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No replication of Alzheimer’s disease genetics as a moderator of the association between combat exposure and PTSD risk in 138,592 combat veterans

Nature Mental Health (2024)Cite this article

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Abstract

Large-scale cohort and epidemiological studies suggest that post-traumatic stress disorder (PTSD) confers risk for late-onset Alzheimer’s disease and related dementias (ADRD); however, the basis for this association remains unclear. Several prior studies of military veterans have reported that carriers of the apolipoprotein E (APOE) ε4 gene variant are at heightened risk for the development of PTSD following combat exposure, suggesting that PTSD and ADRD may share some genetic risk. Here we designed a cohort study to further examine the hypothesis that ADRD genetic risk also confers risk for PTSD. To do so, we examined APOE ε4 and ε2 genotypes, an Alzheimer’s disease polygenic risk score, and other veteran-relevant risk factors for PTSD in age-stratified groups of individuals of European (n = 123,372) and African (n = 15,220) ancestry in the US Department of Veterans Affairs’ Million Veteran Program. Analyses revealed no significant main effect associations between the APOE ε4 (or ε2) genotype or the Alzheimer’s disease polygenic risk score on PTSD severity or diagnosis. There were also no significant interactions between measures of Alzheimer’s disease genetic risk and either combat exposure severity or history of head injury in association with PTSD in any age group. We conclude that the association between PTSD and the primary ADRD genetic risk factor, APOE ε4, that was reported previously was not replicable in this large and relevant dataset. Thus, the epidemiological association between PTSD and ADRD is not likely to be driven by the major genetic factors underlying ADRD risk.

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Data availability

The phenotypes and genetic data analyzed here are available to all researchers with MVP access. Approval to access the individual-level MVP data is only available to VA researchers for an approved and funded MVP project, either through a VA Merit Award or a Career Development Award. See https://www.research.va.gov/funding/Guidance-MVP-Data-Access-Merit-Award.pdf for details. All GWAS results for MVP are made available on dbGAP.

Code availability

Analytic code is available for those with approved MVP access by writing to the corresponding author. Our group generated this code.

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Acknowledgements

This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration. It was supported by VA BLR&D grant 1 I01 BX004192 (MVP015) to M.W.L. and by the Department of VA Clinical Science Research and Development Career Development Award IK2CX002192-01A2 to J.R.F. 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 US government.

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Authors and Affiliations

  1. National Center for PTSD, Behavioral Science Division, VA Boston Healthcare System, Boston, MA, USA

    Erika J. Wolf, Mark W. Miller, Rui Zhang & Mark W. Logue

  2. Boston University Chobanian & Avedisian School of Medicine, Department of Psychiatry, Boston, MA, USA

    Erika J. Wolf, Mark W. Miller, Kelly M. Harrington, Jennifer R. Fonda & Mark W. Logue

  3. Boston University Chobanian & Avedisian School of Medicine, Biomedical Genetics, Boston, MA, USA

    Richard Sherva & Mark W. Logue

  4. Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare System, Boston, MA, USA

    Kelly M. Harrington & J. Michael Gaziano

  5. Translational Research Center for TBI and Stress Disorders and Geriatric Research, Educational and Clinical Center, VA Boston Healthcare System, Boston, MA, USA

    Jennifer R. Fonda

  6. Harvard Medical School, Department of Psychiatry, Boston, MA, USA

    Jennifer R. Fonda & Nikolaos P. Daskalakis

  7. McLean Hospital, Belmont, MA, USA

    Nikolaos P. Daskalakis

  8. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Nikolaos P. Daskalakis

  9. Division of Aging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    J. Michael Gaziano

  10. Boston University School of Public Health, Department of Biostatistics, Boston, MA, USA

    Mark W. Logue

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Contributions

M.W.L., M.W.M., R.S., K.M.H., J.R.F., E.J.W. and J.M.G. were responsible for conceptualization. R.Z. and R.S. were responsible for data analysis and data curation. M.W.M., M.W.L., E.J.W., R.Z., R.S. and N.P.D. were responsible for data interpretation. M.W.L., J.M.G. and K.M.H. developed the methodology. M.W.L. acquired the funding. E.J.W., M.W.M. and M.W.L. wrote the original draft. All authors edited and approved the paper. J.M.G. was responsible for resources.

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Correspondence to Mark W. Logue.

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Wolf, E.J., Miller, M.W., Zhang, R. et al. No replication of Alzheimer’s disease genetics as a moderator of the association between combat exposure and PTSD risk in 138,592 combat veterans. Nat. Mental Health (2024). https://doi.org/10.1038/s44220-024-00225-1

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