LONGITUDINAL CHANGES IN GLUCOCORTICOID RECEPTOR 1F METHYLATION AND PSYCHOPATHOLOGY AFTER MILITARY DEPLOYMENT

Abstract

Background The glucocorticoid receptor (GR) 1F region is involved in transcription and expression of the GR protein and influences hypothalamic-pituitary-adrenal (HPA)-axis activity. Several studies have investigated GR-1F DNA methylation in the context of traumatic stress and psychiatric disorders, such as major depressive disorder and posttraumatic stress disorder (PTSD). However, longitudinal studies examining GR-1F DNA methylation before and after exposure to traumatic stress are lacking. We therefore aimed to investigate prospective DNA methylation changes in the GR-1F region after military deployment and its relation to the emergence of psychopathology. Methods Whole blood DNA methylation in the entire GR-1F region (52 CpGs) before and six months after deployment was quantified using pyrosequencing (N=92). Methylation levels were linked to post-deployment mental health problems (Revised Symptom Checklist, SCL-90), PTSD symptoms (Self-Rating Inventory for PTSD) and trauma exposure during deployment. Moreover, methylation was related to GR-1F expression, GR binding and genetic variation in the GR. Mean methylation, the number of methylated sites (methylation burden), mean methylation at transcription factor binding sites and at CpGs significantly associated with GR-1F expression (functional methylation) were examined. Results Trauma exposure during deployment and the emergence of mental health problems were significantly related to an increased methylation burden (t=2.23, p=2.8x10-2, =0.45 and t=2.24, p=2.7x10-2 and =0.085, respectively), which was associated with both decreased GR-1F expression (t=-2.92, p=4.7x10-3, =-1.93) and GR binding (t=-2.13, p=3.9x10-2, =-2.9x10-3). Moreover, development of psychopathology symptoms was significantly associated with increased methylation at functionally relevant CpGs (mental health problems: t=3.73, p=3.5x10-4, =1.2x10-2; PTSD symptoms: t=2.10, p=3.8x10-2, =0.59). Change in mean methylation was associated with a change in mental health problems (t=1.99, p=5.0x10-2, =4.1x10-3) and in GR-1F expression (t=-2.35, p=2.2x10-2, =-0.074). Discussion This longitudinal study in a military cohort shows that GR-1F DNA methylation levels are related to trauma exposure during deployment and the development of post-deployment psychopathology symptoms, particularly at functionally relevant sites. Together, our results provide further insight in transcriptional regulation of the glucocorticoid receptor gene, by demonstrating that GR-1F DNA methylation levels can vary over time and are related to stress vulnerability and the emergence of post-deployment psychopathology symptoms