DNA Methylation Analysis of the NR3C1 Gene in Patients with Schizophrenia

Schizophrenia is a heterogeneous mental disorder caused by genetic and environmental factors, and epigenetic mechanisms play a vital role in its pathogenesis. Evidence suggests that some psychiatric disorders are linked to methylation of the glucocorticoid receptor gene NR3C1, a key regulator of the hypothalamic-pituitary-adrenal (HPA) axis. However, the contribution of NR3C1 methylation to schizophrenia has not yet been investigated. By applying a case-control approach (N = 128 controls, N = 80 patients), we for the first time examined the methylation state of the NR3C1 gene promoter region and its role in schizophrenia. Using peripheral blood samples, NR3C1 methylation in exons 1_D, 1_B, 1_F, and 1_H was assessed via sodium bisulfite treatment combined with the MethylTarget method. NR3C1 methylation at exon 1_B was positively associated with schizophrenia in females but not in males. Nonetheless, specific CpG sites in exon 1_D, 1_B, 1_H, and 1_F regions were found to be associated with schizophrenia, usually with sex specificity. These results suggest that epigenetic aberrations of NR3C1 are associated with the pathophysiology of schizophrenia, and epigenetic processes possibly mediate psychopathology through effects on HPA axis activity. Correlation analysis between NR3C1 gene methylation and schizophrenia may be helpful for the assessment of forensic psychiatry.