title: Glucocorticoid receptor DNA methylation, childhood maltreatment and major depression.
abstract: Altered DNA methylation (DNAm) levels of hypothalamic-pituitary-adrenal (HPA) axis genes has been associated with exposure to childhood maltreatment (CM) and depression; however, it is unknown whether CM and depression have joint and potentially interacting effects on the glucocorticoid receptor (NR3C1) DNAm. We investigated the impact of CM and lifetime major depressive disorder (MDD) on NR3C1 DNAm and gene expression (GE) in 147 adult participants from the Detroit Neighborhood Health Study.
  
  
  
  NR3C1 promoter region DNAm was assessed via pyrosequencing using whole blood-derived DNA. Quantitative RT-PCR assays measured GE from leukocyte-derived RNA. Linear regression models were used to examine the relationship among CM, MDD, and DNAm.
  
  
  
  Both CM and MDD were significant predictors of NR3C1 DNAm: CM was associated with an increase in DNAm in an EGR1 transcription factor binding site (TFBS), whereas MDD was associated with a decrease in DNAm downstream of the TFBS. No significant CM-MDD interactions were observed. CM alone was associated with significantly lower NR3C1 GE.
  
  
  
  Our report of CM is a retrospective self-report of abuse, which may introduce recall bias. DNAm was measured in whole blood and may not reflect brain-derived DNAm levels.
  
  
  
  CM and MDD are both associated with altered DNAm levels in the NR3C1 promoter region, however the location and direction of effects differ between the two exposures, and the functional effects, as measured by GE, appear to be limited to CM exposure alone. CM exposure may be biologically embedded in this key HPA axis gene.
authors.affiliation: Neuroscience Program University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Bustamante
authors.affiliation: Department of Epidemiology, University of North Carolina, Gillings School of Global Public Health, Chapel Hill, NC 27599 USA.
authors.forename: Allison E
authors.initials: AE
authors.lastname: Aiello
authors.affiliation: Boston University, School of Public Health, Boston, MA 02118, USA.
authors.forename: Sandro
authors.initials: S
authors.lastname: Galea
authors.affiliation: Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ratanatharathorn
authors.affiliation: Wayne State University, Detroit, Michigan, 48201, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Noronha
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA.
authors.forename: Derek E
authors.initials: DE
authors.lastname: Wildman
authors.affiliation: Neuroscience Program University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA; Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA. Electronic address: muddin@illinois.edu.
authors.forename: Monica
authors.initials: M
authors.lastname: Uddin
mesh_terms: D054523:Adult Survivors of Child Abuse / Q000523:psychology*; D019175:DNA Methylation; D003865:Major Depressive Disorder / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012189:Retrospective Studies
chemical_list: D051766:Early Growth Response Protein 1; C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid
keywords: Childhood maltreatment; Depression; Development; Epigenetics; Gene expression