Posttraumatic Stress Disorder Epigenome-Wide Association Studies in the Million Veteran Program

Genomic studies have improved our understanding of posttraumatic stress disorder (PTSD) biology. Epigenetic differences in DNA methylation can reflect environmental influences, which are critical in PTSD etiology, and may additionally differentiate between PTSD cases and controls or distinguish severity of PTSD symptoms. We conducted epigenome-wide association studies (EWAS) of PTSD in 22,141 subjects from the United States V.A. Million Veteran Program (MVP), using the PTSD Checklist (PCL-C), including 17,674 European ancestry (EUR), 3,430 African ancestry (AFR), and 1,037 admixed American descent (AMR) individuals. We evaluated the 17-item PCL-C and its symptom subdomains (re-experiencing, avoidance, and hyperarousal) and used our previously-reported algorithmically-defined PTSD diagnoses validated against clinical records. There were 9,413 total cases of Lifetime PTSD and 27,257 controls, with 5,184 cases and 19,382 controls in EUR, 3,095 cases and 6,240 controls in AFR, and 1,134 cases and 1,635 controls in AMR. We identified a total of 272 epigenome-wide-significant associated CpG sites across all PTSD traits, or 28 after adjusting for smoking status. We replicated 5 out of 11 CpG sites reported in a prior (Psychiatric Genomics Consortium) PTSD EWAS. There was significant enrichment of genes downregulated in somatostatin interneurons and of genes expressed in GABAergic interneurons. Regression analyses showed that PTSD case status was significantly correlated with accelerated DNA methylation aging. Contrary to previous PTSD EWAS findings, smoking status stratification suggested that the association between PTSD and methylation of the AHRR gene may be confounded by smoking status. This is the largest-scale PTSD EWAS in multiple ancestries and the first large PTSD EWAS on symptom severity. We replicate findings from previous EWAS and greatly extend knowledge of the epigenetics of PTSD.