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Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder

Molecular Psychiatry (2024)Cite this article

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Abstract

Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self-reported SB and ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) among 3,942 SCZ and 5,414 BPI patients receiving care within the Veterans Health Administration (VHA). These cross-sectional data were integrated with electronic health records (EHRs), and compared across lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. PGS were constructed using available genomic data for related traits. Genome-wide association studies were performed to identify and prioritize specific loci. Only 20% of the veterans who reported SB had a corroborating ICD-9/10 EHR code. Among those without prior SB, more than 20% reported new-onset SB at follow-up. SB were associated with a range of additional clinical diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking initiation, suicide attempt, and major depressive disorder were associated with SB. The GWAS for SB yielded no significant loci. Among individuals with a diagnosed mental illness, self-reported SB were strongly associated with clinical variables across several EHR domains. Analyses point to sequelae of substance-related and psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in health records, underscoring the value of regular screening with direct, in-person assessments, especially among high-risk individuals.

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Fig. 1: Phenotypic correlations for C-SSRS and EHR-based ratings of suicidality.
Fig. 2: PheWAS for suicidality phenotypes in CSP #572.
Fig. 3: Associations of self-reported suicidality with pharmacological treatment history.
Fig. 4: Associations of PGS with suicidality behaviors in SCZ and BPI.
Fig. 5: Comparisons with follow-up screenings for suicidality, mortality, and attributed cause of death.

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Data availability

All data sources are described in the manuscript and supplemental information. No new data were collected. Only data from existing cohorts of VA participants were analyzed, which have restricted access to protect the privacy of the study participants. The process for obtaining the GWAS summary statistics used in these analyses are described in the corresponding original GWAS publications.

Code availability

No custom algorithms or software was developed in this study. All code is available by request from the corresponding author. All primary analyses completed in R 4.2.2.

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Acknowledgements

This research was supported by the Department of Veterans Affairs Cooperative Studies Program (CSP #572), the Million Veteran Program (MVP-000) and a Clinical Sciences Research and Development award (lK6BX003777). The MVP is supported by the Office of Research and Development, Department of Veterans Affairs. Full acknowledgements for CSP #572 and MVP are presented in the Supplement. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. TBB was supported by a 2019 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (#28276). This analysis uses data from the Externalizing Consortium, supported by the National Institute on Alcohol Abuse and Alcoholism (R01AA015416), and the National Institute on Drug Abuse (R01DA050721). Additional funding for investigator effort has been provided by K02AA018755, U10AA008401, P50AA022537, and a European Research Council Consolidator Grant (647648 EdGe). The content does not necessarily represent the views of these funding bodies. We would also like to thank the participants and employees of 23andMe, Inc. for making this work possible. We are grateful to Drs. R. Karlsson Linnér and T.T. Mallard for sharing their script for plotting PheWAS results. LJS, original co-Principal Investigator for CSP #572, passed away in February 2021.

Author information

Author notes

  1. These authors contributed equally: Tim B. Bigdeli, Peter B. Barr.

Authors and Affiliations

  1. VA New York Harbor Healthcare System, Brooklyn, NY, US

    Tim B. Bigdeli, Peter B. Barr, Sundar Natarajan & Ayman H. Fanous

  2. Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, US

    Tim B. Bigdeli, Peter B. Barr, Jacquelyn L. Meyers & Roseann E. Peterson

  3. Institute for Genomics in Health, SUNY Downstate Health Sciences University, Brooklyn, NY, US

    Tim B. Bigdeli, Peter B. Barr, Jacquelyn L. Meyers & Roseann E. Peterson

  4. Department of Epidemiology and Biostatistics, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY, US

    Tim B. Bigdeli, Peter B. Barr, Jacquelyn L. Meyers & Roseann E. Peterson

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

    Nallakkandi Rajeevan, Yuli Li, Frederick Sayward, Hongyu Zhao & Mihaela Aslan

  6. Yale University School of Medicine, New Haven, CT, USA

    Nallakkandi Rajeevan, Yuli Li, Frederick Sayward, Hongyu Zhao, Sumitra Muralidhar, John Concato, John Concato & Mihaela Aslan

