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 PTSD epigenome-wide association studies (EWAS) in a large cohort, n = 22,141 subjects from the United States V.A. Million Veteran Program (MVP), with the PTSD Checklist (PCL-17), including 17,674 European ancestry (EUR), 3,430 African ancestry (AFR), and 1,037 admixed American descent (AMR). We evaluated the 17-item PCL-Total as well as symptom subdomains (re-experiencing, avoidance, and hyperarousal), and used lasso regression on electronic health records to define lifetime PTSD diagnoses. 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 241 epigenome-wide-significant associated CpG sites across all PTSD traits. We replicated 5 out of 11 CpG sites reported in a prior (Psychiatric Genomics Consortium) PTSD EWAS. Overlap with differentially methylated CpG sites in subregions of the amygdala and hippocampus of human postmortem brains of individuals with PTSD vs. controls was evaluated at the CpG and gene levels. Ten genes of the 195 identified in the brain study overlapped with the 192 identified in our EWAS. There was significant enrichment of genes downregulated in somatostatin interneurons and brain endothelial cells. Regression analyses showed that PTSD case status was significantly associated 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. Our findings showcase the largest-scale PTSD EWAS in multiple ancestries and the first large PTSD EWAS on symptom severity. We replicated several findings from previous EWAS and greatly extended current knowledge of the relationship between epigenetics and PTSD.