Longitudinal associations between glucocorticoid receptor methylation and late-life depression

It has been suggested that hypothalamus-pituitary-adrenal (HPA) axis dysregulation plays a role in the etiology of depression. HPA axis function is mediated by glucocorticoid receptors (GRs), which are influenced by epigenetic mechanisms (DNA methylation). The association between the DNA methylation of the GR gene (nuclear receptor subfamily 3, group C, member 1; NR3C1) and late-life depression as well as the role of NR3C1 methylation in the prediction of the incidence of depression have not yet been investigated. Therefore, we examined the independent and longitudinal effects of the methylation of three CpG sites in exon 1_F of NR3C1 on late-life depression using peripheral blood. In total, 732 Korean community residents aged ≥65 years were assessed; 521 individuals in this group without depression at baseline were followed 2 years later. The Geriatric Mental State Schedule was used to identify depression, and demographic and clinical covariates were evaluated. The effects of NR3C1 methylation (the individual methylation status of three CpG sites and their average values) on current and follow-up depression were calculated using a multivariate logistic regression model. Higher NR3C1 methylation levels at CpG 2 and 3 and the average methylation value were independently associated with the prevalence of depression at baseline. Additionally, a higher NR3C1 methylation level at CpG 2 was associated with depression incidence 2 years later in this population. These findings suggest an association between the methylation of NR3C1 exon 1_F, especially at CpG 2, and depression later in life.