SpringerLink
Log in

Epigenome-wide meta-analysis of PTSD symptom severity in three military cohorts implicates DNA methylation changes in genes involved in immune system and oxidative stress

  • Article
  • Published:
Molecular Psychiatry Submit manuscript

Abstract

Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1, and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: PTSS associates with DNAm across the genome.

Similar content being viewed by others

Data availability

The main summary statistics data that support the findings of this study are available within Supplementary Data. Owing to military cohort data sharing restrictions, data from MRS, Army STARRS, and PRISMO cannot be publicly posted. Individual-level data from the cohorts or cohort-level summary statistics will be made available to researchers following an approved analysis proposal through the PGC Post-traumatic Stress Disorder group with agreement of the cohort PIs. For additional information on access to these data, including PI contact information for the contributing cohorts, please contact the corresponding author.

Code availability

The scripts generated to perform the Meta-Analysis 1, Meta-Analysis 2, and DMR analysis are available in https://github.com/PGC-PTSD-EWAS/PGC-PTSD-Longitudinal-Analysis.

References

  1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5®). 5th ed. Washington, DC: American Psychiatric Pub; 2013.

  2. Benjet C, Bromet E, Karam EG, Kessler RC, McLaughlin KA, Ruscio AM, et al. The epidemiology of traumatic event exposure worldwide: results from the World Mental Health Survey Consortium. Psychol Med. 2016;46:327–43.

    Article  CAS  PubMed  Google Scholar 

  3. Kessler RC, Berglund P, Demler O, ** R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593–602.

    Article  PubMed  Google Scholar 

  4. Daskalakis NP, Rijal CM, King C, Huckins LM, Ressler KJ. Recent genetics and epigenetics approaches to PTSD. Curr Psychiatry Rep. 2018;20:30.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Morrison FG, Miller MW, Logue MW, Assef M, Wolf EJ. DNA methylation correlates of PTSD: recent findings and technical challenges. Prog Neuropsychopharmacol Biol Psychiatry. 2019;90:223–34.

    Article  CAS  PubMed  Google Scholar 

  6. Sheerin CM, Lind MJ, Bountress KE, Nugent NR, Amstadter AB. The genetics and epigenetics of PTSD: overview, recent advances, and future directions. Curr Opin Psychol. 2017;14:5–11.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Uddin M, Aiello AE, Wildman DE, Koenen KC, Pawelec G, de Los Santos R, et al. Epigenetic and immune function profiles associated with posttraumatic stress disorder. Proc Natl Acad Sci USA. 2010;107:9470–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Smith AK, Conneely KN, Kilaru V, Mercer KB, Weiss TE, Bradley B, et al. Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. Am J Med Genet B Neuropsychiatr Genet. 2011;156B:700–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Kuan PF, Waszczuk MA, Kotov R, Marsit CJ, Guffanti G, Gonzalez A, et al. An epigenome-wide DNA methylation study of PTSD and depression in World Trade Center responders. Transl Psychiatry. 2017;7:e1158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Uddin M, Ratanatharathorn A, Armstrong D, Kuan PF, Aiello AE, Bromet EJ, et al. Epigenetic meta-analysis across three civilian cohorts identifies NRG1 and HGS as blood-based biomarkers for post-traumatic stress disorder. Epigenomics. 2018;10:1585–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rutten BPF, Vermetten E, Vinkers CH, Ursini G, Daskalakis NP, Pishva E, et al. Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder. Mol Psychiatry. 2018;23:1145–56.

    Article  CAS  PubMed  Google Scholar 

  12. Snijders C, Maihofer AX, Ratanatharathorn A, Baker DG, Boks MP, Geuze E, et al. Longitudinal epigenome-wide association studies of three male military cohorts reveal multiple CpG sites associated with post-traumatic stress disorder. Clin Epigenetics. 2020;12:11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Logue MW, Miller MW, Wolf EJ, Huber BR, Morrison FG, Zhou Z, et al. An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci. Clin Epigenetics. 2020;12:46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Smith AK, Ratanatharathorn A, Maihofer AX, Naviaux RK, Aiello AE, Amstadter AB, et al. Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR. Nat Commun. 2020;11:5965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Verhulst B, Neale MC. Best practices for binary and ordinal data analyses. Behav Genet. 2021;51:204–14.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Barfield RT, Kilaru V, Smith AK, Conneely KN. CpGassoc: an R function for analysis of DNA methylation microarray data. Bioinformatics. 2012;28:1280–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. McCartney DL, Walker RM, Morris SW, McIntosh AM, Porteous DJ, Evans KL. Identification of polymorphic and off-target probe binding sites on the Illumina Infinium MethylationEPIC BeadChip. Genom Data. 2016;9:22–4.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Fortin JP, Triche TJ Jr., Hansen KD. Preprocessing, normalization and integration of the Illumina HumanMethylationEPIC array with minfi. Bioinformatics. 2017;33:558–60.

