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Clinical and genetic contributions to medical comorbidity in bipolar disorder: a study using electronic health records-linked biobank data

Molecular Psychiatry (2024)Cite this article

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Abstract

Bipolar disorder is a chronic and complex polygenic disease with high rates of comorbidity. However, the independent contribution of either diagnosis or genetic risk of bipolar disorder to the medical comorbidity profile of individuals with the disease remains unresolved. Here, we conducted a multi-step phenome-wide association study (PheWAS) of bipolar disorder using phenomes derived from the electronic health records of participants enrolled in the Mayo Clinic Biobank and the Mayo Clinic Bipolar Disorder Biobank. First, we explored the conditions associated with a diagnosis of bipolar disorder by conducting a phenotype-based PheWAS followed by LASSO-penalized regression to account for correlations within the phenome. Then, we explored the conditions associated with bipolar disorder polygenic risk score (BD-PRS) using a PRS-based PheWAS with a sequential exclusion approach to account for the possibility that diagnosis, instead of genetic risk, may drive such associations. 53,386 participants (58.7% women) with a mean age at analysis of 67.8 years (SD = 15.6) were included. A bipolar disorder diagnosis (n = 1479) was associated with higher rates of psychiatric conditions, injuries and poisonings, endocrine/metabolic and neurological conditions, viral hepatitis C, and asthma. BD-PRS was associated with psychiatric comorbidities but, in contrast, had no positive associations with general medical conditions. While our findings warrant confirmation with longitudinal-prospective studies, the limited associations between bipolar disorder genetics and medical conditions suggest that shared environmental effects or environmental consequences of diagnosis may have a greater impact on the general medical comorbidity profile of individuals with bipolar disorder than its genetic risk.

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Fig. 1: Phenotype-based PheWAS.
Fig. 2: PRS-based PheWAS.

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Data availability

No data were generated as part of this study. We analyzed electronic health record data as well as genetic data from Project Generation, and the authors do not have permissions to publicly share these datasets.

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Acknowledgements

The Mayo Clinic Bipolar Disorder Biobank was supported by the Marriott Foundation, and this study was supported by the Thomas and Elizabeth Grainger Fund in Bipolar Functional Genomics and Drug Development, and National Institute of Mental Health grant R01MH121924. The Mayo Clinic Biobank and Project Generation were supported in part by Mayo Clinic Center for Individualized Medicine. We acknowledge Regeneron Genetics Center for providing the genetic data for Mayo Clinic Biobank participants, and a subset of participants in the Bipolar Biobank. We also acknowledge the Mayo Clinic Biobank and Mayo Clinic Bipolar Biobank research teams as well as the patient-participants who consented to participate in these research programs.

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Authors and Affiliations

  1. Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, USA

    Jorge A. Sanchez-Ruiz, Aysegul Ozerdem, Manuel A. Gardea-Resendez, Alfredo B. Cuellar-Barboza, Miguel L. Prieto, Mark A. Frye & Joanna M. Biernacka

  2. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA

    Brandon J. Coombes, Vanessa M. Pazdernik, Lindsay M. Melhuish Beaupre, Greg D. Jenkins, Richard S. Pendegraft, Anthony Batzler & Joanna M. Biernacka

  3. Lindner Center of HOPE/University of Cincinnati, Cincinnati, OH, USA

    Susan L. McElroy

  4. Department of Psychiatry, Universidad Autónoma de Nuevo León, Monterrey, Mexico

    Manuel A. Gardea-Resendez & Alfredo B. Cuellar-Barboza

  5. Department of Psychiatry, Faculty of Medicine, Universidad de Los Andes, Santiago, Chile

    Miguel L. Prieto

  6. Mental Health Service, Clínica Universidad de los Andes, Santiago, Chile

    Miguel L. Prieto

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  1. Jorge A. Sanchez-Ruiz
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Contributions

Jorge A. Sanchez-Ruiz: Conceptualization, Investigation, Methodology, Validation, Writing – original draft, Writing – review & editing. Brandon J. Coombes: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Writing – original draft, Writing – review & editing. Vanessa M. Pazdernik: Conceptualization, Data curation, Formal analysis, Methodology, Software, Validation, Visualization, Writing – original draft, Writing – review & editing. Lindsay M. Melhuish Beaupre: Conceptualization, Validation, Writing – original draft, Writing – review & editing. Greg D. Jenkins and Richard S. Pendegraft: Conceptualization, Data curation, Software, Validation. Anthony Batzler: Conceptualization, Data curation, Software. Aysegul Ozerdem: Conceptualization, Methodology, Supervision, Writing – review & editing. Susan L. McElroy, Manuel A. Gardea-Resendez, Alfredo B. Cuellar-Barboza, and Miguel L. Prieto: Conceptualization, Investigation, Resources, Writing – review & editing. Regeneron Genetics Center: Investigation. Mark A. Frye: Conceptualization, Funding acquisition, Investigation, Project administration, Resources, Supervision, Validation, Writing – review & editing. Joanna M. Biernacka: Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review & editing. All authors have contributed to and approved the final manuscript. This manuscript has not been published elsewhere nor submitted for publication to another journal.

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Correspondence to Joanna M. Biernacka.

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Competing interests

SLM reports receiving personal fees for advisory boards and/or consultation from Idorsia, Levo, Novo Nordisk, Otsuka, Sunovion, and Takeda; receiving grant support from Idorsia, Janssen, Marriott Foundation, Myriad, National Institute of Mental Health, Novo Nordisk, Otsuka, and Sunovion; and receiving payments from Johnson & Johnson for being an inventor on US Patent No. 6,323,236 B2. ABCB has received lecture and consulting fees from Asofarma and Exeltis. MLP has served on an advisory board for Janssen and has received grant support from ANID FONDECYT Regular 1181365, FONDEF ID19I10116 and Basal Funding for Scientific and Technological Center of Excellence, IMPACT, #FB210024. MAF reports the following conflicts of interest: grant support from Assurex Health and Mayo Foundation; CME/travel/honoraria from Carnot Laboratories, American Physician Institute; and financial interest/stock ownership/royalties in Chymia LLC. All other authors declare no competing interests.

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Sanchez-Ruiz, J.A., Coombes, B.J., Pazdernik, V.M. et al. Clinical and genetic contributions to medical comorbidity in bipolar disorder: a study using electronic health records-linked biobank data. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02530-8

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