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Genome-wide association study of post-traumatic stress disorder reexperiencing symptoms in >165,000 US veterans

Nature Neuroscience volume 22, pages 1394–1401 (2019)Cite this article

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Abstract

Post-traumatic stress disorder (PTSD) is a major problem among military veterans and civilians alike, yet its pathophysiology remains poorly understood. We performed a genome-wide association study and bioinformatic analyses, which included 146,660 European Americans and 19,983 African Americans in the US Million Veteran Program, to identify genetic risk factors relevant to intrusive reexperiencing of trauma, which is the most characteristic symptom cluster of PTSD. In European Americans, eight distinct significant regions were identified. Three regions had values of P < 5 × 10−10: CAMKV; chromosome 17 closest to KANSL1, but within a large high linkage disequilibrium region that also includes CRHR1; and TCF4. Associations were enriched with respect to the transcriptomic profiles of striatal medium spiny neurons. No significant associations were observed in the African American cohort of the sample. Results in European Americans were replicated in the UK Biobank data. These results provide new insights into the biology of PTSD in a well-powered genome-wide association study.

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Fig. 1: Manhattan plots.
Fig. 2: Regional Manhattan plots, chromosome 17.
Fig. 3: eQTLs.
Fig. 4: Manhattan plot of gene-based association results.
Fig. 5: Enrichment analyses.

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Data availability

The GWAS summary statistics generated during and/or analyzed during the current study are available via dbGAP; the dbGaP accession assigned to the Million Veteran Program is phs001672.v1.p. The website is: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001672.v1.p1. Additionally, the data that support the findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

This research is based on data from the Million Veteran Program (MVP), Office of Research and Development, Veterans Health Administration, and was supported by the MVP and the VA Cooperative Studies Program (CSP) study no. 575B. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.

Author information

Author notes

  1. These authors contributed equally: J. Gelernter, M. B. Stein.

  2. A list of members and affiliations appears in the Supplementary Note.

Authors and Affiliations

  1. Psychiatry Service, VA Connecticut Healthcare System, West Haven, CT, USA

    Joel Gelernter, Renato Polimanti, Robert. Pietrzak & Daniel F. Levey

  2. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Joel Gelernter, Renato Polimanti, Robert. Pietrzak & Daniel F. Levey

  3. VA Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, CT, USA

    Ning Sun, Krishnan Radhakrishnan, Mihaela Aslan, Kei-Hoi Cheung, Yuli Li, Nallakkandi Rajeevan, Frederick Sayward, Quan Chen, John Concato & Hongyu Zhao

  4. Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA

    Ning Sun, Qiongshi Lu, Yiming Hu, Boyang Li, Quan Chen & Hongyu Zhao

  5. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Julien Bryois & Patrick F. Sullivan

  6. College of Medicine, University of Kentucky, Lexington, KY, USA

    Krishnan Radhakrishnan

  7. Department of Medicine, Yale University School of Medicine, New Haven, CT, USA

    Mihaela Aslan & John Concato

  8. Department of Emergency Medicine, Yale University School of Medicine, New Haven, CT, USA

    Kei-Hoi Cheung

  9. Yale Center for Medical Informatics, Yale University School of Medicine, New Haven, CT, USA

    Yuli Li, Nallakkandi Rajeevan & Frederick Sayward

  10. Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA

    Kelly Harrington, Kelly Cho, Saiju Pyarajan, Rachel Quaden, Yunling Shi, Haley Hunter-Zinck & J. Michael Gaziano

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

    Kelly Harrington

  12. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Kelly Cho, Saiju Pyarajan & J. Michael Gaziano

  13. Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA

    Patrick F. Sullivan

  14. Psychiatry Service, VA San Diego Healthcare System, San Diego, CA, USA

    Murray B. Stein

  15. Departments of Psychiatry and of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA

    Murray B. Stein

Authors
  1. Joel Gelernter
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Consortia

Department of Veterans Affairs Cooperative Studies Program (#575B) and Million Veteran Program

Contributions

Genotyping effort: S.P., Y.S. and H.H.-Z. Analyses team: N.S., J.B., Q.L., Y.H., B.L., R. Polimanti, Q.C. and D.F.L. CSP575B team (database, phenotype and analytic efforts): K.R., M.A., K.H.C., Y.L., N.R., F.S., K.H., K.C., R.Q. and R. Pietrzak. MVP leadership (overall MVP design and supervision): J.M.G. and J.C. Analysis design: R. Polimanti, P.F.S., H.Z., J.G. and M.B.S. Project design and project leadership: J.G., J.C. and M.B.S. Writing leads: J.G. and M.B.S.

Corresponding author

Correspondence to Joel Gelernter.

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Competing interests

J.G. is named as a co-inventor on PCT patent application no. 15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed 24 January 2018. M.B.S. has in the past 3 years been a consultant for Actelion, Aptinyx, Bionomics, Dart Neuroscience, Healthcare Management Technologies, Janssen, Jazz Pharmaceuticals, Neurocrine Biosciences, Oxeia Biopharmaceuticals, Pfizer, and Resilience Therapeutics. M.B.S. owns founders shares and stock options in Resilience Therapeutics and has stock options in Oxeia Biopharmaceuticals.

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Gelernter, J., Sun, N., Polimanti, R. et al. Genome-wide association study of post-traumatic stress disorder reexperiencing symptoms in >165,000 US veterans. Nat Neurosci 22, 1394–1401 (2019). https://doi.org/10.1038/s41593-019-0447-7

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