Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies novel methylation loci

Abstract

Differences in susceptibility to posttraumatic stress disorder (PTSD) may be related to epigenetic differences between PTSD cases and trauma-exposed controls. Such epigenetic differences may provide insight into the biological processes underlying the disorder. Here we describe the results of the largest DNA methylation meta-analysis of PTSD to date with data from the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup. Ten cohorts, military and civilian, contributed blood-derived DNA methylation data (HumanMethylation450 BeadChip) from 1,896 PTSD cases (42%) and trauma-exposed controls (58%). Utilizing a common QC and analysis strategy, we identified ten CpG sites associated with PTSD (9.61E-07<p<4.72E-11) after adjustment for multiple comparisons (FDR<.05). Several CpGs were located in genes previously implicated in PTSD and other psychiatric disorders. The top four CpG sites fell within the aryl-hydrocarbon receptor repressor (AHRR) locus and were associated with lower DNA methylation in PTSD cases relative to controls. Interestingly, this association appeared to uncorrelated with smoking status and was most pronounced in non-smokers with PTSD.Additional evaluation of metabolomics data supported our findings and revealed that AHRR methylation associated with kynurenine levels, which were lower among subjects with PTSD relative to controls. Overall, this study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci

“…According to iMethyl (accessed Jan 21, 2020), adjacent loci (chr5:373,355 and chr5:373,398) are negatively associated with expression of the AHRR gene in monocytes (p < 5 × 10 -6 ). Additionally, as reported in Smith et al, methylation at this locus is associated with lower kynurenine and kynurenic acid [17]. Based on the examination of the impact of the smoking score and our follow-up analyses using the score and smoking, we conclude that our data are consistent with a PTSD effect which is independent of the association with smoking.…”

“…These findings are highly relevant to the epigenetics of PTSD because PTSD samples, especially from veteran cohorts, tend to have an elevated prevalence of cigarette smoking relative to the general population [23]. The AHRR locus cg05575921 that was associated with PTSD in the Smith et al EWAS [17] was also highly significant in both the Joehanes et al EWAS of smoking [21] and the Li et al EWAS of smoking [22], and in the latter, was the most significant locus. Based on this, Smith et al also performed analyses stratified by smoking status and found that the association between PTSD and cg05575921 was strongest among non-smokers suggesting an association between PTSD and AHRR independent of smoking.…”

“…This could point to a possible role of these loci in the inter-generational transmission of the effects of trauma. Finally, Smith et al [17] recently reported results of the largest PTSD EWAS conducted to date based on a meta-analysis of n = 1896 participants from 10 cohorts with methylation assessed at~450K loci. Ten loci achieved genome-wide significance, the most significant of which, cg05575921 (p = 4.27 × 10 -11 , FDR = 2.15 × 10 -5 ), was located in the smokingassociated gene AHRR.…”

A decennial review of psychotraumatology: what did we learn and where are we going?

“…The most recent meta-analyses of GWAS data from the PGC PTSD workgroup (n~200,000) revealed numerous significant variants and quantified the molecular heritability of PTSD (Nievergelt et al, 2019). Collaborative efforts from the PGC have led to progress on finding epigenome-wide significant sites related to risk for PTSD (Smith et al, 2019). Systems biology advances, in large part driven by complex data-driven agnostic analytic approaches to multidimensional data (Neylan, Schadt, & Yehuda, 2014), are developing and hold promise and will be needed to co-analyse data on multiple omics platforms simultaneously.…”

Meta-analysis of longitudinal epigenome-wide association studies of military cohorts reveals multiple CpG sites associated with post-traumatic stress disorder

“…All subjects were free of a PTSD diagnosis at pre-deployment and had CAPS scores ≤ 25. After return from a ~7-months deployment period, PTSD cases (following the DSM-IV full or partially stringent diagnosis [11,12]) were selected either at the three-or the six-month follow-up visit, based on when these subjects had their highest recorded CAPS scores. Subsequently, controls were frequency matched to the selected cases for age, ancestry, and time of post-deployment visit.…”