenic methods to examine co-heritability between AUDIT and several personality and psychiatric traits. We identified positive genetic correlations between AUDIT, smoking lifetime use, and educational attainment, and negative correlations with BMI/obesity. The unexpected, positive genetic correlation between AUDIT and educational attainment (rg= 0.27, P= 6.1 × 10−3), and the negative genetic correlations between AUDIT and both BMI/obesity (rg= -0.26, P= 1.4 × 10−4; rg= -0.23, P= 2.1 × 10−3), may be a consequence of the fact that the population we studied had very modest levels of alcohol use. Discussion We conclude that AUDIT score is a modestly heritable trait that is related to AUD and has a highly polygenic genetic architecture. We also demonstrate that conducting a genetic study using data from a generally unselected cohort of research participants who responded to a self-reported questionnaire may represent a cost-effective strategy for elucidating the etiology of AUD.