title: 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.
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: M S
authors.initials: MS
authors.lastname: Breen
authors.affiliation: Department of Psychiatry, University of California San Diego, California, USA.
authors.forename: A X
authors.initials: AX
authors.lastname: Maihofer
authors.affiliation: Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), Departments of Psychiatry and Behavioral Sciences and Neuroscience and Physiology, Medical Genetics Research Center, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Glatt
authors.affiliation: Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), Departments of Psychiatry and Behavioral Sciences and Neuroscience and Physiology, Medical Genetics Research Center, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Tylee
authors.affiliation: Department of Psychiatry, University of California San Diego, California, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Chandler
authors.affiliation: Department of Psychiatry, University of California San Diego, California, USA.|Veterans Affairs Center of Excellence for Stress and Mental Health, San Diego, California, USA.|Veterans Affairs San Diego Healthcare System, San Diego, California, USA.|Institute of Genomic Medicine, University of California, San Diego, La Jolla, California, USA.|Center for Behavioral Genomics, Department of Psychiatry, University of California San Diego, California, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Tsuang
authors.affiliation: Department of Psychiatry, University of California San Diego, California, USA.|Veterans Affairs Center of Excellence for Stress and Mental Health, San Diego, California, USA.
authors.forename: V B
authors.initials: VB
authors.lastname: Risbrough
authors.affiliation: Department of Psychiatry, University of California San Diego, California, USA.|Veterans Affairs Center of Excellence for Stress and Mental Health, San Diego, California, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Baker
authors.affiliation: Institute of Genomic Medicine, University of California, San Diego, La Jolla, California, USA.|Departments of Medicine and Pharmacology, University of California San Diego, California, USA.
authors.forename: D T
authors.initials: DT
authors.lastname: O'Connor
authors.affiliation: Department of Psychiatry, University of California San Diego, California, USA.|Veterans Affairs Center of Excellence for Stress and Mental Health, San Diego, California, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Nievergelt
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: C H
authors.initials: CH
authors.lastname: Woelk
mesh_terms: D015870:Gene Expression; D053263:Gene Regulatory Networks; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008297:Male; D008889:Military Personnel; D013313:Stress Disorders, Post-Traumatic / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult