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.

Automated summary

This study explored the potential role of DNA methylation in stress-relevant genes, particularly in Nuclear Factor of Activated T Cells 1 (NFATC1), as a mechanism linking different trauma types with the risk for post-traumatic stress disorder (PTSD). The results showed that all five trauma types were associated with altered methylation levels at specific CpG sites in NFATC1, indicating their potential involvement in the development of PTSD. Furthermore, the methylation levels at these CpG sites partially mediated the relationship between certain trauma types and the risk for PTSD. These findings suggest that NFATC1 5-mC may play a significant role in the biological embedding of trauma and the subsequent development of PTSD.