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kkoenen@hsph.harvard.edu

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cnievergelt@ucsd.edu

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kressler@mclean.harvard.edu

Smith A.K., Ratanatharathorn A., Maihofer A.X., … Uddin M., Nievergelt C.M. Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies novel methylation loci. Nature Communications (2020)

Post-traumatic stress disorder (PTSD) is characterized by reexperiencing, avoidance, and hyperarousal symptoms that can negatively impact mood and physiologic health. Although not everyone who experiences trauma goes on to
develop PTSD, those who do often experience severe and disabling symptomatology. Research suggests that both genetic and environmental factors contribute to risk for developing PTSD. Given the necessary, but not sufficient, role of environmental exposure (i.e., trauma) in the development of PTSD, it is critical to characterize the pathways underlying differential risk and resilience. Studies that contexualize the role of environmental influences provide additional insight into modifiable factors that may promote post-trauma resilience. For example, lack of social
support at the time of trauma is associated with increased risk of developing PTSD in both military and civilian contexts. Similarly, studies that investigate how presumed environmental influences might affect biological pathways could provide insights into the genes whose regulation patterns differ in those with PTSD. A growing line of research aimed at elucidation of mechanisms by which environmental factors contribute to PTSD, has focused on epigenetic modifications, which regulate gene function in response to environmental triggers. Epigenetic modifications, such as DNA methylation at cytosine-guanine dinucleotides (CpG sites), can induce changes in gene expression that are maintained through each round of cell division. Multiple reviews have linked traumatic stress to differences in the proportion of methylated DNA intensity to non-methylated DNA intensity (ß) at specific CpG sites. Indeed, a number of epigenome-wide association studies (EWAS) of individual cohorts have identified PTSD-associated CpG sites in genes and pathways related to neurotransmission and immune function11–15. Similarly, studies using methylation of specific CpG sites that predict chronological age with reasonably high accuracy to capture age acceleration (deviations from a line of prefect prediction), demonstrate associations with PTSD and link differences in peripheral DNA methylation to memory formation and neural integrity. Although promising, the extant literature of EWAS studies on PTSD is limited by use of individual cohorts with small sample sizes and varying analytic pipelines that can make it challenging to synthesize findings. Consortia efforts can overcome these limitations by providing a shared analytic pipeline and increasing sample size and thus statistical power. The goal of this study is to capitalize on consortium strengths by conducting a meta-analysis of DNA methylation across 10 military and civilian cohorts participating in the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup. Our results suggest that lower aryl-hydrocarbon receptor repressor (AHRR) methylation in those with PTSD correlates with lower kynerunine levels, which may contribute to immune dysregulation in PTSD.

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