Association between Glucocorticoid Receptor Methylation and Hippocampal Subfields in Major Depressive Disorder

<div><p>Background</p><p>DNA methylation in the promoter region of the glucocorticoid receptor gene (<i>NR3C1</i>) is closely associated with childhood adversity and suicide. However, few studies have examined <i>NR3C1</i> methylation in relation to major depressive disorder (MDD) and hippocampal subfield volumes. We investigated the possible association between <i>NR3C1</i> methylation and structural brain alterations in MDD in comparison with healthy controls.</p><p>Methods</p><p>We compared the degree of <i>NR3C1</i> promoter methylation in the peripheral blood of non-psychotic outpatients with MDD and that of healthy controls. Correlations among <i>NR3C1</i> promoter methylation, structural abnormalities in hippocampal subfield volumes and whole-brain cortical thickness, and clinical variables were also analyzed.</p><p>Results</p><p>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.</p><p>Conclusions</p><p>Lower methylation in the <i>NR3C1</i> 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 <i>NR3C1</i> methylation.</p></div

Differences in left cortical thickness between patients with major depressive disorder and healthy controls.

<p><i>FWE</i>-corrected <i>p</i><0.05 through Monte-Carlo permutation test.</p

Demographic and clinical data for patients with major depressive disorder and healthy controls.

<p>All data are represented as mean (SD) or number (%).</p><p>MDD: major depressive disorder, HC: healthy controls, HRSD: Hamilton Rating Scale for Depression, PSS: Perceived Stress Scale.</p><p><i>p</i><0.001.</p

Correlations between <i>NR3C1</i> methylation at CpG1 and hippocampal subfield volumes among participants.

<p>Correlations between <i>NR3C1</i> methylation at CpG1 and hippocampal subfield volumes among participants.</p

Differences in right cortical thickness between patients with major depressive disorder and healthy controls.

<p><i>FWE</i>-corrected <i>p</i><0.05 through Monte-Carlo permutation test.</p

Comparison of hippocampal subfield volumes between patients with major depressive disorder and healthy controls, mean (SD).

<p>Comparison of hippocampal subfield volumes between patients with major depressive disorder and healthy controls, mean (SD).</p

Primers for bisulfite polymerase chain reaction and pyrosequencing.

<p>^a Distance (nt) from transcription start site (+1).</p

Correlations between <i>NR3C1</i> methylation at CpG2-3 and hippocampal subfield volumes among participants.

<p>Correlations between <i>NR3C1</i> methylation at CpG2-3 and hippocampal subfield volumes among participants.</p

Comparison of <i>NR3C1</i> methylation between patients with major depressive disorder and healthy controls, mean (SD).

<p>^*<i>p</i><0.01.</p