DNA methylation of Nuclear Factor of Activated T Cells 1 mediates the prospective relation between exposure to different traumatic event types and post-traumatic stress disorder.

The mechanisms through which exposure to differing trauma types become biologically embedded to shape the risk for post-traumatic stress disorder (PTSD) is unclear. DNA methylation (5-mC), particularly in stress-relevant genes, may play a role in this relationship. Here, we conducted path analysis using generalized structural equation modeling to investigate whether blood-derived 5-mC in Nuclear Factor of Activated T Cells 1 (NFATC1) mediates the prospective association between each of five different trauma types ("assaultive violence", "other injury or shocking experience", "learning of trauma to loved one", "sudden, unexpected death of a close friend or relative", and "other") and lifetime PTSD. All five trauma types were significantly associated with reduced methylation at NFATC1 CpG site, cg17057218. Two of the five trauma types were significantly associated with increased methylation at NFATC1 CpG site, cg22324981. Moreover, methylation at cg17057218 significantly mediated 21-32% of the total effect for four of the five trauma types, while methylation at cg22324981 mediated 27-40% of the total effect for two of the five trauma types. These CpG sites were differentially associated with transcription factor binding sites and chromatin state signatures. NFATC1 5-mC may be a potential mechanism in the relationship between some trauma types and prospective risk for PTSD.