Epigenetic Biomarkers Of PTSD: Updates From The EWAS Working Group of The PTSD PGC

Abstract

Trauma exposure is unfortunately quite common, yet only a minority of individuals develop PTSD following trauma. The Epigenome-Wide Association Study (EWAS) group of the PTSD PGC is working to identify DNA methylation-based epigenetic biomarkers of PTSD that can serve as important indicators of the disorder, and to characterize which of these biomarkers identify individuals who may be most at risk following trauma. Existing, blood-derived DNA methylation microarray data from three civilian and seven military cohorts were analyzed using a common pipeline that tested each CpG site for an association with PTSD, controlling for age, genomic-derived ancestry estimates, leukocyte cell proportions as well as study-specific covariates if applicable (i.e. gender, plate, or bisulfite conversion). A meta-analysis across all cohorts and separately within Civilian and Military cohorts was subsequently conducted to identify robust biomarkers of PTSD. Results from primary analyses of all 1,896 samples revealed that the top four CpG sites fell within the AHRR locus (FDR for all sites <0.0003) and were all associated with reduced DNA methylation in PTSD. However, the associations at all four sites were substantially attenuated (FDR for all sites >0.69) in additional analyses that controlled for smoking. In contrast, the fifth ranked CpG site within RNF6 (FDR=0.007) from the primary analyses became the top-ranked CpG site associated with PTSD in our additional analyses that controlled for smoking (N=1,841), although results did not reach statistical significance (FDR=0.09). The meta-analysis of Civilian cohorts (N = 545) yielded two significant CpG sites within the NRG1 (FDR = 0.023) and HGS (FDR = 0.033) loci. Both loci remained significant after controlling for smoking. A sensitivity analysis of two cohorts found that the association with PTSD was consistent within each cohort after controlling for childhood maltreatment. Longitudinal analyses are ongoing to assess whether these differences pre-date trauma exposure that precipitates PTSD, or whether they associate with PTSD onset.