title: Methylation of the leukocyte glucocorticoid receptor gene promoter in adults: associations with early adversity and depressive, anxiety and substance-use disorders.
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.
authors.affiliation: Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, RI, USA.|Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Tyrka
authors.affiliation: Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.|Bradley/Hasbro Children's Research Center, E. P. Bradley Hospital, East Providence, RI, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Parade
authors.affiliation: Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, RI, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Welch
authors.affiliation: Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, RI, USA.|Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: K K
authors.initials: KK
authors.lastname: Ridout
authors.affiliation: Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, RI, USA.|Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: L H
authors.initials: LH
authors.lastname: Price
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.|Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: C
authors.initials: C
authors.lastname: Marsit
authors.affiliation: Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, RI, USA.|Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.|Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence, RI, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Philip
authors.affiliation: Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, RI, USA.|Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: Carpenter
mesh_terms: D000328:Adult; D054523:Adult Survivors of Child Abuse / Q000523:psychology*; D000069586:Adult Survivors of Child Adverse Events / Q000523:psychology; D001008:Anxiety Disorders / Q000235:genetics* / Q000523:psychology; D018899:CpG Islands; D019175:DNA Methylation; D003866:Depressive Disorder / Q000235:genetics* / Q000523:psychology; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D019966:Substance-Related Disorders / Q000235:genetics* / Q000523:psychology; D055815:Young Adult
chemical_list: C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid