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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.

Genome-wide differentially methylated genes associated with posttraumatic stress disorder and longitudinal change in methylation in rape survivors