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Gene networks specific for innate immunity define post-traumatic stress disorder

Abstract

The molecular factors involved in the development of Post-Traumatic Stress Disorder (PTSD) remain poorly understood. Previous transcriptomic studies investigating the mechanisms of PTSD apply targeted approaches to identify individual genes under a cross-sectional framework lack a holistic view of the behaviours and properties of these genes at the system-level. Here we sought to apply an unsupervised gene-network based approach to a prospective experimental design using whole-transcriptome RNA-Seq gene expression from peripheral blood leukocytes of U.S. Marines (N=188), obtained both pre- and post-deployment to conflict zones. We identified discrete groups of co-regulated genes (i.e., co-expression modules) and tested them for association to PTSD. We identified one module at both pre- and post-deployment containing putative causal signatures for PTSD development displaying an over-expression of genes enriched for functions of innate-immune response and interferon signalling (Type-I and Type-II). Importantly, these results were replicated in a second non-overlapping independent dataset of U.S. Marines (N=96), further outlining the role of innate immune and interferon signalling genes within co-expression modules to explain at least part of the causal pathophysiology for PTSD development. A second module, consequential of trauma exposure, contained PTSD resiliency signatures and an over-expression of genes involved in hemostasis and wound responsiveness suggesting that chronic levels of stress impair proper wound healing during/after exposure to the battlefield while highlighting the role of the hemostatic system as a clinical indicator of chronic-based stress. These findings provide novel insights for early preventative measures and advanced PTSD detection, which may lead to interventions that delay or perhaps abrogate the development of PTSD.

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Gene Expression Omnibus

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Acknowledgements

We thank and extend our deepest gratitude to the late Dr Daniel T O’Connor whose passion and intellect of clinical, translational, and basic research brought considerable knowledge and insight to various realms of this research project and numerous others. This work was supported in part by the Naval Medical Research Center's Advanced Medical Development program (Naval Medical Logistics Command Contract #N62645-11-C-4037, for MRS II (DGB), and this Demonstration Project (CN and DOC). Replication of findings on a non-overlapping cohort was supported in part by both the National Institute of Mental Health R21 (MH085240) and R01 (MHO85560). Further support was provided by R01 (MH093500), R01 (MH085521), the Gerber Foundation, the Sidney R Baer, Jr Foundation and NARSAD: The Brain and Behavior Research Foundation. We acknowledge assistance of the MRS-II administrative core, A Patel, A De La Rosa and other members of the MRS-II Team. Likewise, we acknowledge administrative support from the Veterans Medical Research Foundation (VMRF) and valuable input from M.E. Polak, D Baldwin and A Collins who assisted in critical reading of the manuscript. We also thank the Marine and Navy volunteers for their military service and for their participation in this study.

Author Contributions

DGB, CN, CHW and DOC obtained the funding for this study. AXM curated clinical information regarding all participants. SJG, DST and SDC generated microarray data. MSB conducted the study which entailed generating RNA-Seq data, writing code for quality testing and computational interrogation of both RNA-Seq and microarray data. MSB drafted and wrote the manuscript with the participation of remaining authors.

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Correspondence to M S Breen or C M Nievergelt.

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Breen, M., Maihofer, A., Glatt, S. et al. Gene networks specific for innate immunity define post-traumatic stress disorder. Mol Psychiatry 20, 1538–1545 (2015). https://doi.org/10.1038/mp.2015.9

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