The current Career Development Award-Level 2 (CDA-2) proposal will further advance Dr. Peter Na’s research scope in psychiatric genetics through comprehensive training in psychiatric genomics, statistical genetics, epigenetics, functional genomics and advanced psychiatric epidemiology. His mentors are leading experts in the field of psychiatric genetics and psychosocial epidemiology - Drs. Joel Gelernter and Robert Pietrzak. 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., adverse childhood experiences), and psychosocial (e.g., purpose in life, social support) (EP) factors that moderate polygenic susceptibility for substance use disorders (SUDs) in Veterans using state-of-the art polygenic risk scores (PRS) computed from large contemporary genome-wide association studies (GWAS) of SUDs. Further, the proposed study will advance the field’s understanding of the biopsychosocial etiology of SUDs using cutting-edge genetic research methodologies such as epigenetic, gene enrichment and drug- repositioning analyses. While there have been advances in the understanding of genetics of SUDs and EP risk and protective factors for this disorder, the interaction between biological and EP factors in predicting SUDs remain poorly understood. To address this gap, the proposed study aims to identify EP factors that moderate polygenic liability for SUDs in Veterans using multiple large data sets, including the Million Veteran Program (MVP), National Health and Resilience in Veterans Study (NHRVS) and 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., SUDs, precision medicine, diseases with a high healthcare burden in Veterans). The moderating EP variables identified in the proposed study will elucidate targets for clinical interventions to prevent and treat SUDs in Veterans and ultimately help guide VA clinical practices. PRS will be derived using the GWAS of SUDs from the MVP cohort. Potential moderating EP factors will be selected based on previous literature. The associations between PRS, selected EP factors, and their interaction in predicting SUDs will be examined using machine learning analyses. PRS enrichment analysis will be conducted to examine the biological processes affected by the interaction. Further, drug repositioning analysis will be performed to examine the biological mechanisms and identify candidate medications for SUDs that may be further tested in animal and pilot studies. In addition, epigenetic analyses using longitudinal data will help identify longitudinal genome-wide DNA methylation differences associated with alcohol use phenotypes in Veterans. Upon successful completion of the proposed training and research project, Dr. Na will acquire sufficient expertise and preliminary dat...