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