Project Summary It is not clear why some people develop posttraumatic stress disorder (PTSD) in response to a traumatic event. DNA methylation, an epigenetic mark that associates with trauma and other environmental exposures, associates with PTSD in multiple studies, and DNA methylation of some genes may be informative for early prediction and treatment of PTSD. Over the last 3 years, the Epigenetics Workgroup of the Psychiatric Genomics Consortium for PTSD (PGC-PTSD) has brought together data from 10 studies, with over 90 investigators from 10 countries to facilitate meta-analyses of DNA methylation (DNAm) data from cross- sectional and longitudinal studies of PTSD in civilian and military cohorts. In this renewal proposal, we will build on this highly productive collaboration by replicating our findings in an independent meta-analysis and performing the largest epigenome-wide association study (EWAS) to date in >4,700 subjects, characterizing PTSD-associated CpGs in postmortem brain tissue, identifying methylation quantitative trait loci (meQTLs) in blood and brain relevant to PTSD, and characterizing DNAm changes over the course of PTSD treatment. We are poised to rapidly and efficiently identify epigenetic markers informative for early prediction and treatment and to provide context to genetic variants that predict risk and resilience following traumatic events. This study, which aligns with ongoing PGC-PTSD efforts, will inform critical questions in the field related to the role of blood-based methylation patterns as clinically-informative biomarkers and the degree to which they reflect epigentic patterns in the brain; it will also provide insight into the biologic pathways underlying PTSD, complement ongoing efforts to identify therapeutic targets, and inform prospective studies of PTSD and trauma exposure that are underway.