Abstract Posttraumatic stress disorder (PTSD) is a major problem among military veterans and civilians alike, yet despite ongoing improvements in our understanding, its pathophysiology requires further intensive investigation. The Veterans Affairs (VA) Million Veteran Program (MVP) is an ideal setting for study of this problem, and we have led first a highly productive Cooperative Studies Program project (CSP#575B) in the MVP context to identify genetic risk factors relevant to PTSD and related traits; then, the first iteration of our MERIT project (MVP025), for which this is a competing renewal. From our prior work, we published PTSD genetics data in multiple high-impact journals; and other products of the project relating to anxiety, depression, alcohol use, and other traits. Over the course of the research, we assembled an expert team well-qualified to continue productively. To continue and extend this work, we propose analyses of PTSD and related traits in the growing MVP sample, including epigenetics and whole genome sequence (WGS) data, considering additional kinds of genetic variation, and more extensive post-GWAS analysis. Some of our key findings have concerned the relationship of PTSD to other psychiatric and medical disorders, for example, cardiovascular disease – we will expand upon this work also. Other work pertaining to PTSD (e.g. study of resilience traits, individual PCL- 17 item phenotypes, and sex-specific analyses) is underway. We will continue to explore PTSD subtypes and individual signs and symptoms from a genetic perspective. Discerning subtypes will be critical for the advancement of precision treatment of PTSD: genetic subtype may predict treatment response. With more MVP subjects there will be increased power to map relevant traits. We will continue GWAS of traits related to PTSD in the expanded sample. There is very high comorbidity of PTSD with substance use disorder traits; we propose to explore substance use-related traits as well, including alcohol, opioid, nicotine, stimulants, and other substances. We will also study additional traits phenotypically associated with PTSD, such as cognitive decline, Alzheimer’s disease, persistent post-concussive symptoms, and other traits with higher or lower risk or differing course in PTSD subjects than in the general population. We will investigate polygenic overlap between PTSD and related traits. We will use approaches that permit testing of causality among these correlated traits (e.g., Mendelian Randomization) and that can help establish the genetic relationships between sets of traits, such as genomic structural equation modeling. We will apply methods such as MiXeR to identify unique and shared polygenic components. To maximize the scientific value of these data we will undertake meta-analyses and replicate our findings in collaboration with other EHR-linked biobank consortia and collaborate with and share data with the Psychiatric Genomics Consortium (PGC) PTSD Workgroup...