Associations between human oxytocin receptor gene promoter DNA methylation and brain structural connectome in panic...

Epigenetic regulation of the oxytocin receptor gene (OXTR), particularly DNA methylation (DNAm), has been linked to insecure attachment, anxiety-related phenotypes, and suicidality. However, its role in panic disorder (PD) and brain network dysfunction remains unclear. This study examined whether peripheral OXTR DNAm and OXTR DNAm-associated structural connectivity are related to clinical symptoms of PD.

We investigated OXTR DNAm and its structural connectivity in 563 patients with PD and 210 healthy controls (HCs). Peripheral blood OXTR promoter (-934) DNAm was quantified by pyrosequencing. In a neuroimaging subset, diffusion MRI tractography reconstructed the structural connectome. Network-based statistics tested the diagnosis-by-OXTR DNAm and diagnosis-by-clinical symptomatology effects using separation-related life events (SLEs), Anxiety Sensitivity Index-Revised (ASI-R), and the Scale for Suicidal Ideation (SSI). A preliminary bagging ensemble regression model was used to evaluate treatment response prediction.

Patients with PD exhibited significantly lower OXTR DNAm levels than HCs, adjusting for age, sex, education, smoking status, and body mass index. Within PD, reduced OXTR DNAm was significantly negatively correlated with elevated SLEs, ASI-R, and SSI scores. Diagnosis-by-OXTR DNAm interactions revealed reduced connectivity across the hippocampus, amygdala, orbitofrontal, and precentral regions converging on the extended fear network. Importantly, OXTR DNAm-associated connectivity in the orbitofrontal and lateral occipital cortices showed a cross-validated association with the 8-week treatment outcomes.

Lower peripheral OXTR DNAm was associated with higher PD-related symptomatology and altered extended fear network connectivity. These findings suggest that peripheral OXTR DNAm may index aspects of clinical and neural heterogeneity in PD.