On average, 18 Veterans die by suicide each day. In fact, from 2009 to 2018, more than 64,000 Veterans died by suicide, which is roughly the same number of U.S. military fatalities that resulted from the wars in Vietnam, Iraq, and Afghanistan combined. While heritability estimates for suicidal thoughts and behaviors range from 30- 55%, the genetic basis of suicide remains largely unknown. Our research team has led and participated in many of the largest genome-wide association studies (GWAS) of suicidal thoughts and behaviors to date, including each of the largest conducted in Veteran and military samples. Our most recent work has involved conducting a GWAS of suicide attempts among more than 400,000 Veterans enrolled in the Million Veteran Program (MVP). This study identified multiple pan-ethnic and ancestry-specific genome-wide significant loci associated with risk for attempting suicide among Veterans. Moreover, pathway analyses found evidence of overrepresentation of many biological pathways with high clinical significance, including oxytocin signaling, glutamatergic synapse, cortisol synthesis and secretion, dopaminergic synapse, and circadian rhythm. In parallel, we have been studying a broad array of environmental risk factors for suicidal thoughts and behaviors in Veterans, such as sexual trauma, PTSD, depression, substance use disorders, borderline personality disorder, chronic pain, traumatic brain injury, and sleep disturbance (among others). We are also actively working to identify novel environmental risk factors, including geospatial factors [e.g., socioeconomic status (SES), rurality], many of which have not been previously examined in large-scale genetic studies of suicide risk. We believe that complete understanding of a complex phenotype requires understanding of relevant genetic risk factors, relevant environmental risk factors, as well as the ways in which these risk factors interact. Accordingly, during the next phase of our program of research, we propose to conduct the largest gene-by- environment genome-wide interaction study (GEWIS) of suicidal thoughts and behaviors to date. This work will enable us to identify new ways to improve the identification of high-risk Veterans, while also greatly increasing our understanding of the biological basis of suicide. Our long-term goal is to develop effective screening and intervention strategies to reduce the occurrence of suicide and suicidal behavior among Veterans. The overall objective of this specific application is to discover novel, replicable GxE interactions that increase Veterans’ risk for suicidal thoughts and behaviors. The rationale for this research is that identification of genetic variants, environmental factors, and GxE interactions that are reliably associated with suicidal thoughts and behaviors could lead to improved identification of high-risk Veterans and the discovery of additional clinically-meaningful biological pathways. Such findings could, in turn, lead t...