CRHR1 promoter hypomethylation: An epigenetic readout of panic disorder?

The corticotropin releasing hormone receptor 1 (CRHR1) is crucially involved in the hypothalamic-pituitary-adrenal axis and thus a major regulator of the stress response. CRHR1 gene variation is associated with several mental disorders including anxiety disorders. Studies in rodents have demonstrated epigenetic regulation of CRHR1 gene expression to moderate response to stressful environment. In the present study, we investigated CRHR1 promoter methylation for the first time regarding its role in panic disorder applying a case-control approach (N=131 patients, N=131 controls). In an independent sample of healthy volunteers (N=255), CRHR1 methylation was additionally analyzed for association with the Beck Anxiety Inventory (BAI) score as a dimensional panic-related intermediate phenotype. The functional relevance of altered CRHR1 promoter methylation was investigated by means of luciferase-based reporter gene assays. In panic disorder patients, a significantly decreased CRHR1 methylation was discerned (p<0.001). Accordingly, healthy controls with high BAI scores showed significantly decreased CRHR1 methylation. Functional analyses revealed an increased gene expression in presence of unmethylated as compared to methylated pCpGl_CRHR1 reporter gene vectors. The present study identified a potential role of CRHR1 hypomethylation - conferring increased CRHR1 expression - in panic disorder and a related dimensional intermediate phenotype. This up-regulation of CRHR1 gene expression driven by de-methylation might constitute a link between the stress response and panic disorder risk.