Methylation of the leukocyte glucocorticoid receptor gene promoter in adults: associations with early adversity and depressive, anxiety and substance-use disorders.

A R Tyrka,C Marsit,N S Philip,K K Ridout,E S Welch,S H Parade,L H Price,L L Carpenter

doi:10.1038/tp.2016.112

Abstract

Early adversity increases risk for developing psychopathology. Epigenetic modification of stress reactivity genes is a likely mechanism contributing to this risk. The glucocorticoid receptor (GR) gene is of particular interest because of the regulatory role of the GR in hypothalamic–pituitary–adrenal (HPA) axis function. Mounting evidence suggests that early adversity is associated with GR promoter methylation and gene expression. Few studies have examined links between GR promoter methylation and psychopathology, and findings to date have been mixed. Healthy adult participants (N=340) who were free of psychotropic medications reported on their childhood experiences of maltreatment and parental death and desertion. Lifetime depressive and anxiety disorders and past substance-use disorders were assessed using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Methylation of exon 1F of the GR gene (NR3C1) was examined in leukocyte DNA via pyrosequencing. On a separate day, a subset of the participants (n=231) completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Childhood adversity and a history of past substance-use disorder and current or past depressive or anxiety disorders were associated with lower levels of NR3C1 promoter methylation across the region as a whole and at individual CpG sites (P<0.05). The number of adversities was negatively associated with NR3C1 methylation in participants with no lifetime disorder (P=0.018), but not in those with a lifetime disorder. GR promoter methylation was linked to altered cortisol responses to the Dex/CRH test (P<0.05). This study presents evidence of reduced methylation of NR3C1 in association with childhood maltreatment and depressive, anxiety and substance-use disorders in adults. This finding stands in contrast to our prior work, but is consistent with emerging findings, suggesting complexity in the regulation of this gene.

Highlights

Substantial evidence from animal models and human studies implicates impairments in glucocorticoid signaling in stressrelated psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD)
In this study we found that adults with a history of childhood adversity had reduced levels of methylation in exon 1F of the promoter of the glucocorticoid receptor (GR) gene
The group with lifetime depressive, anxiety and substance-use disorders who did not have a history of childhood adversity had trend-level reductions in mean methylation across this region, with a few of the individual CpG sites showing significantly lower methylation in this group

Summary

Introduction

Substantial evidence from animal models and human studies implicates impairments in glucocorticoid signaling in stressrelated psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). Changes in glucocorticoid receptor (GR) number and function in the brain and in peripheral cells such as leukocytes have been shown with PTSD, MDD and early stress exposure,[1,2,3,4,5,6,7,8] and alterations of diurnal and reactive cortisol concentrations are seen in adults and children with these conditions.[9,10,11] GR-mediated negative feedback has a critical role in dampening activity of the hypothalamic–pituitary– adrenal (HPA) axis so that changes in GR number or function can influence activity of this system and, the biological adaptation to stressful or traumatic experiences. Consistent with this, genes such as NR3C1 that are highly expressed typically have low levels of promoter methylation.[17,21,22]

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