Longitudinal Changes In Glucocorticoid Receptor 1f Methylation And Psychopathology After Military Deployment

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 methylationin 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 methylationbefore and after exposure to traumatic stress are lacking. We therefore aimed to investigate prospective DNA methylationchanges in the GR-1F region after military deploymentand its relation to the emergence of psychopathology. Methods Whole blood DNA methylationin the entire GR-1F region (52 CpGs) before and six months after deployment was quantified using pyrosequencing(N=92). Methylationlevels 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, methylationwas related to GR-1F expression, GR binding and genetic variation in the GR. Mean methylation, the number of methylatedsites ( methylationburden), mean methylationat 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 methylationburden (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 psychopathologysymptoms was significantly associated with increased methylationat 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 methylationwas 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 methylationlevels are related to trauma exposure during deployment and the development of post-deployment psychopathologysymptoms, particularly at functionally relevant sites. Together, our results provide further insight in transcriptional regulation of the glucocorticoid receptorgene, by demonstrating that GR-1F DNA methylationlevels can vary over time and are related to stress vulnerability and the emergence of post-deployment psychopathologysymptoms.