Background: Charting the clinical course of substance use disorders (SUDs) to identify etiologic contributors to milestone onset and progression could inform intervention efforts. Methods: We calculated polygenic risk scores (PRS) in 5,692 European-ancestry individuals (EUR) (56.2% male) and 4,918 African-ancestry (AFR) individuals (54.9% male) using genome-wide association studies (GWAS) of alcohol use disorder (AUD), opioid use disorder (OUD), and smoking trajectory (SMK). Using Cox regression, we examined the association of polygenic risk with age of first substance use, regular use, reported problems, and dependence diagnosis and with progression from regular use to onset of problems and dependence. Results: EUR and males reported earlier onset and shorter progression times than AFR and females, respectively. Among EUR, higher AUD PRS predicted earlier onset and more rapid progression to alcohol-related milestones (p<0.0001) and although a stronger moderator of problem onset among females (p=0.0165), it was more predictive of the progression to problems among males (p=0.0054). OUD and SMK PRS in EUR also predicted earlier onset of the respective milestones (p=0.0002). Among AFR, where power is lower, AUD PRS predicted age of regular alcohol use (p=0.039) and dependence (p=0.001) and progression from regular use to diagnosis (p=0.045), while SMK PRS predicted earlier age of initiation (p=0.036). Conclusions: Genetic risk for SUDs predicts milestones and symptom progression in EUR and, to a lesser extent, among AFR. Larger, diverse discovery GWAS and target samples are needed to enhance the power of PRS to personalize interventions for individuals at genetic risk of serious substance-related outcomes.

Dr. Kranzler is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, and Enthion Pharmaceuticals; a consultant to Sobrera Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which was supported in the last three years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, and Otsuka. Drs. Gelernter and Kranzler hold U.S. Patent 10,900,082: Genotype-guided Dosing of Opioid Receptor Agonists, 26 Jan. 2021. The other authors have no disclosures to make.

Supported by the Veterans Integrated Service Network 4 Mental Illness Research, Education and Clinical Center and NIH grants P30 DA046345, R01 AA026364, and K01 AA028292 (to RLK)

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Institutional Review Board of the University of Pennsylvania approved collection of data from the Yale-Penn sample. The Central Institutional Review Board of the Department of Veterans Affairs approved collection of data from the Million Veteran Program sample.

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