The current Career Development Award-Level 1 (CDA-1) proposal will expand Dr. Peter Na’s research scope to incorporate psychiatric genetics skills through comprehensive training in psychiatric genomics, statistical genetics, functional genomics and advanced psychiatric epidemiology. His mentors are leading experts in the field of psychiatric genetics and psychosocial epidemiology - Drs. Joel Gelernter, Robert Pietrzak, and Renato Polimanti, with collaboration from Dr. Hang Zhou, a computational biologist. Dr. Na will also pursue additional training through advanced workshops, seminars and courses offered by Yale University and other institutions. The proposed research project will investigate environmental (e.g., trauma load), psychosocial (e.g., purpose in life), and lifestyle (e.g., physical exercise) (EPL) factors that moderate polygenic susceptibility for alcohol use disorder (AUD) in Veterans using state-of-the art polygenic risk scores (PRS) computed from the world’s largest contemporary genome-wide association studies (GWAS) of this disorder. Further, the proposed study will advance the field’s understanding of the biopsychosocial etiology of AUD and alcohol consumption using cutting-edge genetic research methodologies such as gene enrichment and drug-repositioning analyses. While there have been advances in the understanding of genetics of AUD and psychosocial risk and protective factors for this disorder, the interaction between biological and EPL factors in predicting AUD remain poorly understood. To address this gap, the proposed study aims to identify EPL factors that moderate polygenic liability for AUD in Veterans using multiple large data sets, including the Million Veteran Program (MVP), the National Health and Resilience in Veterans Study (NHRVS) and the Yale-Penn Study. This line of research directly addresses the top priority research areas of the Veterans Health Administration (VHA) and this RFA (i.e., substance use disorders, precision medicine, diseases with a high healthcare burden in Veterans). The moderating EPL variables identified in the proposed study will elucidate targets for clinical interventions to prevent and treat AUD in Veterans and ultimately help guide VA clinical practices. PRS will be derived using the GWAS of AUD from the MVP cohort (N=267,391), of alcohol dependence from the Psychiatric Genomics Consortium (N=46,568), of the quantity-frequency trait derived from the Alcohol Use Disorders Identification Test from the UK Biobank (N=121,604), and of alcohol consumption (drinks/week) from GSCAN (GWAS & Sequencing Consortium of Alcohol and Nicotine use; N=537,352). Potential moderating EPL factors will be selected based on previous literature. The associations between PRS, selected EPL factors, and their interaction in predicting AUD and alcohol consumption will be examined using binomial and multinomial logistic regression analyses. PRS enrichment analysis will be conducted to examine the biological processes...