Genetic underpinnings of the transition from alcohol consumption to alcohol use disorder: shared and unique genetic architectures in a cross-ancestry sample

Recent GWAS of alcohol-related traits have uncovered key differences in the underlying genetic architectures of alcohol consumption and alcohol use disorder (AUD), with the two traits having opposite genetic correlations with psychiatric disorders. Understanding the genetic factors that underlie the transition from heavy drinking to AUD has important theoretical and clinical implications. We utilized longitudinal data from the cross-ancestry Million Veteran Program sample to identify 1) novel loci associated with AUD and alcohol consumption [measured by the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C)] and 2) genetic variants with direct effects on AUD not mediated through alcohol consumption. We identified 26 loci associated with AUD, including 5 ancestry-specific and 6 novel loci and 22 loci associated with AUDIT-C, including 3 ancestry-specific and 8 novel loci. In secondary GWAS that excluded individuals who report abstinence, we identify 7 additional loci for AUD and 8 additional loci for AUDIT-C. We demonstrate that, although the heterogeneity of the abstinent group biases the GWAS findings, unique variance between alcohol consumption and disorder remains after the group is excluded. Finally, using mediation analysis, we identified a set of variants with effects on AUD that are not mediated through alcohol consumption. The distinct genetic architectures of alcohol consumption and AUD suggest different biological contributions to the traits. Genetic variants with direct effects on AUD are potentially relevant to understanding the transition from heavy alcohol consumption to AUD and targets for translational prevention and treatment efforts.