Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Ramchand R, Schell TL, Karney BR, Osilla KM, Burns RM, Caldarone LB . Disparate prevalence estimates of PTSD among service members who served in Iraq and Afghanistan: possible explanations. J. Trauma. Stress 2010; 23: 59–68.

    PubMed  Google Scholar 

  2. Heinzelmann M, Gill J . Epigenetic Mechanisms Shape the Biological Response to Trauma and Risk for PTSD: A Critical Review. Nursing Research and Practice 2013; 2013: 1–10.

    Article  Google Scholar 

  3. Zieker J, Zieker D, Jatzko A, Dietzsch J, Niesel K, Schmitt A et al. Differential gene expression in peripheral blood of patients suffering from post-traumatic stress disorder. Molecular Psychiatry 2007; 12.2: 116–118.

    Article  Google Scholar 

  4. Yehuda R, Holsboer F, Buxbaum JD, Miller-Myhsok B, Schmeidler J, Rein T et al. Gene Expression Patterns Associated with Posttraumatic Stress Disorder Following Exposure to the World Trade Center Attacks. Biological Psychiatry 2009; 66.7: 708–711.

    Article  Google Scholar 

  5. Neylan TC, Sun B, Rempel H, Ross J, Lenoci M, O’Donovan A et al. Suppressed monocyte gene expression profile in men versus women with PTSD. Brain, Behavior, and Immunity 2011; 25.3: 524–531.

    Article  Google Scholar 

  6. Sarapas C, Cai G, Bierer LM, Golier JA, Galea S, Ising M et al. Genetic Markers for PTSD Risk and Resilience Among Survivors of the World Trade Center Attacks. Disease Markers 2011; 30.2-3: 101–110.

    Article  Google Scholar 

  7. Mehta D, Gonik M, Klengel T, Rex-Haffner M, Menke A, Rubel J et al. Using Polymorphisms in FKBP5 to Define Biologically Distinct Subtypes of Posttraumatic Stress Disorder: Evidence From Endocrine and Gene Expression Studies. Archives of General Psychiatry 2011; 68.9: 901–910.

    Article  Google Scholar 

  8. Pace TW, Wingenfeld K, Schmidt I, Meinlschmidt G, Hellhammer DH, Heim CM . Increased peripheral NF-KB pathway activity in women with childhood abuse-related posttraumatic stress disorder. Brain, Behavior, and Immunity 2012; 26.1: 13–17.

    Article  Google Scholar 

  9. van Zuiden M, Heijnen CJ, Maas M, Amarouchi K, Vermetten E, Geuze E et al. Glucocorticoid sensitivity of leukocytes predicts PTSD, depressive and fatigue symptoms after military deployment: A prospective study. Psychoneuroendocrinology 2012; 37.11: 1822–1836.

    Article  Google Scholar 

  10. van Zuiden M, Geuze E, Willemen HL, Vermetten E, Maas M, Amarouchi K et al. Glucocorticoid Receptor Pathway Components Predict Posttraumatic Stress Disorder Symptom Development: A Prospective Study. Biological Psychiatry 2012; 71.4: 309–316.

    Article  Google Scholar 

  11. Matić G, Milutinović DV, Nestorov J, Elaković I, Jovanović SM, Perišić T et al. Lymphocyte glucocorticoid receptor expression level and hormone-binding properties differ between war trauma-exposed men with and without PTSD. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2013; 43: 238–245.

    Article  Google Scholar 

  12. Glatt SJ, Tylee DS, Chandler SD, Pazol J, Nievergelt CM, Woelk CH et al. Blood-based gene-expression predictors of PTSD risk and resilience among deployed marines: A pilot study. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2013; 162.4: 313–326.

    Article  Google Scholar 

  13. Langfelder P, Horvath S . WGCNA: An R Package for Weighted Correlation Network Analysis. BMC Bioinformatics 2008; 9.1: 559.13.

    Google Scholar 

  14. Miller JA, Oldham MC, Geschwind DH . A Systems Level Analysis of Transcriptional Changes in Alzheimer's Disease and Normal Aging. Journal of Neuroscience 2008; 28.6: 1410–1420.

    Article  Google Scholar 

  15. Saris C, Horvath S, van Vught PWJ, vanEs MA, Blaue HM, Fuller TF et al. Weighted gene co-expression network analysis of the peripheral blood from Amyotrophic Lateral Sclerosis patients. BMC Genomics 2009; 10.1: 405.

    Article  Google Scholar 

  16. Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 2011; 474.7351: 380–384.

    Article  Google Scholar 

  17. Hwang Y, Kim J, Shin JY, Kim JI, Seo JS, Webster MJ et al. Gene expression profiling by mRNA sequencing reveals increased expression of immune/inflammation-related genes in the hippocampus of individuals with schizophrenia. Translational Psychiatry 2013; 3.10: e321.

