Project Summary Psychiatric Genomics Consortium for PTSD Posttraumatic stress disorder (PTSD) occurs only in vulnerable individuals after exposure to severe traumatic events. This risk is due, in part, to 40-50% heritability of differential vulnerability. Due to increasing collaborations across the field of PTSD genomics and the advent of new analytical tools, it is a very exciting time for PTSD genetic risk discovery. The purpose of this application is to facilitate meta-analyses of genome- wide association study (GWAS) data for symptoms and diagnosis of PTSD. We propose to conduct large-scale meta-analyses through the PTSD group of the Psychiatric Genomics Consortium (PGC). The PGC was created in 2007 to conduct field-wide mega-analyses of individual data for 5 major psychiatric disorders. With its current 11 working groups, it is the largest consortium (>800 scientists from 40 countries) in the history of psychiatry. The PGC has produced major findings with regard to the genetic architecture of psychiatric disorders. The PGC-PTSD group was launched in 2013 and has been enormously successful. Currently our multi-ethnic data collection includes genotypes from 90 studies with a total N of over 1.25 million combined cases and trauma-exposed controls. We recently identified 95 genome-wide significant loci and generated a polygenic risk score to identify individuals at highest risk for PTSD after trauma exposure. We hypothesize that with an increased sample size and deeper phenotype characterization, the PGC- PTSD will accelerate our current understanding of the genetic architecture of PTSD. Our progress thus far demonstrates feasibility and successes of the proposed work. Aim 1 proposes to increase sample size to 450,000 PTSD cases, including 100,000 cases of non-European ancestry, conduct GWAS meta-analyses to detect novel common variants, and identify rare copy-number variants (CNVs) and single nucleotide variants (SNV) hypothesized to contribute to PTSD heritability. This aim will be supplemented by the contribution of diverse ancestry groups to ensure that advances in our genetic understanding of PTSD extend across ancestral backgrounds in Aim 2. Aim 3 is centered around the characterization of functional consequences of identified variants. Lastly, we will address the heterogeneity of PTSD and its overlap with internalizing disorders in Aim 4. Identifying the genetic pathways underlying PTSD will lead to improved neurobiological understanding, enhanced prevention, and improved treatment of this debilitating and prevalent syndrome.