The sex-different effect of oxytocin receptor gene methylation on cerebral gray matter structures and clinical symptoms in Korean patients with panic disorder

Abstract

Background: Panic disorder (PD) is sexually dimorphic in its clinical manifestation, possibly due to differences in brain processing of fear and anxiety. Given oxytocin's role in socio-emotional regulation, epigenetic alterations in the oxytocin receptor gene (OXTR) constitute one possible mechanism underlying sexual dimorphism in PD. We investigated the sex difference in cerebral gray matter volume (GMV) and its association with OXTR methylation in PD patients. Methods: Forty-six PD patients (24 women) and 55 healthy controls (HCs; 31 women) underwent a high-resolution T1-weighted magnetic resonance imaging scan and provided peripheral blood samples at baseline. GMV differences were analyzed using FreeSurfer, and OXTR methylation was measured through pyrosequencing. The severity of PD symptoms was assessed using the Panic Disorder Severity Scale (PDSS) and Albany Panic and Phobia Questionnaire (APPQ). Results: PD patients exhibited smaller GMVs in the right frontal pole, post-central gyrus, superior temporal gyrus, parahippocampal gyrus, and left insula compared to HCs, independent of sex. An interaction effect of sex and PD diagnosis was found in the left precuneus; PD women had larger volume than men, and vice versa in HCs. OXTR methylation, lower in PD patients irrespective of sex, correlated negatively with precuneus volume in women. Larger precuneus volume was associated with more severe agoraphobia in PD women, with an inverse correlation discovered in PD men. Conclusion: Epigenetic changes of OXTR may contribute sex-specific brain structure alterations in PD. The inverse association between precuneus volume and agoraphobia severity across sexes highlights the neurobiological basis of the sex-different manifestation of PD.