Association between glucocorticoid receptor methylation and hippocampal subfields in major depressive disorder

PLoS One. 2014 Jan 21;9(1):e85425. doi: 10.1371/journal.pone.0085425. eCollection 2014.


Background: DNA methylation in the promoter region of the glucocorticoid receptor gene (NR3C1) is closely associated with childhood adversity and suicide. However, few studies have examined NR3C1 methylation in relation to major depressive disorder (MDD) and hippocampal subfield volumes. We investigated the possible association between NR3C1 methylation and structural brain alterations in MDD in comparison with healthy controls.

Methods: We compared the degree of NR3C1 promoter methylation in the peripheral blood of non-psychotic outpatients with MDD and that of healthy controls. Correlations among NR3C1 promoter methylation, structural abnormalities in hippocampal subfield volumes and whole-brain cortical thickness, and clinical variables were also analyzed.

Results: In total, 117 participants (45 with MDD and 72 healthy controls) were recruited. Patients with MDD had significantly lower methylation than healthy controls at 2 CpG sites. In MDD, methylations had positive correlations with the bilateral cornu ammonis (CA) 2-3 and CA4-dentate gyrus (DG) subfields. However, in healthy controls, methylations had positive correlation with the subiculum and presubiculum. There were no differences in total and subfield volumes of the hippocampus between patients with MDD and healthy controls. Compared with healthy controls, patients with MDD had a significantly thinner cortex in the left rostromiddle frontal, right lateral orbitofrontal, and right pars triangularis areas.

Conclusions: Lower methylation in the NR3C1 promoter, which might have compensatory effects relating to CA2-3 and CA4-DG, is a distinct epigenetic characteristic in non-psychotic outpatients with MDD. Future studies with a longitudinal design and a comprehensive neurobiological approach are warranted in order to elucidate the effects of NR3C1 methylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • CA2 Region, Hippocampal / metabolism*
  • CA2 Region, Hippocampal / physiopathology
  • CA3 Region, Hippocampal / metabolism*
  • CA3 Region, Hippocampal / physiopathology
  • Case-Control Studies
  • DNA Methylation
  • Dentate Gyrus / metabolism*
  • Dentate Gyrus / physiopathology
  • Depressive Disorder, Major / genetics*
  • Depressive Disorder, Major / metabolism
  • Depressive Disorder, Major / physiopathology
  • Epigenesis, Genetic*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Promoter Regions, Genetic
  • Receptors, Glucocorticoid / genetics*
  • Receptors, Glucocorticoid / metabolism


  • NR3C1 protein, human
  • Receptors, Glucocorticoid

Grant support

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2011-0023272). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.