    Article  CAS  PubMed  Google Scholar 

  19. Leek JT, Johnson WE, Parker HS, Jaffe AE, Storey JD. The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics. 2012;28:882–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Du P, Zhang X, Huang CC, Jafari N, Kibbe WA, Hou L, et al. Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis. BMC Bioinform. 2010;11:587.

    Article  CAS  Google Scholar 

  21. Teschendorff AE, Breeze CE, Zheng SC, Beck S. A comparison of reference-based algorithms for correcting cell-type heterogeneity in Epigenome-Wide Association Studies. BMC Bioinform. 2017;18:105.

    Article  CAS  Google Scholar 

  22. Salas LA, Koestler DC, Butler RA, Hansen HM, Wiencke JK, Kelsey KT, et al. An optimized library for reference-based deconvolution of whole-blood biospecimens assayed using the Illumina HumanMethylationEPIC BeadArray. Genome Biol. 2018;19:64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Barfield RT, Almli LM, Kilaru V, Smith AK, Mercer KB, Duncan R, et al. Accounting for population stratification in DNA methylation studies. Genet Epidemiol. 2014;38:231–41.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ratanatharathorn A, Boks MP, Maihofer AX, Aiello AE, Amstadter AB, Ashley-Koch AE, et al. Epigenome-wide association of PTSD from heterogeneous cohorts with a common multi-site analysis pipeline. Am J Med Genet B Neuropsychiatr Genet. 2017;174:619–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. de Bakker PI, Ferreira MA, Jia X, Neale BM, Raychaudhuri S, Voight BF. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum Mol Genet. 2008;17:R122–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Lee CH, Cook S, Lee JS, Han B. Comparison of two meta-analysis methods: inverse-variance-weighted average and weighted sum of Z-scores. Genomics Inform. 2016;14:173–80.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Cochran WG. Some methods for strengthening the common χ2 tests. Biometrics. 1954;10:417–51.

    Article  Google Scholar 

  28. Mansell G, Gorrie-Stone TJ, Bao Y, Kumari M, Schalkwyk LS, Mill J, et al. Guidance for DNA methylation studies: statistical insights from the Illumina EPIC array. BMC Genom. 2019;20:366.

    Article  Google Scholar 

  29. Peters TJ, Buckley MJ, Statham AL, Pidsley R, Samaras K, Reginald VL, et al. De novo identification of differentially methylated regions in the human genome. Epigenetics Chromatin. 2015;8:6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Braun PR, Han S, Hing B, Nagahama Y, Gaul LN, Heinzman JT, et al. Genome-wide DNA methylation comparison between live human brain and peripheral tissues within individuals. Transl Psychiatry. 2019;9:47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Bonder MJ, Luijk R, Zhernakova DV, Moed M, Deelen P, Vermaat M, et al. Disease variants alter transcription factor levels and methylation of their binding sites. Nat Genet. 2017;49:131–8.

    Article  CAS  PubMed  Google Scholar 

  32. Phipson B, Maksimovic J, Oshlack A. missMethyl: an R package for analyzing data from Illumina’s HumanMethylation450 platform. Bioinformatics. 2016;32:286–8.

    Article  CAS  PubMed  Google Scholar 

  33. Nemeroff CB, Bremner JD, Foa EB, Mayberg HS, North CS, Stein MB. Posttraumatic stress disorder: a state-of-the-science review. J Psychiatr Res. 2006;40:1–21.

    Article  PubMed  Google Scholar 

  34. Yehuda R. Risk and resilience in posttraumatic stress disorder. J Clin Psychiatry. 2004;65:29–36.

    CAS  PubMed  Google Scholar 

  35. Brewin CR, Holmes EA. Psychological theories of posttraumatic stress disorder. Clin Psychol Rev. 2003;23:339–76.

    Article  PubMed  Google Scholar 

  36. Jose RJ, Williams AE, Chambers RC. Proteinase-activated receptors in fibroproliferative lung disease. Thorax. 2014;69:190–2.

    Article  PubMed  Google Scholar 

  37. Tylee DS, Chandler SD, Nievergelt CM, Liu X, Pazol J, Woelk CH, et al. Blood-based gene-expression biomarkers of post-traumatic stress disorder among deployed marines: a pilot study. Psychoneuroendocrinology. 2015;51:472–94.

