Sex-dependent association of mineralocorticoid receptor gene (NR3C2) DNA methylation and schizophrenia

Abstract

Schizophrenia is a complex disease caused by genetic and environmental factors. Epigenetic regulation mediates gene-environment interactions by modulating gene expression. Abnormal activation of the hypothalamic-pituitary-adrenal (HPA) axis has been widely reported in schizophrenia patients. The DNA methylation levels of critical genes are associated with HPA axis activity, which is linked to schizophrenia pathogenesis. The mineralocorticoid receptor gene NR3C2 regulates HPA axis activity. However, how NR3C2 methylation affects the development of schizophrenia remains unknown. Here, we investigated the DNA methylation state of NR3C2, including the promoter P1 (NR3C2–1, NR3C2–2 and NR3C2–3) and exon 1α and its downstream sequence (NR3C2–4), in schizophrenia. Peripheral blood DNA from 80 schizophrenia patients and 128 healthy controls was used to assess NR3C2 DNA methylation via sodium bisulfite treatment and the MethylTarget method. NR3C2–4 region was hypermethylated in schizophrenia patients compared with healthy controls in the female group. Specific CpG sites in P1 and NR3C2–4 region were associated with schizophrenia, with sex-specific effects. These findings showed a relationship between NR3C2 DNA methylation and schizophrenia, revealing that epigenetic processes may mediate schizophrenia pathophysiology. Further research should address the potential epigenetic mechanisms of the relationship between NR3C2 and schizophrenia.