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Towards scalable biomarker discovery in posttraumatic stress disorder: triangulating genomic and phenotypic evidence from a health system biobank

Molecular Psychiatry (2026)Cite this article

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Abstract

Biomarkers can potentially improve the diagnosis, monitoring, and treatment of posttraumatic stress disorder (PTSD). However, PTSD biomarkers that are scalable and easily integrated into real-world clinical settings have not been identified. The analysis was conducted between June to November 2024 using genomic samples and laboratory test results recorded in the Mass General Brigham (MGB) Health System. The analysis included 23,743 European ancestry participants from the nested MGB Biobank study. The first exposure was polygenic risk score (PRS) for PTSD, calculated using the largest available European ancestry genome-wide association study (GWAS), employing a Bayesian polygenic scoring method. The second exposure was a clinical diagnosis of PTSD, determined by the presence of two or more instances of PTSD-related diagnostic codes in the longitudinal electronic health records (EHR). The primary outcomes were the inverse normal quantile transformed, median lab values of 241 laboratory traits with non-zero h2SNP estimates. Sixteen unique laboratory traits across the cardiometabolic, hematologic, hepatic, and immune systems were implicated in both genomic and phenotypic lab-wide association scans (LabWAS). Two-sample Mendelian randomization analyses provided evidence of potential unidirectional causal effects of PTSD liability on hepatic (decreased albumin and total bilirubin), cardiometabolic (decreased HDL cholesterol and increased VLDL cholesterol), and hematologic (decreased mean platelet volume) markers. These findings demonstrate the potential of a triangulation approach to uncover scalable and clinically relevant biomarkers for PTSD.

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Fig. 1: Manhattan plots of genomic and phenotypic laboratory-wide association scans (LabWAS).
Fig. 2: Statistical significance after Bonferroni correction from the genomic LabWAS (triangles) and phenotypic LabWAS (circles), grouped by physiological system.

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Data availability

MGB Biobank data were accessed under a protocol approved by the MGB Institutional Review Board for the current study (# 2019P003696) and are not publicly available due to restrictions on the data.

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Acknowledgements

This study would not be possible without the contributions of Mass General Brigham (MGB) patients and Biobank participants. We would also like to thank the research coordinators and the MGB Biobank study for their tremendous effort in participant recruitment and sample collection. Lastly, we would like to acknowledge the MGB Research Patient Data Registry (RPDR) team for their work maintaining the enterprise research patient data warehouse.

Funding

Financial support for the Psychiatric Genomics Consortium (PGC) PTSD Working Group was provided by the Cohen Veterans Bioscience, Stanley Center for Psychiatric Research at the Broad Institute, One Mind, and the National Institute of Mental Health (NIMH; R01MH106595, R01MH124847, R01MH124851, R01MH118233). JHL is individually supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) K23 DK131345. YHL and NS are supported by the Broad Trauma Initiative. ALED is supported by NIMH T32 MH 017119.

Author information

Authors and Affiliations

  1. Broad Trauma Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Younga Heather Lee, Karestan C. Koenen & Natalie Slopen

  2. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Younga Heather Lee, Josephine H. Li, Justin D. Tubbs, Yen-Chen Anne Feng, Tian Ge, Jordan W. Smoller & Karestan C. Koenen

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

    Younga Heather Lee, Justin D. Tubbs, Yen-Chen Anne Feng, Tian Ge, Jordan W. Smoller & Karestan C. Koenen

  4. Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA

    Younga Heather Lee, Yingzhe Zhang, Ana Lucia Espinosa Dice & Karestan C. Koenen

  5. Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    Josephine H. Li

  6. Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Josephine H. Li

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

    Josephine H. Li

  8. Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University, Taipei, Taiwan

    Yen-Chen Anne Feng

  9. Center for Precision Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    Tian Ge & Jordan W. Smoller

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

    Adam X. Maihofer & Caroline M. Nievergelt

  11. Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA

    Adam X. Maihofer & Caroline M. Nievergelt

  12. Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA

    Adam X. Maihofer & Caroline M. Nievergelt

  13. Department of Social and Behavioral Sciences, Harvard T. H. Chan School of Public Health, Boston, MA, USA

    Karestan C. Koenen & Natalie Slopen

  14. Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA

    Andrea L. Roberts

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Contributions

Conceptualization and design of the project: YHL, NS, ALR, KCK, YZ, ALED; Phenotypic data extraction and preprocessing: YHL, YZ; Genomic data extraction and preprocessing: TG, YAF; Genome-wide analyses: CMN, AXM; Polygenic risk scoring: YZ; Laboratory test-wide scan analyses: YHL, YZ; Interpretation of results, writing, and editing of the manuscript: YHL, NS, ALR, YZ, ALED, JHL, JDT, TG, KCK, JWS; Critical revision and supervision: YHL, NS, ALR, JWS, KCK.

Corresponding authors

Correspondence to Younga Heather Lee or Natalie Slopen.

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Ethics declarations

JWS is a member of the Scientific Advisory Board of Sensorium Therapeutics (with options), has received a consulting fee from Data Driven, Inc., and has received grant support from Biogen, Inc. KCK receives consulting fees from the US Department of Justice and Covington Burling LLP and has royalties from Guilford Press and Oxford University Press. All other authors report no biomedical financial interests or potential conflicts of interest.

Ethics approval and consent to participate

MGB Biobank participants are enrolled through a broad-based consent process by research coordinators at health system practices, public hospital locations, dual consent as part of collaborating studies, or electronically through Patient Gateway, the MGB patient portal. All participants provided informed consent prior to enrollment, agreeing to contribute a blood sample linked to their electronic health record. The seven-page consent form (available upon request) covers key provisions, including the use of samples for any type of research, recontact by Biobank staff as needed, and the return of medically actionable findings.

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Lee, Y.H., Zhang, Y., Espinosa Dice, A.L. et al. Towards scalable biomarker discovery in posttraumatic stress disorder: triangulating genomic and phenotypic evidence from a health system biobank. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03553-z

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