Associations between the development of PTSD symptoms and longitudinal changes in the DNA methylome of deployed military servicemen:A comparison with polygenic risk scores

Objective: Military servicemen deployed to war zones are at increased risk of developing posttraumatic stress disorder (PTSD) and successful adaptation to stress is important. Epigenetic alterations in response to trauma have been identified as mechanism of adaptation and may therefore predict deployment-related PTSD symptoms. To date, human studies of epigenetic marks for traumatic stress have been largely constrained by short-term analyses of one or two time points. Method: This study in a prospective Dutch military cohort (N ?= ?125) examined longitudinal changes of DNA methylation profiles before, as well as one and six months after deployment-related combat exposure in relation to the development of PTSD symptoms over a period of up to five years after deployment. We investigated the predictive value of specific methylation changes for immediate and delayed-onset PTSD symptoms and recovery. This epigenetic prediction was compared to polygenic risk score predictions obtained from the currently available largest genome-wide association study of PTSD. Results: A total of fourteen genomic regions were identified in which PTSD symptom levels were associated with methylation changes over time (pre-deployment, one, and six months post-deployment). Of these regions, four were significant determinants of longitudinal development of PTSD symptoms. In addition, we observed that, together with risk level during deployment (operating inside or outside the military base) and physical childhood trauma, post-deployment decreases in methylation at a genomic region in EP300/miRNA1281 was associated with a delayed onset of PTSD compared to a resilient profile. Polygenic risk, in contrast, was related to PTSD onset within six months after deployment but was not associated with long term outcomes. Conclusion: The present study suggests predictive utility of changes in DNA methylation for the subsequent development of PTSD symptoms and showed that the currently available measure of polygenic risk is primarily related to non-delayed disease onset