    Article  CAS  PubMed  Google Scholar 

  38. Hong F, Liu B, Wu BX, Morreall J, Roth B, Davies C, et al. CNPY2 is a key initiator of the PERK-CHOP pathway of the unfolded protein response. Nat Struct Mol Biol. 2017;24:834–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bornhauser BC, Olsson PA, Lindholm D. MSAP is a novel MIR-interacting protein that enhances neurite outgrowth and increases myosin regulatory light chain. J Biol Chem. 2003;278:35412–20.

    Article  CAS  PubMed  Google Scholar 

  40. Miller MW, Lin AP, Wolf EJ, Miller DR. Oxidative stress, inflammation, and neuroprogression in chronic PTSD. Harv Rev Psychiatry. 2018;26:57–69.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wang YP, Huang LY, Sun WM, Zhang ZZ, Fang JZ, Wei BF, et al. Insulin receptor tyrosine kinase substrate activates EGFR/ERK signalling pathway and promotes cell proliferation of hepatocellular carcinoma. Cancer Lett. 2013;337:96–106.

    Article  CAS  PubMed  Google Scholar 

  42. Millard TH, Dawson J, Machesky LM. Characterisation of IRTKS, a novel IRSp53/MIM family actin regulator with distinct filament bundling properties. J Cell Sci. 2007;120:1663–72.

    Article  CAS  PubMed  Google Scholar 

  43. Alhassen S, Chen S, Alhassen L, Phan A, Khoudari M, De Silva A, et al. Intergenerational stress transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction. Commun Biol. 2021;4:783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Woodward DF, Jones RL, Narumiya S. International Union of Basic and Clinical Pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress. Pharmacol Rev. 2011;63:471–538.

    Article  CAS  PubMed  Google Scholar 

  45. Offermanns S. Activation of platelet function through G protein-coupled receptors. Circ Res. 2006;99:1293–304.

    Article  CAS  PubMed  Google Scholar 

  46. Smyth EM. Thromboxane and the thromboxane receptor in cardiovascular disease. Clin Lipido. 2010;5:209–19.

    Article  CAS  Google Scholar 

  47. Sadowitz PD, Setty BN, Stuart M. The platelet cyclooxygenase metabolite 12-L-hydroxy-5, 8, 10-hepta-decatrienoic acid (HHT) may modulate primary hemostasis by stimulating prostacyclin production. Prostaglandins. 1987;34:749–63.

    Article  CAS  PubMed  Google Scholar 

  48. Campbell PB, Tolson TA. Modulation of human monocyte leukotactic responsiveness by thromboxane A2 and 12-hydroxyheptadecatrienoic acid (12-HHT). J Leukoc Biol. 1988;43:117–24.

    Article  CAS  PubMed  Google Scholar 

  49. Hecker M, Ullrich V. 12(S)-Hydroxy-5,8,10 (Z,E,E)-heptadecatrienoic acid (HHT) is preferentially metabolized to its 12-keto derivative by human erythrocytes in vitro. Eicosanoids. 1988;1:19–25.

    CAS  PubMed  Google Scholar 

  50. Del Rio D, Stewart AJ, Pellegrini N. A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress. Nutr Metab Cardiovasc Dis. 2005;15:316–28.

    Article  PubMed  Google Scholar 

  51. Xue SS, He JL, Zhang X, Liu YJ, Xue FX, Wang CJ, et al. Metabolomic analysis revealed the role of DNA methylation in the balance of arachidonic acid metabolism and endothelial activation. Biochim Biophys Acta. 2015;1851:1317–26.

    Article  CAS  PubMed  Google Scholar 

  52. Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structures, properties, and functions. Physiol Rev. 1999;79:1193–226.

    Article  CAS  PubMed  Google Scholar 

  53. Mitsumori T, Furuyashiki T, Momiyama T, Nishi A, Shuto T, Hayakawa T, et al. Thromboxane receptor activation enhances striatal dopamine release, leading to suppression of GABAergic transmission and enhanced sugar intake. Eur J Neurosci. 2011;34:594–604.

    Article  PubMed  Google Scholar 

  54. Dahoun T, Nour MM, McCutcheon RA, Adams RA, Bloomfield MAP, Howes OD. The relationship between childhood trauma, dopamine release and dexamphetamine-induced positive psychotic symptoms: a [(11)C]-(+)-PHNO PET study. Transl Psychiatry. 2019;9:287.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Bloomfield MA, McCutcheon RA, Kempton M, Freeman TP, Howes O. The effects of psychosocial stress on dopaminergic function and the acute stress response. Elife. 2019;8:e46797.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, et al. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry. 2009;66:13–20.

