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

Background The mechanisms through which exposure to differing trauma types become biologically embedded to shape the risk for subsequent post-traumatic stress disorder (PTSD) is unclear. DNA methylation (5-mC), particularly in stress-relevant genes, may play a role in this relationship. Methods 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 ) mediated 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 assessed prospectively in the Detroit Neighborhood Health Study (n=183). Results All five trauma types were significantly associated with reduced methylation at NFATC1 CpG site, cg17057218. Three of the five trauma types were significantly associated with increased methylation at NFATC1 CpG site, cg22324981. Moreover, methylation at cg17057218 significantly mediated 23-34% of the total effect for three of the five trauma types (assaultive violence, other injury or shocking experience, and learning of trauma to a loved one), while methylation at cg22324981 mediated 36-53% of the total effect for two of the five trauma types (other injury or shocking experience and other). These CpG sites were differentially associated with transcription factor binding sites and chromatin state signatures. Limitations Prospective assessment of lifetime PTSD, rather than PTSD onset. Conclusions NFATC1 5-mC may be a potential mechanism in the relationship between some trauma types and prospective risk for PTSD. This finding may help inform treatment for trauma-specific PTSD.