Glucocorticoid receptor gene methylation moderates the association of childhood trauma and cortisol stress reactivity

Exposure to childhood trauma (CT) has been linked to sustained dysregulations of major stress response systems, including findings of both exaggerated and attenuated hypothalamus-pituitary-adrenal (HPA) axis activity. Likewise, CT constitutes a common risk factor for a broad range of psychiatric conditions that involve distinct neuroendocrine profiles. In this study, we investigated the role of epigenetic variability in a stress-related gene as a potential mediator or moderator of such differential trajectories in CT survivors. For this, we screened adult volunteers for CT and recruited a healthy sample of 98 exposed (67 with mild-moderate, 31 with moderate-severe exposure) and 102 control individuals, with an equal number of males and females in each group. DNA methylation (DNAM) levels of the glucocorticoid receptor exon 1F promoter (NR3C1-1F) at functionally relevant sites were analyzed via bisulfite pyrosequencing from whole blood samples. Participants were exposed to a laboratory stressor (Trier Social Stress Test) to assess salivary cortisol stress responses. The major finding of this study indicates that DNAM in a biologically relevant region of NR3C1-1F moderates the specific direction of HPA-axis dysregulation (hypo- vs. hyperreactivity) in adults exposed to moderate-severe CT. Those trauma survivors with increased NR3C1-1F DNAM displayed, on average, 10.4 nmol/l (62.3%) higher peak cortisol levels in response to the TSST compared to those with low DNAM. In contrast, unexposed and mildly-moderately exposed individuals displayed moderately sized cortisol stress responses irrespective of NR3C1-1F DNAM. Contrary to some prior work, however, our data provides no evidence for a direct association of CT and NR3C1-1F DNAM status. According to this study, epigenetic changes of NR3C1-1F may provide a more in-depth understanding of the highly variable neuroendocrine and pathological sequelae of CT.