    Article  PubMed  Google Scholar 

  57. Avram M, Brandl F, Cabello J, Leucht C, Scherr M, Mustafa M, et al. Reduced striatal dopamine synthesis capacity in patients with schizophrenia during remission of positive symptoms. Brain. 2019;142:1813–26.

    Article  PubMed  Google Scholar 

  58. Boukezzi S, Baunez C, Rousseau PF, Warrot D, Silva C, Guyon V, et al. Posttraumatic Stress Disorder is associated with altered reward mechanisms during the anticipation and the outcome of monetary incentive cues. Neuroimage Clin. 2020;25:102073.

    Article  PubMed  Google Scholar 

  59. Wang Q, **ang B, Deng W, Wu J, Li M, Ma X, et al. Genome-wide association analysis with gray matter volume as a quantitative phenotype in first-episode treatment-naive patients with schizophrenia. PLoS ONE. 2013;8:e75083.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Maihofer AX, Choi KW, Coleman JRI, Daskalakis NP, Denckla CA, Ketema E, et al. Enhancing discovery of genetic variants for PTSD through integration of quantitative phenotypes and trauma exposure information. Biological Psychiatry. 2021. e-pub ahead of print. https://doi.org/10.1016/j.biopsych.2021.09.020.

  61. Lindsay S, Monk M, Holliday R, Huschtscha L, Davies KE, Riggs AD, et al. Differences in methylation on the active and inactive human X chromosomes. Ann Hum Genet. 1985;49:115–27.

    Article  CAS  PubMed  Google Scholar 

  62. Yu S, Chen C, Pan Y, Kurz MC, Datner E, Hendry PL, et al. Genes known to escape X chromosome inactivation predict co-morbid chronic musculoskeletal pain and posttraumatic stress symptom development in women following trauma exposure. Am J Med Genet B Neuropsychiatr Genet. 2019;180:415–27.

    CAS  PubMed  Google Scholar 

  63. Tanaka M, Li H, Zhang X, Singh J, Dalgard CL, Wilkerson M, et al. Region- and time-dependent gene regulation in the amygdala and anterior cingulate cortex of a PTSD-like mouse model. Mol Brain. 2019;12:25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Grybek V, Aubry L, Maupetit-Mehouas S, Le Stunff C, Denis C, Girard M, et al. Methylation and transcripts expression at the imprinted GNAS locus in human embryonic and induced pluripotent stem cells and their derivatives. Stem Cell Rep. 2014;3:432–43.

    Article  CAS  Google Scholar 

  65. Plongthongkum N, van Eijk KR, de Jong S, Wang T, Sul JH, Boks MP, et al. Characterization of genome-methylome interactions in 22 nuclear pedigrees. PLoS ONE. 2014;9:e99313.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Castellani CA, Laufer BI, Melka MG, Diehl EJ, O’Reilly RL, Singh SM. DNA methylation differences in monozygotic twin pairs discordant for schizophrenia identifies psychosis related genes and networks. BMC Med Genom. 2015;8:17.

    Article  CAS  Google Scholar 

  67. Sokolowski M, Wasserman J, Wasserman D. Gene-level associations in suicide attempter families show overrepresentation of synaptic genes and genes differentially expressed in brain development. Am J Med Genet B Neuropsychiatr Genet. 2018;177:774–84.

    Article  CAS  PubMed  Google Scholar 

  68. Muhie S, Gautam A, Chakraborty N, Hoke A, Meyerhoff J, Hammamieh R, et al. Molecular indicators of stress-induced neuroinflammation in a mouse model simulating features of post-traumatic stress disorder. Transl Psychiatry. 2017;7:e1135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Shu C, Zhang X, Aouizerat BE, Xu K. Comparison of methylation capture sequencing and infinium methylationEPIC array in peripheral blood mononuclear cells. Epigenetics Chromatin. 2020;13:51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Michopoulos V, Powers A, Gillespie CF, Ressler KJ, Jovanovic T. Inflammation in fear- and anxiety-based disorders: PTSD, GAD, and beyond. Neuropsychopharmacology. 2017;42:254–70.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institute of Mental Health (NIMH; 2R01MH108826 and 2R01MH106595). The Marine Corps, Navy Bureau of Medicine and Surgery (BUMED) and VA Health Research and Development (HSR&D) provided funding for MRS data collection. Acknowledged are Mark A. Geyer (UCSD), Daniel T. O’Connor (UCSD), and all MRS investigators, as well as the MRS administrative core and data collection staff. Data collection of PRISMO was funded by the Dutch Ministry of Defense, and DNAm analyses were funded by the VIDI Award fellowship from the Netherlands Organization for Scientific Research (NWO, grant number 917.18.336 to BPFR). Army STARRS was sponsored by the Department of the Army and funded under cooperative agreement number U01MH087981 (2009–2015) with the National Institutes of Health, National Institute of Mental Health (NIH/NIMH).

