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. 2016 Jul 5;6(7):e848.
doi: 10.1038/tp.2016.112.

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

A R Tyrka  1   2 , S H Parade  2   3 , E S Welch  1 , K K Ridout  1   2 , L H Price  1   2 , C Marsit  4   5 , N S Philip  1   2   6 , L L Carpenter  1   2
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Methylation of the leukocyte glucocorticoid receptor gene promoter in adults: associations with early adversity and depressive, anxiety and substance-use disorders

A R Tyrka et al. Transl Psychiatry. .

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.

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Figures

Figure 1
Figure 1
Group differences in methylation at individual NR3C1 CpG sites Note. tP<0.10; *P<0.05; **P<0.01.
Figure 2
Figure 2
Cortisol response to dexamethasone/corticotropin-releasing hormone (Dex/CRH) test in relation to adversity/disorder grouping. Note: the general linear model testing the effect of group on cortisol response over time did not reach significance (F(3, 220)=2.08, P=0.103).
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References

    1. Anacker C, Zunszain PA, Carvalho LA, Pariante CM. The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology 2011; 36: 415–425. - PMC - PubMed
    1. Barden N. Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of depression. J Psychiatry Neurosci 2004; 29: 185–193. - PMC - PubMed
    1. Klengel T, Binder EB. Allele-specific epigenetic modification: a molecular mechanism for gene-environment interactions in stress-related psychiatric disorders? Epigenomics 2013; 5: 109–112. - PubMed
    1. van Zuiden M, Geuze E, Willemen HL, Vermetten E, Maas M, Heijnen CJ et al. Pre-existing high glucocorticoid receptor number predicting development of posttraumatic stress symptoms after military deployment. Am J Psychiatry 2011; 168: 89–96. - PubMed
    1. Yehuda R, Flory JD, Pratchett LC, Buxbaum J, Ising M, Holsboer F. Putative biological mechanisms for the association between early life adversity and the subsequent development of PTSD. Psychopharmacology 2010; 212: 405–417. - PubMed

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