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Cited by 48Posttraumatic Stress Disorder ResearchEpigenetics and DNA MethylationChild Abuse and Trauma

Epigenetic biotypes of post-traumatic stress disorder in war-zone exposed veteran and active duty males

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Yang, Ruoting, Gautam, Aarti, Getnet, Derese, Daigle, Bernie J., Miller, Stacy, Misganaw, Burook, Dean, Kelsey R., Kumar, Raina +23 more·2021·Molecular Psychiatry
DOI 10.1038/s41380-020-00966-2PMC PMC8550967
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Abstract

Post-traumatic stress disorder (PTSD) is a heterogeneous condition evidenced by the absence of objective physiological measurements applicable to all who meet the criteria for the disorder as well as divergent responses to treatments. This study capitalized on biological diversity observed within the PTSD group observed following epigenome-wide analysis of a well-characterized Discovery cohort (N = 166) consisting of 83 male combat exposed veterans with PTSD, and 83 combat veterans without PTSD in order to identify patterns that might distinguish subtypes. Computational analysis of DNA methylation (DNAm) profiles identified two PTSD biotypes within the PTSD+ group, G1 and G2, associated with 34 clinical features that are associated with PTSD and PTSD comorbidities. The G2 biotype was associated with an increased PTSD risk and had higher polygenic risk scores and a greater methylation compared to the G1 biotype and healthy controls. The findings were validated at a 3-year follow-up (N = 59) of the same individuals as well as in two independent, veteran cohorts (N = 54 and N = 38), and an active duty cohort (N = 133). In some cases, for example Dopamine-PKA-CREB and GABA-PKC-CREB signaling pathways, the biotypes were oppositely dysregulated, suggesting that the biotypes were not simply a function of a dimensional relationship with symptom severity, but may represent distinct biological risk profiles underpinning PTSD. The identification of two novel distinct epigenetic biotypes for PTSD may have future utility in understanding biological and clinical heterogeneity in PTSD and potential applications in risk assessment for active duty military personnel under non-clinician-administered settings, and improvement of PTSD diagnostic markers.

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  • Epigenetic alterations affect almost every biological pathway involved in the pathophysiology of MDD and other stress-related disorders, such as anxiety disorders and PTSD.

    “The importance of epigenetic alterations and their effects on almost every biological pathway involved in the pathophysiology of MDD and other stress-related disorders, such as anxiety disorders and post-traumatic stress disorder (PTSD) is increasingly appreciated.35–37”

    From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [35]

    The Introduction (page unavailable) says there is growing evidence that epigenetic processes play an important role in psychological disorders and PTSD. The Discussion (page unavailable) links methylation in specific signaling pathways to anxiety and depressive symptoms. Neither passage supports the broader claim that epigenetic alterations affect almost every biological pathway involved in MDD, anxiety disorders, and PTSD. (LLM, conf=0.86)

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Cited by

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Authors
Yang, R., Gautam, A., Getnet, D., Daigle, B. J., Miller, S., Misganaw, B., Dean, K. R., Kumar, R., Muhie, S., Wang, K., Lee, I., Abu-Amara, D., Flory, J. D., The PTSD Systems Biology Consortium, Hoke, A., Chakraborty, N., Petzold, L., Wu, G., Guffanti, G., Kim, T.-K., Lee, M. Y., Bierer, L., Hood, L., Wolkowitz, O. M., Mellon, S. H., Doyle, F. J., Yehuda, R., Marmar, C. R., Ressler, K. J., Hammamieh, R., & Jett, M.
Affiliations
  • Frederick National Laboratory for Cancer Research (US)
  • Walter Reed Army Institute of Research (US)
  • University of Memphis (US)
  • Harvard University (US)
  • Institute for Systems Biology (US)
  • James J. Peters VA Medical Center (US)
  • University of California, Santa Barbara (US)
  • University of California, San Francisco (US)
  • McLean Hospital (US)
Corresponding author
Yang, Ruoting
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2020-12-18
Volume
26
Issue
8
Pages
4300-4314
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-020-00966-2
PMC
PMC8550967
OpenAlex
W3117637371
Cited by
48
References
13
Citations by year
2026: 4 · 2025: 7 · 2024: 7 · 2023: 12 · 2022: 11 · 2021: 6
FWCI
2.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • United States Department of Defense | United States Army | U.S. Army Research, Development and Engineering Command | Army Research Office (W911NF-13-1-0376;W911NF-17-2-0086;W911NF-18-2-0056)
  • United States Department of Defense | United States Army | Army Medical Command | Medical Research and Materiel Command (W81XWH-10-1-0021, W81XWH-09-2-0044, and W81XWH-14-1-0043, W911NF-17-1-0069)
  • United States Department of Defense | United States Army | U.S. Army Research, Development and Engineering Command | Army Research Laboratory (W911NF-17-1-0069, W81XWH-10-1-0021, W81XWH-09-2-0044, and W81XWH-14-1-0043)
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, combat veterans, PTSD subtypes, polygenic risk score, active duty military personnel, PTSD comorbidity, diagnostic biomarkers
MeSH terms
Epigenome, Humans, Male, Military Personnel, Stress Disorders, Post-Traumatic, Veterans, Epigenesis, Genetic

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