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Understanding the comorbidity between posttraumatic stress severity and coronary artery disease using genome-wide information and electronic health records

Molecular Psychiatry volume 27, pages 3961–3969 (2022)Cite this article

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Abstract

The association between coronary artery disease (CAD) and posttraumatic stress disorder (PTSD) contributes to the high morbidity and mortality observed for these conditions. To understand the dynamics underlying PTSD-CAD comorbidity, we investigated large-scale genome-wide association (GWA) statistics from the Million Veteran Program (MVP), the UK Biobank (UKB), the Psychiatric Genomics Consortium, and the CARDIoGRAMplusC4D Consortium. We observed a genetic correlation of CAD with PTSD case-control and quantitative outcomes, ranging from 0.18 to 0.32. To investigate possible cause-effect relationships underlying these genetic correlations, we performed a two-sample Mendelian randomization (MR) analysis, observing a significant bidirectional relationship between CAD and PTSD symptom severity. Genetically-determined PCL-17 (PTSD 17-item Checklist) total score was associated with increased CAD risk (odds ratio = 1.04; 95% confidence interval, 95% CI = 1.01–1.06). Conversely, CAD genetic liability was associated with reduced PCL-17 total score (beta = −0.42; 95% CI = −0.04 to −0.81). Because of these opposite-direction associations, we conducted a pleiotropic meta-analysis to investigate loci with concordant vs. discordant effects on PCL-17 and CAD, observing that concordant-effect loci were enriched for molecular pathways related to platelet amyloid precursor protein (beta = 1.53, p = 2.97 × 10−7) and astrocyte activation regulation (beta = 1.51, p = 2.48 × 10−6) while discordant-effect loci were enriched for biological processes related to lipid metabolism (e.g., triglyceride-rich lipoprotein particle clearance, beta = 2.32, p = 1.61 × 10−10). To follow up these results, we leveraged MVP and UKB electronic health records (EHR) to assess longitudinal changes in the association between CAD and posttraumatic stress severity. This EHR-based analysis highlighted that earlier CAD diagnosis is associated with increased PCL-total score later in life, while lower PCL total score was associated with increased risk of a later CAD diagnosis (Mann–Kendall trend test: MVP tau = 0.932, p < 2 × 10−16; UKB tau = 0.376, p = 0.005). In conclusion, both our genetically-informed analyses and our EHR-based follow-up investigation highlighted a bidirectional relationship between PTSD and CAD where multiple pleiotropic mechanisms are likely to be involved.

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Fig. 1: Genetic correlation analysis.
Fig. 2: Bidirectional Mendelian randomization analysis.
Fig. 3: EHR-based follow-up analysis.

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All data used discussed in this study are provided as Supplementary Material.

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Acknowledgements

We thank the veterans who participated in this study, and the members of the VA CSP and MVP study teams, without whom this work would not have been possible. This research has been also conducted using the UK Biobank Resource (application reference no. 58146).

Funding

This research is based on data from the MVP, Office of Research and Development, Veterans Health Administration and was supported by funding from the VA Cooperative Studies Program (CSP, no. CSP575B) and the Veterans Affairs Office of Research and Development MVP (grant nos. MVP000 and VA Merit MVP025). 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.

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Authors and Affiliations

  1. Department of Psychiatry, Yale School of Medicine, West Haven, CT, USA

    Renato Polimanti, Frank R. Wendt, Gita A. Pathak, Daniel S. Tylee, Daniel F. Levey, Keyrun Adhikari & Joel Gelernter

  2. VA CT Healthcare Center, West Haven, CT, USA

    Renato Polimanti, Frank R. Wendt, Gita A. Pathak, Daniel S. Tylee, Daniel F. Levey, Keyrun Adhikari & Joel Gelernter

  3. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Catherine Tcheandjieu, Austin T. Hilliard & Themistocles L. Assimes

  4. VA Palo Alto Healthcare System, Palo Alto, CA, USA

    Austin T. Hilliard & Themistocles L. Assimes

  5. Department of Medicine, VA Boston Healthcare System, Boston, MA, USA

    J. Michael Gaziano & Christopher J. O’Donnell

  6. Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    J. Michael Gaziano & Christopher J. O’Donnell

  7. Department of Medicine, Harvard Medical School, Boston, MA, USA

    J. Michael Gaziano & Christopher J. O’Donnell

  8. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    Murray B. Stein

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

    Murray B. Stein

  10. Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA

    Murray B. Stein

  11. Departments of Genetics and of Neuroscience, Yale School of Medicine, New Haven, CT, USA

    Joel Gelernter

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Contributions

RP, CJO, TLA, MBS, JG designed the study. RP, FRW, GAP, DST, CT, ATH, DFL, KA, JMG, CJO, TLA, MBS, JG collected and interpreted the data. RP, FRW, GAP, DST analyzed the data. RP wrote the manuscript. RP, FRW, GAP, DST, CT, ATH, DFL, KA, JMG, CJO, TLA, MBS, JG edited the manuscript. RP, CJO, TLA, MBS, JG supervised the study.

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Correspondence to Renato Polimanti.

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Competing interests

RP received a research grant from Alkermes. RP and JG received personal fees from Karger Publishers for their editorial work for Complex Psychiatry. JG is named as co-inventor on Patent Cooperation Treaty application no. 15/878,640 titled ‘Genotype-guided dosing of opioid agonists’, filed on January 24, 2018. CJO. received payment for editorial work for UpToDate and JAMA Cardiology and is currently employed by Novartis Institute of Biomedical Research. MBS received consulting fees from Acadia Pharmaceuticals, Aptinyx, Bionomics, Boehringer Ingelheim, Clexio Biosciences, EmpowerPharm, Engrail Therapeutics, Epivario, GW Pharmaceuticals, Janssen, and Jazz Pharmaceuticals; and payment for editorial work for UpToDate and the journals Biological Psychiatry and Depression and Anxiety. The other authors declare no competing financial interests.

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Polimanti, R., Wendt, F.R., Pathak, G.A. et al. Understanding the comorbidity between posttraumatic stress severity and coronary artery disease using genome-wide information and electronic health records. Mol Psychiatry 27, 3961–3969 (2022). https://doi.org/10.1038/s41380-022-01735-z

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