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Yang R, Gautam A, Getnet D, et al. Epigenetic biotypes of post-traumatic stress disorder in war-zone exposed veteran and active duty males. Mol Psychiatry. 2020;26(8):4300-4314doi: 10.1038/s41380-020-00966-2.
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., Hood, L., Wolkowitz, O. M., Mellon, S. H., Doyle, F. J., Yehuda, R., Marmar, C. R., Ressler, K. J., Hammamieh, R., & Jett, M. (2021). Epigenetic biotypes of post-traumatic stress disorder in war-zone exposed veteran and active duty males. Molecular psychiatry, 26(8), 4300-4314. https://doi.org/10.1038/s41380-020-00966-2
Yang, Ruoting, et al. "Epigenetic biotypes of post-traumatic stress disorder in war-zone exposed veteran and active duty males." Molecular psychiatry vol. 26,8 (2021): 4300-4314. doi: https://doi.org/10.1038/s41380-020-00966-2
Yang R, Gautam A, Getnet D, Daigle BJ, Miller S, Misganaw B, Dean KR, Kumar R, Muhie S, Wang K, Lee I, Abu-Amara D, Flory JD, Hood L, Wolkowitz OM, Mellon SH, Doyle FJ, Yehuda R, Marmar CR, Ressler KJ, Hammamieh R, Jett M. Epigenetic biotypes of post-traumatic stress disorder in war-zone exposed veteran and active duty males. Mol Psychiatry. 2021 Aug;26(8):4300-4314. doi: 10.1038/s41380-020-00966-2. Epub 2020 Dec 18. PMID: 33339956; PMCID: PMC8550967.
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Mol Psychiatry. 2021 Aug;26(8):4300-4314. doi: 10.1038/s41380-020-00966-2. Epub 2020 Dec 18.

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

Molecular psychiatry

Ruoting Yang, Aarti Gautam, Derese Getnet, Bernie J Daigle, Stacy Miller, Burook Misganaw, Kelsey R Dean, Raina Kumar, Seid Muhie, Kai Wang, Inyoul Lee, Duna Abu-Amara, Janine D Flory, Leroy Hood, Owen M Wolkowitz, Synthia H Mellon, Francis J Doyle, Rachel Yehuda, Charles R Marmar, Kerry J Ressler, Rasha Hammamieh, Marti Jett

Affiliations

  1. Medical Readiness Systems Biology, Walter Reed Army Institute for Research, Silver Spring, MD, USA. [email protected].
  2. Advanced Biomedical Computation Sciences, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. [email protected].
  3. Medical Readiness Systems Biology, Walter Reed Army Institute for Research, Silver Spring, MD, USA.
  4. Departments of Biological Sciences and Computer Science, The University of Memphis, Memphis, TN, USA.
  5. Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA.
  6. Department of Systems Biology, Harvard University, Cambridge, MA, USA.
  7. Advanced Biomedical Computation Sciences, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  8. Institute for Systems Biology, Seattle, WA, USA.
  9. Department of Psychiatry, New York Langone Medical School, New York, NY, USA.
  10. Department of Psychiatry, James J. Peters VA Medical Center, Bronx, NY, USA.
  11. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  12. Department of Psychiatry, University of California, San Francisco, CA, USA.
  13. Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco, CA, USA.
  14. McLean Hospital, Belmont, MA, USA.
  15. Harvard Medical School, Boston, MA, USA.

PMID: 33339956 PMCID: PMC8550967 DOI: 10.1038/s41380-020-00966-2

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.

© 2020. The Author(s).

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