Examining the timing of trauma, PTSD onset, and DNA methylation: A multicohort investigation of candidate CpG sites.

Epigenome-wide association studies (EWAS) have identified cytosine-phosphate-guanine sites (CpGs) associated with trauma and PTSD. However, prior studies have largely focused on cross-sectional associations, and it remains unclear whether epigenetic profiles associated with traumatic stress might predispose individuals to develop PTSD or might change in response to PTSD. In this study, we characterized associations between traumatic stress and three CpGs identified in previous EWAS of PTSD (cg05575921 and cg26703534 in AHRR, and cg19534438 in G0S2) using two cohorts-the Dunedin Multidisciplinary Health and Development Study (n = 846) and the Post-Deployment Mental Health Study (PDMH; n = 2309). We first replicated cross-sectional associations, and then investigated the time course linking PTSD, trauma, and DNA methylation. In cross-sectional analyses, we found trauma and PTSD were consistently associated with hypomethylation at cg05575921-including at age 26, 38, and 45 in the Dunedin Study-whereas neither cg26703534 nor cg19534438 showed consistent associations. These results were robust to multiple methods of accounting for tobacco exposure, which is notable given associations between smoking and changes in AHRR. In the Dunedin Study, we also found that people who developed PTSD between age 26 and 45 showed greater hypomethylation at cg05575921 over the same period, however, people with hypomethylation at cg05575921 at age 26 were no more likely to develop future PTSD. Hypomethylation at cg05575921 was also associated with childhood adversity in the Dunedin Study and a past diagnosis of PTSD in the PDMH. Our findings suggest traumatic stress is associated with cg05575921 in the AHRR gene, and that trauma and PTSD may be associated with changes in cg05575921.