Glucocorticoid receptor gene (NR3C1) DNA methylation, early-life trauma, and resilience in obsessive-compulsive disorder.

INTRODUCTION: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been implicated in obsessive-compulsive disorder (OCD), but epigenetic changes in HPA axis-related genes remain poorly understood. We investigated whether DNA methylation of the glucocorticoid receptor gene (NR3C1), particularly within exon 1F, is associated with OCD and examined its relationship with stress resilience and early-life trauma. METHODS: A total of 275 patients with OCD and 200 healthy controls (aged 19-40 years) were recruited. DNA methylation at three CpG sites within NR3C1 exon 1F was measured using pyrosequencing. Group differences were examined using multivariate analysis of covariance (MANCOVA), and structural equation modeling (SEM) was conducted to evaluate resilience-mediated pathways linking NR3C1 methylation, early-life trauma, and OCD status. RESULTS: Compared to healthy controls, DNA methylation at NR3C1 exon 1F was significantly reduced in women with OCD (p < 0.001), which remained significant in a drug-naïve or drug-free subset. No overall multivariate difference was observed in men. SEM revealed that stress resilience partially mediated the association between NR3C1 methylation and OCD status (indirect β = -0.117, p = 0.014). While early-life trauma was associated with lower methylation at a specific CpG site, the mediation effect of DNA methylation between trauma and OCD did not reach statistical significance. CONCLUSION: These findings suggest that epigenetic alterations of NR3C1 may contribute to stress-related vulnerability in OCD, with resilience representing a key psychological pathway linking stress-related biological processes, including HPA-axis regulation, to clinical outcomes.