Sex-dependent differences in oxytocin receptor gene methylation between posttraumatic stress disorder patients and trauma-exposed healthy controls

Abstract

Rationale: Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition that can develop after experiencing a traumatic event. PTSD risk may depend on an interaction between genetic and environmental vulnerability factors. Epigenetic processes such as DNA-methylation are responsive to environmental factors (e.g. stress) and can alter gene-expression, and have been found to mediate between trauma exposure and PTSD development [1].

Further knowledge of the relation between DNA-methylation and PTSD may provide valuable insights in the neurobiological underpinnings of PTSD psychopathology A promising candidate for research is the oxytocin receptor gene (OXTR). OXTR DNA-methylation has been associated with trauma-exposure as well as mood-and anxiety disorders, and with social processes relevant to PTSD (e.g. [2, 3]). Based on these previous findings, we hypothesized that OXTR methylation may play a role in the neurobiological underpinnings of PTSD.

Methods: In the current study, we compared OXTR methy-lation between trauma-exposed male and female police of ficers with PTSD (n = 31, 14 females) and without PTSD (healthy controls, n = 36, 19 females). Using bisulfite sequencing we assessed DNA-methylation levels in the CpG island located at exon 3 of the OXTR in peripheral blood samples, which was previously associated with OXTR expression and anxiety [4, 5].

Additionally, the association between OXTR methylation and PTSD symptom severity was assessed. PTSD symptom severity was assessed with a clinical interview (Clinician Assessed PTSD Scale, CAPS). Total symptom severity as well as symptom subscales were investigated in relation to OXTR methylation.

Results: We observed a significant interaction effect between group, sex and CpG position on methylation levels (F(6, 65.140) = 4.246, p = 0.001). Post-hoc testing revealed that methylation at two specific CpG sites were significantly higher in PTSD females compared to female trauma-exposed controls after correction for multiple testing (CpGs Chr3:8809437; F(1, 32.37) = 7.440, p = 0.010, Chr3:8809413; F(1, 33.00) = 9.796, p = 0.004).

No significant differences in methylation were observed between male PTSD patients and controls. Furthermore, within PTSD females, methylation in these CpG sites was significantly positively associated with emotional numbing symptoms (Chr3:8809437; r = 0.648, p = 0.014, Chr3:8809413; r = 0.546, p = 0.044), but not with total symptom severity or other subscales (p > 0.05).

Conclusions: We report the first investigation of OXTR DNA-methylation in a sample of PTSD patients and trauma-exposed healthy controls. We observed two OXTR CpG-sites in exon 3 that were significantly hypermethylated in female PTSD patients relative to female controls, whereas in males, PTSD status was not significantly associated with OXTR methylation.

Within female PTSD patients, high methylation at these two OXTR CpG-sites was associated with high emotional numbing symptoms, which includes symptoms as social withdrawal and reduced positive affect. Though the size of the current sample is an important limitation, our findings replicate previously observed (sex-specific) associations of OXTR methylation with (severity of) psychopathology.

Associations between methylation and emo tional numbing suggest OXTR methylation may specifically underlie (social) affective deficits in females with PTSD. Though replication is warranted, the current findings add to the notion that different neurobiological mechanisms underlie specific PTSD symptoms, and that these mechanisms may differ between males and females.