  7. Michael E. DeBakey VA Medical Center, Houston, TX, USA

    David P. Graham, David A. Nielsen, Anna V. Wilkinson, Alan C. Swann & Thomas R. Kosten

  8. Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA

    David P. Graham, David A. Nielsen, Alan C. Swann & Thomas R. Kosten

  9. Massachusetts Area Veterans Epidemiology, Research and Information Center (MAVERIC), Jamaica Plain, MA, USA

    Bryan R. Gorman, Mary Brophy, Yunling Shi, Saiju Pyarajan, J. Michael Gaziano & Michael Gaziano

  10. National Mental Health and Substance Use Policy Laboratory, Substance Abuse and Mental Health Services Administration, Rockville, MD, USA

    Krishnan Radhakrishnan

  11. Department of Epidemiology, Human Genetics and Environmental Science, University of Texas Health Science Center at Houston, Houston, TX, USA

    Anna V. Wilkinson

  12. Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA

    Anil K. Malhotra

  13. Division of Psychiatry Research, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA

    Anil K. Malhotra

  14. Department of Psychiatry, Hofstra Northwell School of Medicine, Hempstead, NY, USA

    Anil K. Malhotra

  15. Boston University School of Medicine, Boston, MA, USA

    Mary Brophy

  16. Office of Research and Development, Veterans Health Administration, Washington, DC, USA

    Timothy J. O’Leary, Theresa Gleason, Ronald Przygodzki, Grant D. Huang, John Concato, Timothy J. O’Leary, Theresa Gleason, Ronald Przygodzki, Sumitra Muralidhar, Grant D. Huang & John Concato

  17. Harvard University, Boston, MA, USA

    J. Michael Gaziano & Michael Gaziano

  18. Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

    John Concato & John Concato

  19. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Larry J. Siever

  20. James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA

    Larry J. Siever

  21. Department of Psychiatry, Cambridge Health Alliance, Cambridge, MA, USA

    Lynn E. DeLisi & Lynn E. DeLisi

  22. Durham VA Health Care System, Durham, NC, USA

    Nathan A. Kimbrel & Jean C. Beckham

  23. VA Mid-Atlantic Mental Illness Research, Education and Clinical Center, Durham, NC, USA

    Nathan A. Kimbrel & Jean C. Beckham

  24. Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA

    Nathan A. Kimbrel & Jean C. Beckham

  25. Department of Psychiatry, University of Arizona College of Medicine Phoenix, Phoenix, AZ, USA

    Ayman H. Fanous

  26. Bruce W. Carter Miami Veterans Affairs (VA) Medical Center, Miami, FL, USA

    Philip D. Harvey

  27. University of Miami School of Medicine, Miami, FL, USA

    Philip D. Harvey

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Consortia

Cooperative Studies Program (CSP) #572

  • Anil K. Malhotra
  • , Hongyu Zhao
  • , Mary Brophy
  • , Timothy J. O’Leary
  • , Theresa Gleason
  • , Ronald Przygodzki
  • , Sumitra Muralidhar
  • , Michael Gaziano
  • , Grant D. Huang
  • , John Concato
  • , Larry J. Siever
  • , Lynn E. DeLisi
  • , Thomas R. Kosten
  • , Ayman H. Fanous
  • , Mihaela Aslan
  •  & Philip D. Harvey

Contributions

TBB, MA and PDH conceived the study. PDH and MA oversaw the study. TBB and PBB were the lead analysts. TBB, PBB, NR, AHF, MA and PDH were involved in interpretation of results. TB. and PBB led the writing of the manuscript, with substantive contributions to the writing from PDH and MA. All authors contributed to and critically reviewed the manuscript.

Corresponding author

Correspondence to Tim B. Bigdeli.

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Competing interests

PDH has served as a consultant to multiple pharmaceutical companies and device manufacturers on phase 2 or 3 development; this consulting work has been determined to be unrelated to the content of the paper. No other authors report any relevant conflicts of interest.

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Bigdeli, T.B., Barr, P.B., Rajeevan, N. et al. Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02472-1

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  • DOI: https://doi.org/10.1038/s41380-024-02472-1

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