Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder
Open accessAbstract
In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.
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These exposures have been associated with coordinated alterations in stress-response regulation, circadian and sleep-related pathways, and metabolic processes.
“These exposures have been associated with coordinated alterations in stress-response regulation, circadian and sleep-related pathways, and metabolic processes (102–115).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [103]
The Results (DNA methylation marks and traumatic stress; page unavailable) report enrichment of circadian-rhythm-related genes, and the Discussion (page unavailable) links DNA methylation to stress-related pathways, including HPA-axis and CRF signalling. Our copy does not establish sleep-related alterations beyond circadian rhythm or identify metabolic processes among the associated pathways. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThese differences have been associated with methylation changes in NR3C1, a key regulator of HPA-axis feedback.
“These differences have been associated with methylation changes in NR3C1, a key regulator of HPA-axis feedback (103).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [103]
The Discussion links PTSD symptoms to DNA methylation in pathways involving the HPA axis, but does not identify NR3C1 or report an association with its methylation. The Results instead identify replicated methylation associations at ZFP57, RNF39 and HIST1H2APS2. The NR3C1-specific claim and its role in HPA-axis feedback are not established by this copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredDifferential methylation of sleep and circadian genes such as PAX8 and LHX1 has been reported in veterans with PTSD.
“Differential methylation of sleep and circadian genes such as PAX8 and LHX1 has been reported in veterans with PTSD (103, 109–111).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [103]
The Results section on the Dutch military cohort reports that methylation changes near PAX8 were associated with increasing PTSD symptoms. The paper also reports enrichment of circadian-rhythm-related pathways, but our copy does not identify PAX8 as a sleep or circadian gene or report a methylation finding for LHX1 (searched: LHX1 and sleep/circadian genes). (LLM, conf=0.88)
Experimental — accuracy not yet measuredThese changes have been associated with variation in memory processing, sleep duration, and circadian rhythm regulation, as well as differences in PTSD symptom severity.
“These changes have been associated with variation in memory processing, sleep duration, and circadian rhythm regulation, as well as differences in PTSD symptom severity (103, 109–111).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [103]
The Results (Discovery of PTSD susceptibility: DMRs; page unavailable) associate longitudinal DNA-methylation changes with changes in PTSD symptom scores. The Results (DNA methylation marks and traumatic stress; page unavailable) also identify enrichment of circadian-rhythm-related genes. The paper does not establish associations between the methylation changes and measured memory processing or sleep duration, so those parts of the multi-citation sentence are not supported by this source. (LLM, conf=0.86)
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- Authors
- Rutten, B. P. F., Vermetten, E., Vinkers, C. H., Ursini, G., Daskalakis, N. P., Pishva, E., de Nijs, L., Houtepen, L. C., Eijssen, L., Jaffe, A. E., Kenis, G., Viechtbauer, W., van den Hove, D., Schraut, K. G., Lesch, K.-P., Kleinman, J. E., Hyde, T. M., Weinberger, D. R., Schalkwyk, L., Lunnon, K., Mill, J., Cohen, H., Yehuda, R., Baker, D. G., Maihofer, A. X., Nievergelt, C. M., Geuze, E., & Boks, M. P. M.
- Affiliations
- Maastricht University Medical Centre (NL)
- Leiden University Medical Center (NL)
- University Medical Center Utrecht (NL)
- Lieber Institute for Brain Development (US)
- James J. Peters VA Medical Center (US)
- University of Würzburg (DE)
- Johns Hopkins University (US)
- University of Essex (GB)
- University of Exeter (GB)
- Ben-Gurion University of the Negev (IL)
- University of California San Diego (US)
- Corresponding author
- Rutten, B P F
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2017-06-20
- Volume
- 23
- Issue
- 5
- Pages
- 1145-1156
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC5984086
- OpenAlex
- W2713262478
- Cited by
- 142
- References
- 38
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 20 · 2023: 14 · 2022: 19 · 2021: 15 · 2020: 19 · 2019: 13 · 2018: 18 · 2017: 3
- FWCI
- 17.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Psychiatry (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by-nc-sa)
- Open Research Exeter (University of Exeter) (acceptedVersion, cc-by-nc-sa)
- Open Access at Essex (University of Essex) (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Leiden Repository (Leiden University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Figshare (submittedVersion, cc-by-nc-sa)
- Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by-nc-sa)
- Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (SDR 09-0128)
- Vrije Universiteit Amsterdam
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO 480‐05‐003, 916.11.086, 480- 05-003)
- Ministerie van Defensie
- National Institutes of Health
- National Institute of Mental Health (R01MH093500)
- Bureau of Medicine and Surgery
- Topics
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Keywords
- post-traumatic stress disorder, DNA methylation, epigenetics, war injuries, military deployment, ZFP57, mediation analysis, blood DNA methylation, military personnel
- MeSH terms
- Adult, DNA-Binding Proteins, Genetic Testing, Humans, Longitudinal Studies, Male, Military Personnel, Prospective Studies, Repressor Proteins, Stress Disorders, Post-Traumatic, Transcription Factors, Cohort Studies, Immediate-Early Proteins, DNA Methylation, Genetic Predisposition to Disease, Epigenesis, Genetic
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