LAUSR

Background: Substance use disorders (SUDs) are associated with a variety of co-occurring psychiatric disorders and other SUDs, which partly reflects genetic pleiotropy. Polygenic risk scores (PRS) and phenome-wide association studies (PheWAS) are useful in evaluating pleiotropic effects. The comparatively low prevalence of SUDs and lack of detailed information available in electronic health records limits their informativeness for such analyses. Methods: We used the deeply-phenotyped Yale-Penn sample [(N=10,610; 46.3% African ancestry (AFR), 53.7% European ancestry (EUR)], recruited for genetic studies of substance dependence, to examine pleiotropy for 4 major substance-related traits: alcohol use disorder (AUD), opioid use disorder (OUD), smoking initiation (SMK), and lifetime cannabis use (CAN). The sample includes both affected and control subjects interviewed using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA), a comprehensive psychiatric interview. Results: In AFR individuals PRS for AUD, and in EUR individuals PRS for AUD, OUD, and SMK, were associated with their respective primary DSM diagnoses. These PRS were also associated with additional phenotypes involving the same substance. PheWAS analyses of PRS in EUR individuals identified associations across multiple phenotypic domains, including phenotypes not commonly assessed in PheWAS analyses, such as family environment and early childhood experiences. Conclusions: Smaller, deeply-phenotyped samples can complement large biobank genetic studies with limited phenotyping by providing greater phenotypic granularity. These efforts allow associations to be identified between specific features of disorders and genetic liability for SUDs, which help to inform our understanding of the pleiotropic pathways underlying them.