Glucocorticoid receptor DNA methylation, childhood maltreatment and major depression

Abstract

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.

The effects of childhood maltreatment on epigenetic regulation of stress-response associated genes: an intergenerational approach

“…In line with previous studies [9][10][11][12][13][14] , our results show CM-associated hypomethylation of FKBP5 and hypermethylation of NR3C1. We extend the existing literature by also showing effects on CRHR1 methylation, thus providing a new candidate for CM-associated epigenetic alterations in HPA axis modulators.…”

“…Pregnancy, and especially delivery, can be considered as physiological stressors and cortisol levels are rising during the course of pregnancy, with a peak in the third trimester 50,51 . However, studies on CM-related DNA methylation alterations in non-pregnant cohorts showed similar results with regard to NR3C1-1F methylation 9,12,52 and FKBP5 methylation 13,14 , suggesting that these epigenetic alterations may be stable enough to persist under stressful circumstances (e.g., pregnancy and parturition).…”

“…on previous findings of a FKBP5 × CM interaction on FKBP5 methylation 14 and of hypomethylation of FKBP5 13,14 and hypermethylation of NR3C1 [9][10][11][12][13] in association with CM, directed one-tailed tests were conducted for FKBP5 and NR3C1 mean methylation analyses. Statistical analyses for CRHR1 and all other tests were performed with two-tailed tests.…”

Annual Research Review: Early adversity, the hypothalamic–pituitary–adrenocortical axis, and child psychopathology

“…Postnatal adversity may continue to operate through epigenetic pathways. Individuals with exposure to early physical maltreatment demonstrate greater methylation of the NR3C1 gene measured during adolescence (Romens, McDonald, Svaren, & Pollak, ) and adulthood (Bustamante et al., ; however see Tyrka et al., ). Longer time in orphanage care was associated with lower methylation of the FKBP5 gene during adolescence (Non et al., ), something that might put youth at risk for PTSD.…”

Epigenetik der Depression

“…Die mit Hinblick auf die epigenetischen Grundlagen der Depression am häufigsten untersuchten Gene sind dementsprechend das SLC6A4-und das BDNF-Gen. Der Zusammenhang der Methylierung der Promotorregion von NR3C1 mit der Major Depression wurde dagegen wenig erforscht. Die vorliegenden Studien sprechen allerdings im Kontrast zu der beschriebenen stressassoziierten Hypermethylierung der Region in unmittelbarer Nähe von Exon 1F eher für einen negativen oder gar keinen Zusammenhang von Depression und Methylierungsraten in derselben Region (wenn auch nicht exakt derselben CpG-Sites) (58)(59)(60).…”