Author information

Authors and Affiliations

  1. Department of Gynecology and Obstetrics, Emory University, Atlanta, GA, USA

    Seyma Katrinli & Alicia K. Smith

  2. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    Adam X. Maihofer, Elizabeth Ketema, Dewleen G. Baker, Victoria B. Risbrough, Murray B. Stein & Caroline M. Nievergelt

  3. Genomics Program, College of Public Health, University of South Florida, Tampa, FL, USA

    Agaz H. Wani & Monica Uddin

  4. Department of Psychology, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    John R. Pfeiffer

  5. Carl R. Woese Institute for Genomic Biology, Urbana, IL, USA

    John R. Pfeiffer

  6. Department of Epidemiology, Columbia University, New York, NY, USA

    Andrew Ratanatharathorn

  7. Veterans Affairs San Diego Healthcare System, San Diego, CA, USA

    Dewleen G. Baker, Murray B. Stein & Caroline M. Nievergelt

  8. Veterans Affairs Center of Excellence for Stress and Mental Health, San Diego, CA, USA

    Dewleen G. Baker, Victoria B. Risbrough & Caroline M. Nievergelt

  9. Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands

    Marco P. Boks, Elbert Geuze & Eric Vermetten

  10. Brain Research and Innovation Centre, Netherlands Ministry of Defence, Utrecht, The Netherlands

    Elbert Geuze

  11. Department of Health Care Policy, Harvard Medical School, Boston, MA, USA

    Ronald C. Kessler

  12. Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, School for Mental Health and Neuroscience, Maastricht, The Netherlands

    Bart P. F. Rutten

  13. School of Public Health, University of California San Diego, La Jolla, CA, USA

    Murray B. Stein

  14. Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University School of Medicine, Bethesda, MD, USA

    Robert J. Ursano

  15. Department of Psychiatry, Leiden University Medical Center, ZA, Leiden, The Netherlands

    Eric Vermetten

  16. Research Center, Netherlands Defense Department, UT, AA Utrecht, The Netherlands

    Eric Vermetten

  17. Arq Psychotrauma Expert Group, XE, Diemen, The Netherlands

    Eric Vermetten

  18. National Center for PTSD, Behavioral Science Division at VA Boston Healthcare System, Boston, MA, USA

    Mark W. Logue

  19. Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA

    Mark W. Logue

  20. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA

    Mark W. Logue

  21. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    Mark W. Logue

  22. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA

    Alicia K. Smith

Authors
  1. Seyma Katrinli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adam X. Maihofer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Agaz H. Wani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John R. Pfeiffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elizabeth Ketema
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrew Ratanatharathorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dewleen G. Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marco P. Boks
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Elbert Geuze
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ronald C. Kessler
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Victoria B. Risbrough
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Bart P. F. Rutten
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Murray B. Stein
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Robert J. Ursano
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Eric Vermetten
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Mark W. Logue
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Caroline M. Nievergelt
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Alicia K. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Monica Uddin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Interpreted results, writing, and editing the paper: SK, AKS, and MU. Conceptualization and supervision of project: AKS, MWL, MU, and CMN. Sample and metadata collection: DGB, MPB, EG, RCK, VBR, BPFR, MBS, RJU, EV, MWL, and CMN. Sample preparation: JRP. Formal data analysis: SK, AXM, AW, EK, and AR.

Corresponding author

Correspondence to Monica Uddin.

Ethics declarations

Competing interests

MU was a paid consultant for System Analytic. In the past 3 years, RCK was a consultant for Datastat, Inc., Holmusk, RallyPoint Networks, Inc., and Sage Pharmaceuticals. He has stock options in Mirah, PYM, and Roga Sciences. No other author declares any competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Katrinli, S., Maihofer, A.X., Wani, A.H. et al. Epigenome-wide meta-analysis of PTSD symptom severity in three military cohorts implicates DNA methylation changes in genes involved in immune system and oxidative stress. Mol Psychiatry 27, 1720–1728 (2022). https://doi.org/10.1038/s41380-021-01398-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-021-01398-2

  • Springer Nature Limited

This article is cited by

Search

Navigation