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

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.

Hpa Axis Related Genes and Response to Psychological Therapies: Genetics and Epigenetics

“…Fourth, information on exposure to trauma prior to treatment was not available for this sample. Traumatic experiences in childhood have been demonstrated to have lasting effects on DNA methylation of both the FKBP5 and GR genes 11, 12, 14, 15, 16, 17. Therefore, we are unable to make any conclusions regarding other environmental factors that may have influenced baseline DNA methylation and subsequent changes in DNA methylation during active treatment.…”

“…Studies of early experiences in rats found that DNA methylation of the GR promoter region was altered by maternal care, which in turn was associated with GR expression and HPA responses to stress 12. In humans, stressful life events (e.g., trauma and abuse) have been associated with higher DNA methylation at the GR promoter region13, 14, 15, 16, 17, 18 as well as differential GR expression and biological markers of HPA‐axis activity, such as salivary cortisol 13, 14. Furthermore, GR methylation has been implicated in the development of PTSD following trauma 19.…”

Methylation of the glucocorticoid receptor gene promoter in bulimic women: Associations with borderline personality disorder, suicidality, and exposure to childhood abuse

“…18,19 Such processes could explain associations between adverse environmental exposures, during early development, and later problems of adjustment. Whether or not the preceding is true, evidence associates hypermethylation of various neuroregulatory genes with diverse mental-illness phenotypes, including suicidality, 18 borderline personality disorder (BPD), 20,21 and eating disorders (EDs). [22][23][24] The Present Study…”

“…Based on findings indicating generally altered glucocorticoid functioning in BN, 8,9 and a role of a main GR gene polymorphism in bulimic and associated phenomenology, 6,7 we explored the possibility that women with BN, when compared to noneating-disordered (NED) women, might display propensities toward hypermethylation of the GR gene promoter. We also explored two alternative hypotheses: The first, based on evidence linking developmental stress to altered GR methylation in animals and humans, [15][16][17][18] was that GR gene methylation might be more characteristic of individuals with BN who reported exposure to childhood abuse than of people with BN alone; the second, based on studies associating suicidality 18 and BPD 20,21 with increased GR gene methylation, was that GR methylation might be more pronounced in individuals with BN who also displayed comorbid ''borderline'' or ''suicidal'' manifestations, than of people with BN alone. Guided by previous findings, we targeted CpG sites in GR gene first exon sites 1B, 1C, 1F, and 1H, 16,18 measuring percent methylation at each CpG.…”

Glucocorticoid receptor gene (NR3C1) promoter is hypermethylated in Thai females with major depressive disorder

“…Nevertheless, the pathological mechanism of MDD has not yet been elucidated. Previous research indicates that MDD may be associated with the stress response in the brain as in other stress-related disorders (Weaver et al, 2004;Oberlander et al, 2008;McGowan et al, 2009;Perroud et al, 2011). The stress response is primarily mediated by the hypothalamic-pituitary-adrenal (HPA) axis, whichis regulated by a negative feedback mechanism of the endocrine stress response to control cortisol levels (Meaney, 2001;Moser et al, 2007).…”