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Novel genetic loci associated with osteoarthritis in multi-ancestry analyses in the Million Veteran Program and UK Biobank

Nature Genetics volume 54, pages 1816–1826 (2022)Cite this article

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Abstract

Osteoarthritis is a common progressive joint disease. As no effective medical interventions are available, osteoarthritis often progresses to the end stage, in which only surgical options such as total joint replacement are available. A more thorough understanding of genetic influences of osteoarthritis is essential to develop targeted personalized approaches to treatment, ideally long before the end stage is reached. To date, there have been no large multiancestry genetic studies of osteoarthritis. Here, we leveraged the unique resources of 484,374 participants in the Million Veteran Program and UK Biobank to address this gap. Analyses included participants of European, African, Asian and Hispanic descent. We discovered osteoarthritis-associated genetic variation at 10 loci and replicated findings from previous osteoarthritis studies. We also present evidence that some osteoarthritis-associated regions are robust to population ancestry. Drug repurposing analyses revealed enrichment of targets of several medication classes and provide potential insight into the etiology of beneficial effects of antiepileptics on osteoarthritis pain.

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Fig. 1: Osteoarthritis GWAS study design.
Fig. 2: Fine-mapping of FOXP2 region associated with osteoarthritis in MVP multiancestry analysis.
Fig. 3: Comparison of analytical strategies.
Fig. 4: Summary of osteoarthritis mega-GWAS and transcriptome-wide imputation results.

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Data availability

The MVP GWAS summary statistics generated and/or analyzed during the current study will be made available via dbGAP; the dbGaP accession assigned to the MVP is phs001672.v1.p1 (https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001672.v7.p1). Summary statistics from the UKB results are available in the GWAS catalog (https://www.ebi.ac.uk/gwas/home) under the following accessions: GCST90134279, GCST90134280, GCST90134281, GCST90134282, GCST90134283, GCST90134284, GCST90134285, GCST90134286, GCST90134287, GCST90134288, GCST90134289, GCST90134290.

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Acknowledgements

We thank R. Tindal, a medical student in the McDonald laboratory at UAB, for assistance with manuscript editing, and C. Cole, a summer student in the McDonald laboratory at UAB, for assistance with formatting data. We thank the VA MVP, including members of the MVP Executive Committee, MVP Recruitment/Enrollment, MVP Science and current MVP Local Site Investigators, for providing the datasets used for the MVP analyses. We also thank the UKB for providing the datasets used for the UKB analyses. Please see the Supplementary Note for complete acknowledgement information. This research was based on data from the MVP, Office of Research and Development, Veterans Health Administration, and was supported by award no. I01RX002745 (M.M.B. and J.A.S.). This publication does not represent the views of the Department of Veteran Affairs or the United States Government.

Author information

Author notes

  1. These authors contributed equally: Marcas M. Bamman and Jasvinder A. Singh.

Authors and Affiliations

  1. Birmingham Veterans Affairs Health Care System (BVAHCS), Birmingham, AL, USA

    Merry-Lynn N. McDonald, Preeti Lakshman Kumar, Vinodh Srinivasasainagendra, Ashwathy Nair, Joshua S. Richman, Cynthia J. Brown, Marcas M. Bamman & Jasvinder A. Singh

  2. Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA

    Merry-Lynn N. McDonald, Preeti Lakshman Kumar, Ashwathy Nair, Alison P. Rocco, Ava C. Wilson, Joe W. Chiles & Sarah A. Pinson

  3. Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA

    Merry-Lynn N. McDonald, Ava C. Wilson & Jasvinder A. Singh

  4. Department of Genetics, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Merry-Lynn N. McDonald

  5. Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA

    Vinodh Srinivasasainagendra & Hemant K. Tiwari

  6. Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Joshua S. Richman

  7. Central Arkansas Veterans Healthcare System (CAVHS), Little Rock, AR, USA

    Richard A. Dennis & Vivek Jagadale

  8. Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Cynthia J. Brown

  9. Center for Data and Computational Sciences (C-DACS), Veterans Affairs Boston Healthcare System (VABHS), Boston, MA, USA

    Saiju Pyarajan

  10. Department of Cell, Developmental, and Integrative Biology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Marcas M. Bamman

  11. Florida Institute for Human & Machine Cognition, Pensacola, FL, USA

    Marcas M. Bamman

  12. Division of Rheumatology and Clinical Immunology, Department of Medicine at the School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Jasvinder A. Singh

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  1. Merry-Lynn N. McDonald
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Contributions

All authors contributed substantially to this manuscript. M.-L.N.M., J.S.R., R.D., V.J., C.J.B., H.K.T., M.M.B. and J.A.S. conceived and designed the study. P.L.K., V.S., A.N., A.P.R., S.A.P. and A.C.W. executed and summarized analyses. J.C. summarized analyses. H.K.T. and S.P. advised on statistical models and computational implementation. M.-L.N.M. wrote and revised the manuscript, which all authors reviewed and edited.

Corresponding author

Correspondence to Merry-Lynn N. McDonald.

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Competing interests

All authors declare competing financial interests in the form of employment at UAB and/or US Veterans Health Administration. M.-L.N.M., J.C.R., R.D., C.J.B., S.P., H.K.T., J.A.S. and M.M.B. have received research support from the National Institutes of Health. J.A.S. has received consultant fees from Crealta/Horizon, Medisys, Fidia, UBM LLC, Trio health, Medscape, WebMD, PK Med, Two labs Inc., Adept Field Solutions, Clinical Care options, Clearview healthcare partners, Putnam associates, Focus forward, Navigant consulting, Spherix, Practice Point communications, the National Institutes of Health and the American College of Rheumatology. J.A.S. has received institutional research support from Zimmer Biomet Holdings. J.A.S. received food and beverage payments from Intuitive Surgical Inc./Philips Electronics North America. J.A.S. owns stock options in TPT Global Tech, Vaxart Pharmaceuticals, Atyu Biopharma, Adaptimmune Therapeutics, GeoVax Labs, Pieris Pharmaceuticals, Enzolytics Inc., Seres Therapeutics, Tonix Pharmaceuticals Holding Corp. and Charlotte’s Web Holdings, Inc. J.A.S. previously owned stock options in Amarin, Viking and Moderna pharmaceuticals. J.A.S. is on the speakers’ bureau of Simply Speaking. J.A.S. is a member of the executive of Outcomes Measures in Rheumatology, an organization that develops outcome measures in rheumatology and receives arms-length funding from 12 companies. J.A.S. serves on the FDA Arthritis Advisory Committee. J.A.S. is the chair of the Veterans Affairs Rheumatology Field Advisory Committee. J.A.S. is the editor and the Director of the UAB Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis. J.A.S. previously served on the following committees: member of the American College of Rheumatology (ACR) Annual Meeting Planning Committee and Quality of Care Committees, Chair of the ACR Meet-the-Professor, Workshop and Study Group Subcommittee, and cochair of the ACR Criteria and Response Criteria subcommittee.

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Nature Genetics thanks Unnur Styrkarsdottir and Fernando Rivadeneira for their contribution to the peer review of this work.

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McDonald, ML.N., Lakshman Kumar, P., Srinivasasainagendra, V. et al. Novel genetic loci associated with osteoarthritis in multi-ancestry analyses in the Million Veteran Program and UK Biobank. Nat Genet 54, 1816–1826 (2022). https://doi.org/10.1038/s41588-022-01221-w

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