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

TLDR

Childhood maltreatment epigenetically modifies the glucocorticoid receptor gene (NR3C1), influencing the HPA axis and suggesting peripheral blood can serve as a proxy for such environmental effects. The study examined whether the severity of childhood maltreatment correlates with increased methylation of the exon 1F NR3C1 promoter in patients with BPD, MDD, and PTSD. The authors measured exon 1F NR3C1 promoter methylation in 101 BPD, 99 MDD, and 15 MDD‑PTSD patients to assess this association. Higher NR3C1 methylation was associated with greater severity and diversity of childhood maltreatment, especially sexual abuse, and in BPD patients repeated and penetrative abuses further increased methylation, indicating that early life trauma can permanently alter the HPA axis via epigenetic changes and may underlie adult psychopathology.

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.