Glucocorticoid receptor gene methylation and HPA-axis regulation in adolescents. The TRAILS study

• We investigated the association between HPA-axis regulation and NR3C1 methylation.
• HPA-axis regulation was operationalized as stress response activation and recovery.
• NR3C1 methylation was not associated with activation of the stress response.
• NR3C1 methylation was associated with a slower recovery of the stress response.
• NR3C1 methylation possibly impairs negative feedback of the HPA-axis.

SummaryEarly life adversity and psychopathology are thought to be linked through HPA-axis deregulation. Changes in methylation levels of stress reactivity genes such as the glucocorticoid receptor gene (NR3C1) can be induced by adversity. Higher NR3C1 methylation levels have been associated with a reduced NR3C1 expression, possibly leading to impaired negative feedback regulation of the HPA-axis. In this study we tested whether methylation levels of NR3C1 were associated with HPA-axis regulation, operationalized as cortisol responses. In 361 adolescents (mean age 16.1, SD = 0.6), salivary cortisol samples were collected before, during, and after a social stress task, from which response measures (cortisol activation and recovery) were calculated. Higher NR3C1 methylation levels were associated with a flattened cortisol recovery slope, indicating a delayed recovery time. Cortisol response activation was not associated with NR3C1 methylation. These results suggest that methylation of NR3C1 may impair negative feedback of the HPA-axis in adolescents.