High polygenic risk scores are associated with age of onset of alcohol use disorder in adolescents and young adults at risk

ABSTRACT Background Genome-wide association studies (GWAS) have been conducted in Alcohol Use Disorder (AUD) and they permit the use of polygenic risk scores (PRS), in combination with clinical variables, to predict the onset of AUD in vulnerable populations. Methods 2794 adolescent/young adult subjects from the Collaborative Study on the Genetics of Alcoholism (COGA) were followed with clinical assessments every two years. Subjects were genotyped using a genome-wide chip. Separate PRS analyses were performed for subjects of European ancestry (EA) and African Ancestry (AA). Age of onset of DSM-5 AUD was evaluated using the Cox proportional hazard model. Predictive power was assessed using Receiver Operating Characteristic (ROC) curves and by analysis of the distribution of PRS. Results EA Subjects with higher than median PRS were at greater risk for onset of AUD than subjects with lower than median PRS (p = 3e-7). Area under the curve for the ROC analysis peaked at 0.88-0.95 using PRS plus sex, family history, comorbid disorders, age at first drink, and peer drinking; predictive power was primarily driven by clinical variables. In this high risk sample EA subjects with a PRS score in the highest quartile showed a 72% risk for developing AUD and a 35% risk of developing severe AUD (compared to risks of 54% and 16% in the lowest quartile). Conclusions Predictive power for PRS scores in the extremes of the distribution suggests that these may have future clinical utility. Uncertainties in interpretation at the individual level still preclude current application.