    Article  Google Scholar 

  18. Chen C, Cheng L, Grennan K, Pibiri F, Zhang C, Badner JA et al. Two gene co-expression modules differentiate psychotics and controls. Molecular Psychiatry 2012; 18.12: 1308–1314.

    Google Scholar 

  19. Torkamani A, Dean B, Schork NJ, Thomas EA . Coexpression Network Analysis of Neural Tissue Reveals Perturbations in Developmental Processes in Schizophrenia. Genome Research 2010; 20.4: 403–412.

    Article  Google Scholar 

  20. Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD, Charney DS et al. The development of a Clinician-Administered PTSD Scale. J. Trauma. Stress 1995; 8: 75–90.

    Article  CAS  Google Scholar 

  21. King DW, Leskin GA, King LA, Weathers FW . Confirmatory factor analysis of the Clinician-Administered PTSD Scale: Evidence for the dimensionality of posttraumatic stress disorder. Psychol. Assess 1998; 10: 90–96.

    Article  Google Scholar 

  22. Weathers FW, Keane TM, Davidson JR . Clinician-administered PTSD scale: a review of the first ten years of research. Depress. Anxiety 2001; 13: 132–156.

    Article  CAS  Google Scholar 

  23. Weathers FW, Ruscio AM, Keane TM . Psychometric properties of nine scoring rules for the clinician-administered posttraumatic stress disorder scale. Psychol. Assess 1999; 11: 124–133.

    Article  Google Scholar 

  24. American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 4th edition. American Psychiatric Press: Washington DC, 2000.

  25. Blanchard EB, Hickling EJ, Taylor AE, Loos WR . Psychiatric morbidity associated with motor vehicle accidents. J. Nerv. Ment. Dis. 1995; 183: 495–504.

    Article  CAS  Google Scholar 

  26. Blanchard EB, Hickling EJ, Vollmer AJ, Loos WR, Buckley TC, Jaccard J . Short-term follow-up of post-traumatic stress symptoms in motor vehicle accident victims. Behaviour Research and Therapy 1995; 33: 369–377.

    Article  CAS  Google Scholar 

  27. Blanchard EB, Hickling EJ, Barton KA, Taylor AE, Loos WR, Jones-Alexander J . One-year prospective follow-up of motor vehicle accident victims. Behaviour Research and Therapy 1996; 34: 775–786.

    Article  CAS  Google Scholar 

  28. Robinson MD, McCarthy DJ, Smyth GK . edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 2010; 26: 139–140.

    Article  CAS  Google Scholar 

  29. Smyth GK . Limma: linear models for microarray data. In Gentlemen R, Carey V, Dudoit S, Irizarry R, Huber W (ed) Bioinformatics and Computational Biology Solutions using R and Bioconductor. Springer: New York, 2005, pp 397–420.

    Chapter  Google Scholar 

  30. Huang DW, Sherman BT, Lempicki RA . Systematic and integrative analysis of large gene lists using DAVID Bioinformatics Resources. Nature Protoc 2009; 4: 44–57.

    Article  CAS  Google Scholar 

  31. Miller JA, Cai C, Langfelder P, Geschwind DH, Kurian SM, Salomon DR, Horvath S . Strategies for aggregating gene expression data: the collapse Rows R function. BMC Bioinformatics 2011; 12: 322.

    Article  CAS  Google Scholar 

  32. Geer LY, Marchler-Bauer A, Geer RC, Han L, He J, He S et al. The NCBI BioSystems database. Nucleic Acids Res. 2010; 38: D492–D496.

    Article  CAS  Google Scholar 

  33. Shoemaker JE, Tiago L, Ghosh S, Matsuoka Y, Kawaoka Y, Kitano H . CTen: A Web-based Platform for Identifying Enriched Cell Types from Heterogeneous Microarray Data. BMC Genomics 2012; 13.1: 460.

    Article  Google Scholar 

  34. Zarbock A, Polanowska-Grabowska RK, Ley K . Platelet-neutrophil-interactions: Linking Hemostasis and Inflammation. Blood Reviews 2007; 21.2: 99–111.

    Article  Google Scholar 

  35. Beck F, Geiger J, Gambaryan S, Veit J, Vaudel M, Nollau P et al. Time-resolved characterization of cAMP/PKA-dependent signaling reveals that platelet inhibition is a concerted process involving multiple signaling pathways. Blood 2014; 123: e1–e10.

