Abstract
BackgroundDNA 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.MethodsWe 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.ResultsIn 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.ConclusionsLower 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.
Highlights
Major depressive disorder (MDD) is one of the most common psychiatric illnesses [1]
The results suggest that higher methylation in NR3C1 in relation to early life adversities may have causative roles for depression, which is closely related to suicide
There were no significant differences in age and sex between the 2 groups
Summary
Major depressive disorder (MDD) is one of the most common psychiatric illnesses [1]. According to the World Health organization (WHO), MDD is expected to be the second leading cause of disease burden by 2030 [2]. The methylation at CpG sites in the promoter region of the glucocorticoid receptor gene NR3C1 is one of the most widely investigated epigenetic alterations in the field of psychiatry. Subsequent human studies have reported that prenatal risk factors or childhood adversity was associated with DNA methylation in the exon F1 region of the NR3C1 in the postmortem hippocampus of suicide victims [10,11,12]. The results suggest that higher methylation in NR3C1 in relation to early life adversities may have causative roles for depression, which is closely related to suicide. DNA methylation in the promoter region of the glucocorticoid receptor gene (NR3C1) is closely associated with childhood adversity and suicide. We investigated the possible association between NR3C1 methylation and structural brain alterations in MDD in comparison with healthy controls
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