Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder

Abstract

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.

Dynamic stress-related epigenetic regulation of the glucocorticoid receptor gene promoter during early development: The role of child maltreatment

“…In addition, this hypothesis is supported by research with adult populations consistently finding that hypomethylation is associated with posttraumatic stress disorder (e.g., Labonte et al, 2014; Vukojevic et al, 2014; Yehuda et al, 2015). Furthermore, this hypothesis is also supported by recent research finding that within-subject decreasing DNAm levels over time at several genes, though not NR3C1 , were related to the increasing levels of posttraumatic stress disorder symptoms over time among military veterans (Rutten et al, 2017). If the developmental progression hypothesis is correct, we would expect the current trajectory of change in NR3C1 promoter methylation to continue into middle childhood and adolescence with accompanying onset of posttraumatic stress disorder or severe mood dysregulation.…”

Recent Genetics and Epigenetics Approaches to PTSD

“…Some of the current human EWAS that have examined mDNA alterations in PTSD are summarized in Table 2. EWAS are listed in chronological order (2010–2017) [54•, 55, 56, 57•, 58, 59•, 60, 61]. The sites with differential mDNA together with the nearest gene are reported.…”

“…For example, the EWAS with the largest sample size to date identified epigenetic changes related to synapic plasticity, cholinergic signaling, oxytocin signaling, and inflammatory responses [61]. Smaller studies have implicated immune and inflammatory responses [54•, 55, 59•, 60], endocrine [60] and nervous system [56, 59, 60] pathways. One study has observed differential mDNA profiles in PTSD subjects with and without childhood abuse history [57•].…”

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

“…Multiple reviews have linked traumatic stress to differences in the proportion of methylated DNA (ß) at specific CpG sites [7][8][9][10] . 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 function [11][12][13][14][15] . Similarly, studies using specific CpG sites that capture age acceleration demonstrate associations with PTSD and link differences in peripheral DNA methylation to memory formation and grey matter integrity 16 .…”