A high-resolution PheWAS approach to alcohol-related polygenic risk scores reveals mechanistic influences of alcohol reinforcing value and drinking motives.

This study investigates the motivational mechanisms underlying genetic risk for alcohol use by examining polygenic risk scores (PRSs) related to various alcohol phenotypes—including the Alcohol Use Disorders Identification Test (AUDIT), drinks per week, alcohol use disorder (AUD), and problematic alcohol use (PAU)—in a community sample of 1,534 Europeans. Using a phenome-wide association approach across 42 curated phenotypes spanning alcohol consumption, reinforcing value, drinking motives, comorbid psychiatric syndromes, impulsivity, and personality traits, the study found that PRSs for alcohol consumption (AUDIT-C and drinks per week) were significantly associated with alcohol reinforcing value and both positive (social, enhancement) and negative (coping) drinking motives. Additionally, PRSs for PAU and drinks per week were linked to adverse childhood experiences, suggesting genetic overlap with environmental risk factors. The findings highlight distinct genetic influences on motivational pathways related to alcohol involvement and emphasize the complexity of genetic risk across diverse phenotypic domains, while noting limitations in sample size and ancestry representation.