Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: a link with the severity and type of trauma

N Perroud,R Nicastro,D Mouthon,C Stouder,A Malafosse,S Guillaume,A Salzmann,E Olié,P Prada,K Dieben,P Huguelet,P Courtet,A Paoloni-Giacobino

doi:10.1038/tp.2011.60

Abstract

Childhood maltreatment, through epigenetic modification of the glucocorticoid receptor gene (NR3C1), influences the hypothalamic–pituitary–adrenal axis (HPA axis). We investigated whether childhood maltreatment and its severity were associated with increased methylation of the exon 1F NR3C1 promoter, in 101 borderline personality disorder (BPD) and 99 major depressive disorder (MDD) subjects with, respectively, a high and low rate of childhood maltreatment, and 15 MDD subjects with comorbid post-traumatic stress disorder (PTSD). Childhood sexual abuse, its severity and the number of type of maltreatments positively correlated with NR3C1 methylation (P=6.16 × 10−8, 5.18 × 10−7 and 1.25 × 10−9, respectively). In BPD, repetition of abuses and sexual abuse with penetration correlated with a higher methylation percentage. Peripheral blood might therefore serve as a proxy for environmental effects on epigenetic processes. These findings suggest that early life events may permanently impact on the HPA axis though epigenetic modifications of the NR3C1. This is a mechanism by which childhood maltreatment may lead to adulthood psychopathology.

Highlights

Exposure to early life adverse events, including abuses and neglect, significantly increases the risk of psychopathology in adulthood.[1,2]In humans as well as in animals, response to stress, and to childhood trauma, is mediated by the hypothalamic–pituitary–adrenal (HPA) axis, which includes release of corticotrophin-releasing factor and secondarily results in secretion of glucocorticoids.[3]
Based on evidences from the literature,[29,30] we investigated whether the number of types of childhood maltreatment as a continuous variable was associated with methylation status
According to our primary hypothesis, we showed that childhood sexual abuse was associated with increased NR3C1 promoter methylation in the peripheral blood

Summary

Introduction

Exposure to early life adverse events, including abuses and neglect, significantly increases the risk of psychopathology in adulthood.[1,2]In humans as well as in animals, response to stress, and to childhood trauma, is mediated by the hypothalamic–pituitary–adrenal (HPA) axis, which includes release of corticotrophin-releasing factor and secondarily results in secretion of glucocorticoids.[3]. Life stress has been shown to induce persistent changes in corticotrophin-releasing factor neurotransmission and sustains alteration of the HPA axis.[4,5] Hyperactivity as well as decreased activity of the HPA axis in response to stress has been demonstrated in humans with a history of childhood maltreatment.[4,5,6] It has been speculated that the direction of such HPA alterations may depend on the characteristics of the stressor such as the type, duration, intensity or timing.[7,8] the main role of this HPA axis is to prevent over-response to stress,[9] prolonged exposure to elevated levels of glucocorticoids has damaging effects on the developing brain, which may secondarily lead to behavioral problems later in life.[10,11,12,13]

Methods

Results

Conclusion