Abstract
Rape is associated with a high risk for posttraumatic stress disorder (PTSD). DNA methylation changes may confer risk or protection for PTSD following rape by regulating the expression of genes implicated in pathways affected by PTSD. We aimed to: (1) identify epigenome-wide differences in methylation profiles between rape-exposed women with and without PTSD at 3-months post-rape, in a demographically and ethnically similar group, drawn from a low-income setting; (2) validate and replicate the findings of the epigenome-wide analysis in selected genes (BRSK2 and ADCYAP1); and (3) investigate baseline and longitudinal changes in BRSK2 and ADCYAP1 methylation over six months in relation to change in PTSD symptom scores over 6 months, in the combined discovery/validation and replication samples (n = 96). Rape-exposed women (n = 852) were recruited from rape clinics in the Rape Impact Cohort Evaluation (RICE) umbrella study. Epigenome-wide differentially methylated CpG sites between rape-exposed women with (n = 24) and without (n = 24) PTSD at 3-months post-rape were investigated using the Illumina EPIC BeadChip in a discovery cohort (n = 48). Validation (n = 47) and replication (n = 49) of BRSK2 and ADCYAP1 methylation findings were investigated using EpiTYPER technology. Longitudinal change in BRSK2 and ADCYAP1 was also investigated using EpiTYPER technology in the combined sample (n = 96). In the discovery sample, after adjustment for multiple comparisons, one differentially methylated CpG site (chr10: 61385771/ cg01700569, p = 0.049) and thirty-four differentially methylated regions were associated with PTSD status at 3-months post-rape. Decreased BRSK2 and ADCYAP1 methylation at 3-months and 6-months post-rape were associated with increased PTSD scores at the same time points, but these findings did not remain significant in adjusted models. In conclusion, decreased methylation of BRSK2 may result in abnormal neuronal polarization, synaptic development, vesicle formation, and disrupted neurotransmission in individuals with PTSD. PTSD symptoms may also be mediated by differential methylation of the ADCYAP1 gene which is involved in stress regulation. Replication of these findings is required to determine whether ADCYAP1 and BRSK2 are biomarkers of PTSD and potential therapeutic targets.
Highlights
Rape and sexual assault are associated with a high risk for the development of posttraumatic stress disorder (PTSD) compared to other trauma types [1, 2]
The only variable that differed between the samples was the prevalence of lifetime exposure to the murder of a family member or friend, which was more frequently endorsed in the discovery/validation sample compared to the replication sample (25.5% vs. 8.2%, respectively; χ2 = 5.2, p = 0.022)
In this study, we identified one differentially methylated positions (DMPs) and thirty-four differentially methylated regions (DMRs) associated with PTSD at 3-months post-rape on an epigenome-wide level
Summary
Rape and sexual assault are associated with a high risk for the development of posttraumatic stress disorder (PTSD) compared to other trauma types [1, 2]. Prospective studies have reported PTSD prevalence rates ranging between 35% and 45% at 3-months postrape, with many survivors of sexual assault continuing to experience PTSD symptoms at 6-months and 12-months post-rape [3,4,5,6]. PTSD is a complex, multifactorial disorder and an array of environmental and genetic putative risk and protective factors mediate or contribute to the development of the disorder [3, 5, 7]. Genome-wide approach to study epigenome-wide signatures (while accounting for potential environmental and biological confounding factors), and validating and replicating these findings, may bring us closer to uncovering the complexity of the disorder [10]
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