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Polygenic Risk and Exposure Severity Predict Trajectories of PTSD: A Prospective Cohort Study

Molecular Psychiatry (2025)Cite this article

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Abstract

Posttraumatic stress disorder (PTSD) is persistent over time, thus identifying risk factors for chronic PTSD is crucial for clinical research. Trauma exposure severity and polygenic liability are two established predictors of PTSD onset and severity, but their contributions to the long-term course of PTSD remain largely unknown. In this prospective longitudinal cohort study, we tested whether severity of trauma exposure and polygenic risk for symptoms of PTSD independently predict long-term trajectories of PTSD symptoms. Data included 49,402 observations, spanning July 2002 to December 2022, from n = 5687 World Trade Center responders who had predominately European ancestry (baseline mean age = 37.74, SD = 8.19, range = 16–75; 92.89% male). First, the best-fitting model of 20-year PTSD trajectories was determined. Next, a polygenic risk score and a sum score of traumatic exposures were included as predictors of individual differences in intercepts (initial levels) and slopes (rates of change), adjusting for demographic covariates. The polygenic risk score significantly predicted rates of change in PTSD symptoms, independent of the intercept, such that higher polygenic risk was associated with more rapid increases in the years after trauma and a steeper arch-shaped trajectory. Exposure severity predicted initial levels and rates of change in symptoms, with more pronounced effects on initial levels. These findings indicate that polygenic liability and exposure severity predict the long-term prognosis of PTSD and have the potential to inform future clinical studies in trauma-exposed populations.

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Fig. 1: Distributions of Focal Predictors and Outcome Variables.
Fig. 2: Effects of Polygenic Risk and Exposure Severity on PCL Total Score.
Fig. 3: Effects of Polygenic Risk and Exposure Severity on PCL Subscale Scores.

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Data availability

Data not provided in the article because of space limitations are not publicly shared due to ethical considerations. Study participants provided consent for their data to be analyzed by study personnel. To respect the autonomy and privacy of the WTC responders, the data underlying the reported results will be made available to qualified investigators whose proposed use of the data has been approved by an internal review committee and the Institutional Review Board at Stony Brook University. This access will be granted up to 4 years after publication of this study following rigorous de-identification of sensitive information. Requests for data access will be reviewed, and a response will be provided within 60 days of submission.

Code availability

Correspondence concerning this article should be addressed to the first author, frank.mann@stonybrookmedicine.edu, including requests for a copy of the code that was used to conduct analyses.

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Acknowledgements

We thank the WTC responders from the General Responder Cohort whose participation was integral to this work. Data collection was funded by CDC 2011-200-39361 awarded to B.J.L. and U01OH011864 awarded to M.A.W, and by the SUNY Research Foundation. The analyses were partially funded by R21AG074705-01 awarded to F.D.M.

Author information

Author notes

  1. These authors contributed equally: Frank D. Mann, Monika A. Waszczuk.

Authors and Affiliations

  1. Program in Public Health and Department of Family, Population, and Preventive Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA

    Frank D. Mann & Sean A. P. Clouston

  2. Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA

    Frank D. Mann & Benjamin J. Luft

  3. Department of Psychology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA

    Monika A. Waszczuk

  4. Department of Psychiatry, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA

    Evelyn J. Bromet & Roman Kotov

  5. National Center for Posttraumatic Stress Disorder at VA Boston Healthcare System, Boston, MA, USA

    Brian P. Marx

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

    Brian P. Marx

  7. Department of Psychiatry, Huntsman Mental Health Institute, University of Utah, Salt Lake City, UT, USA

    Andrey A. Shabalin & Anna R. Docherty

  8. Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA

    Pei-Fen Kuan

  9. World Trade Center Program, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA

    Melissa A. Carr, Xiaohua Yang & Benjamin J. Luft

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Contributions

BJL, RK and MAW designed the study. BJL, MAC, and XY. coordinated and supervised data collection. AAS. and ARD. calculated polygenic risk scores. In consultation with RK, FDM. conducted the primary analyses, created tables and figures, and drafted the methods and results. MAW drafted the introduction and discussion. SAP, EJB, BPM, AAS, ARD, PK, MAC, XY, BJL and RK provided critical feedback and revisions, and all authors approved a final version of the manuscript.

Corresponding author

Correspondence to Frank D. Mann.

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The authors declare no competing interests.

Ethics

Data collection was performed in accordance with ethnical guidelines approved by the Institutional Review Board at Stony Brook University (ethical approval number: 604113; WTC Health and Wellness Study) and all participants provided informed written consent. The participants were provided free screening and treatment for WTC-related health conditions and were not compensated otherwise.

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Mann, F.D., Waszczuk, M.A., Clouston, S.A.P. et al. Polygenic Risk and Exposure Severity Predict Trajectories of PTSD: A Prospective Cohort Study. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03235-2

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