    Article  CAS  Google Scholar 

  36. Daly ME . Determinants of Platelet Count in Humans. Haematologica 2010; 96.1: 10–13.

    Google Scholar 

  37. Raslova H, Kauffmann A, Sekkai D, Ripoche H, Larbret F, Robert T et al. Interrelation between Polyploidization and Megakaryocyte Differentiation: A Gene Profiling Approach. Blood 2007; 109.8: 3225–3234.

    Article  Google Scholar 

  38. Rusinova I, Forster S, Yu S, Kannan A, Masse M, Cumming H et al. INTERFEROME V2.0: An Updated Database of Annotated Interferon-regulated Genes. Nucleic Acids Research 2012; 41.D1: D1040–D1046.

    Article  Google Scholar 

  39. Pacak K . Stressor Specificity of Central Neuroendocrine Responses: Implications for Stress-Related Disorders. Endocrine Reviews 2001; 22.4: 502–548.

    Article  Google Scholar 

  40. Bray PF, Mckenzie SE, Edelstein LC, Nagalla S, Delgrosso K, Ertel A . The Complex Transcriptional Landscape of the Anucleate Human Platelet. BMC Genomics 2013; 4.1: 1.

    Article  Google Scholar 

  41. Austin AW, Wissmann T, Von Kanel R . Stress and Hemostasis: An Update. Seminars in Thrombosis and Hemostasis 2013; 39.08: 902–912.

    Article  Google Scholar 

  42. Walburn J, Vedhara K, Hankins M, Rixon L, Weinman J . Psychological stress and wound healing in humans: a systematic review and meta-analysis. J Psychosom Res 2009; 67: 253–271.

    Article  Google Scholar 

  43. Gouin J-P, Kiecolt-Glaser JK . The Impact of Psychological Stress on Wound Healing: Methods and Mechanisms. Immunology and Allergy Clinics of North America 2011; 31.1: 81–93.

    Article  Google Scholar 

  44. Eraly SA, Nievergelt CM, Maihofer AX, Barkauskas DA, Nilima Biswas N, Agorastos A et al. Assessment of Plasma C-Reactive Protein as a Biomarker of Posttraumatic Stress Disorder Risk. JAMA Psychiatry 2014; 71.4: 423.

    Article  Google Scholar 

  45. Maunder RG, Hunter JJ, Feinman SV . Interferon Treatment of Hepatitis C Associated With Symptoms of PTSD. Psychosomatics 1998; 39.5: 461–464.

    Article  Google Scholar 

  46. Dieperink E, Leskela J, Dieperink ME, Evans B, Thuras P, Ho SB . The Effect of Pegylated Interferon-α2b and Ribavirin on Posttraumatic Stress Disorder Symptoms. Psychosomatics 2008; 49.3: 225–229.

    Article  Google Scholar 

  47. Butcher SK, Lord JM . Stress Responses and Innate Immunity: Aging as a Contributory Factor. Aging Cell 2004; 3.4: 151–160.

    Article  Google Scholar 

  48. Clark SM, San J, Francis TC, Nagaraju A, Michael KC, Keegan AD et al. Immune status influences fear and anxiety responses in mice after acute stress exposure. Brain, behavior, and immunity 2014; 38: 192–201.

    Article  CAS  Google Scholar 

  49. Maes M, Kubera M, Leunis J . The gut-brain barrier in major depression: Intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Nueroendocrinology Letters 2008; 29: 117–124.

    Google Scholar 

  50. Aiboshi J, Moore EE, Ciesla CJ, Silliman CC . Blood transfusion and the two-insult model of post-injury multiple organ failure. Shock 2001; 15: 302–306.

    Article  CAS  Google Scholar 

  51. Veldhuis TB, Floris T, van der Meide PH, Vos IM, de Vries HE, Dijkstra CD et al. Interferon-beta prevents cytokine-induced neutrophil infiltration and attenuates blood–brain barrier disruption. J. Cerebral Blood Flow Metab 2003; 23: 1060–1069.

    Article  CAS  Google Scholar 

  52. Bhatia M, Moochhala S . Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J. Pathol. 2004; 202: 145–156.

    Article  CAS  Google Scholar 

  53. Giannoudis PV . Current concepts of the inflammatory response after major trauma: an update. Injury 2003; 34: 397–404.

    Article  CAS  Google Scholar 

  54. Minagar A, Alexander JS . Blood-brain Barrier Disruption in Multiple Sclerosis. Multiple Sclerosis 2003; 9.6: 540–549.

    Article  Google Scholar 

  55. Carmeliet P, Strooper BD . Alzheimer's Disease: A Breach in the Blood–brain Barrier. Nature 2012; 485.7399: 451–452.

    Article  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to M S Breen or C M Nievergelt.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2015.9

This article is cited by

Search

Quick links