Polygenic Risk Factors for Comorbid Diagnoses in Individuals with Substance Use Disorders: A Phenome-Wide Survival Analysis.

Objective: Persons with substance use disorders (SUD) often suffer from additional comorbidities. Researchers have explored this overlap via phenome wide association studies (PheWAS). However, PheWAS are largely cross-sectional, limiting our understanding of whether diagnoses predate development of an SUD. We characterize whether polygenic scores (PGS) are associated with time to comorbid diagnoses in electronic health records (EHR) after the first documented SUD diagnosis. Methods: Using data from All of Us (N = 393,596), we explored: 1) whether social determinants of health (SDoH) are associated with lifetime risk of SUD (N cases = 42,568) and 2) within a subset those with a diagnosed SUD and available genetic data SUD (N = 21,357), whether PGS for alcohol use disorders, cannabis use disorders, depression, externalizing, post-traumatic stress disorder, and schizophrenia were associated with subsequent diagnoses via a phenome-wide survival analysis. Results: Multiple SDoH were associated with lifetime SUD diagnosis, with annual household income having the largest overall associations (e.g., <$10K annually vs $100K-$150K annually: OR = 3.89, 95% CI = 3.66, 4.13). There were 101 phenome-wide significant PGS associations with subsequent diagnoses across various bodily systems. PGSs for alcohol use disorders, post-traumatic stress disorder, and schizophrenia were each associated with time to their respective diagnoses. Conclusions: Social determinants, especially those related to income, have profound associations with lifetime SUD risk. Additionally, PGS for psychiatric conditions are associated with multiple post-SUD diagnoses within those with a SUD, suggesting PGS may capture information beyond lifetime risk, including timing and severity of comorbidities related to SUD.