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Glucocorticoid Receptor DNA Methylation, Childhood Maltreatment and Major Depression


Bustamante, Angela C.; Aiello, Allison E.; Galea, Sandro; Ratanatharathorn, Andrew; Noronha, Carol; Wildman, Derek E.; & Uddin, Monica (2016). Glucocorticoid Receptor DNA Methylation, Childhood Maltreatment and Major Depression. Journal of Affective Disorders, 206, 181-188. PMCID: PMC5077661


INTRODUCTION: 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.
METHODS: 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.
RESULTS: 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.
LIMITATIONS: 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.
CONCLUSIONS: 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.


Reference Type

Journal Article

Year Published


Journal Title

Journal of Affective Disorders


Bustamante, Angela C.
Aiello, Allison E.
Galea, Sandro
Ratanatharathorn, Andrew
Noronha, Carol
Wildman, Derek E.
Uddin, Monica