ABSTRACT Posttraumatic stress disorder (PTSD) is a major problem among military Veterans, yet its pathophysiology is poorly understood. The Veterans Affairs (VA) Million Veteran Program (MVP) is an ideal setting for study of this problem, and we are completing a Cooperative Studies Program project (CSP#575B), in the MVP context, to identify genetic risk factors relevant to PTSD and related traits. Our CSP-MVP Alpha Project for the Genomics of PTSD has been highly successful at mapping gene loci, so far for PTSD re-experiencing and other related phenotypes (such as “maximum habitual alcohol use”). Although PTSD GWAS data per se are under analysis, considerable work still needs to be done to fully develop and maximize the scientific value of the MVP for PTSD and related phenotypes, as the analyzable MVP sample continues to grow. Over the course of this project, we have assembled an expert team well- qualified to continue the work. To continue this work, we propose a set of extended analyses in a larger sample, and post-GWAS analyses. With more subjects there will be increased power to map relevant traits; we will continue GWAS of PTSD and related traits in the expanded sample. There is very high comorbidity of PTSD with substance use disorder traits; we propose to explore SUDs as well, including alcohol dependence, opioid dependence, nicotine dependence, and other SUDs. We will investigate single-gene and polygenic overlap between PTSD and related traits. We will study traits phenotypically associated with PTSD, such as cognitive decline, Alzheimer’s disease, persistent post-concussive symptoms, and immune-related disorders (such as Crohn’s disease, rheumatoid arthritis, and multiple sclerosis) in the MVP sample. We will use approaches that permit testing of causality among these correlated traits (e.g., Mendelian Randomization, MR). We will complete a phenomewide association study (PheWAS) of PTSD top GWAS-identified genes (e.g., CRHR1 and others), PTSD polygenic risk score (PRS) analysis within MVP, and MR to detect causal mechanisms related to PTSD pathogenesis. With the aim of maximizing the scientific value of these data and sharing them with the scientific community, we will also explore the possibility of replication of our findings in collaboration with other EHR-linked biobank consortia such as the Psych-EMERGE network; and the Psychiatric Genomics Consortium PTSD group (in which we participate presently). Finally, the MVP sample is suitable for advancing work in many populations that are generally understudied. We will investigate psychiatric trait-relevant population genetics of AAs, Latinos, East Asians, and South Asians, and other populations in the MVP system, and we will work to maximize information from, and identify results relevant to, all populations.