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Genome-wide association meta-analysis of knee and hip osteoarthritis uncovers genetic differences between patients treated with joint replacement and patients without joint replacement
  1. Cecilie Henkel1,
  2. Unnur Styrkársdóttir2,
  3. Gudmar Thorleifsson2,
  4. Lilja Stefánsdóttir2,
  5. Gyda Björnsdóttir2,
  6. Karina Banasik3,
  7. Søren Brunak3,
  8. Christian Erikstrup4,5,
  9. Khoa Manh Dinh4,
  10. Thomas Folkmann Hansen3,6,
  11. Kaspar René Nielsen7,
  12. Mie Topholm Bruun8,
  13. Joseph Dowsett9,
  14. Thorsten Brodersen10,
  15. DBDS Genomic Consortium,
  16. Thorgeir E Thorgeirsson2,
  17. Kirill Gromov1,11,
  18. Mikael Ploug Boesen11,12,
  19. Henrik Ullum13,
  20. Sisse Rye Ostrowski9,14,
  21. Ole Birger Pedersen10,14,
  22. Kári Stefánsson2,
  23. Anders Troelsen1,11
    1. 1Clinical Orthopaedic Research Hvidovre (CORH), Department of Orthopaedic Surgery, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
    2. 2deCODE genetics/Amgen, Reykjavik, Iceland
    3. 3Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    4. 4Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
    5. 5Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
    6. 6Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Glostrup, Denmark
    7. 7Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark
    8. 8Department of Clinical Immunology, Odense University Hospital, Odense, Denmark
    9. 9Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
    10. 10Department of Clinical Immunology, Zealand University Hospital Køge, Køge, Denmark
    11. 11Clinical Academic Group: Research OsteoArthritis Denmark (CAG ROAD), Greater Copenhagen Health Science Partners, Copenhagen, Denmark
    12. 12Department of Radiology, Bispebjerg Hospital, Copenhagen, Denmark
    13. 13Statens Serum Institut, Copenhagen, Denmark
    14. 14Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    1. Correspondence to Cecilie Henkel, Clinical Orthopaedic Research Hvidovre (CORH), Department of Orthopaedic Surgery, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark; cecilie.henkel{at}regionh.dk

    Abstract

    Objectives Osteoarthritis is a common and severe, multifactorial disease with a well-established genetic component. However, little is known about how genetics affect disease progression, and thereby the need for joint placement. Therefore, we aimed to investigate whether the genetic associations of knee and hip osteoarthritis differ between patients treated with joint replacement and patients without joint replacement.

    Methods We included knee and hip osteoarthritis cases along with healthy controls, altogether counting >700 000 individuals. The cases were divided into two groups based on joint replacement status (surgical vs non-surgical) and included in four genome-wide association meta-analyses: surgical knee osteoarthritis (N = 22 525), non-surgical knee osteoarthritis (N = 38 626), surgical hip osteoarthritis (N = 20 221) and non-surgical hip osteoarthritis (N = 17 847). In addition, we tested for genetic correlation between the osteoarthritis groups and the pain phenotypes intervertebral disc disorder, dorsalgia, fibromyalgia, migraine and joint pain.

    Results We identified 52 sequence variants associated with knee osteoarthritis (surgical: 17, non-surgical: 3) or hip osteoarthritis (surgical: 34, non-surgical: 1). For the surgical phenotypes, we identified 10 novel variants, including genes involved in autophagy (rs2447606 in ATG7) and mechanotransduction (rs202127176 in PIEZO1). One variant, rs13107325 in SLC39A8, associated more strongly with non-surgical knee osteoarthritis than surgical knee osteoarthritis. For all other variants, significance and effect sizes were higher for the surgical phenotypes. In contrast, genetic correlations with pain phenotypes tended to be stronger in the non-surgical groups.

    Conclusions Our results indicate differences in genetic associations between knee and hip osteoarthritis depending on joint replacement status.

    • Osteoarthritis
    • Osteoarthritis, Knee
    • Polymorphism, Genetic
    • Orthopedic Procedures

    Data availability statement

    Data are available in a public, open access repository. Summary results from the meta-analyses will be available at https://www.decode.com/summarydata at the time of the publication. Due to data privacy concerns, individual level genotypic and/or phenotypic data cannot be shared. Access to individual level data can be obtained by applying to each data source individually, given that relevant approvals are acquired.

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    Data availability statement

    Data are available in a public, open access repository. Summary results from the meta-analyses will be available at https://www.decode.com/summarydata at the time of the publication. Due to data privacy concerns, individual level genotypic and/or phenotypic data cannot be shared. Access to individual level data can be obtained by applying to each data source individually, given that relevant approvals are acquired.

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    Footnotes

    • Handling editor Josef S Smolen

    • Twitter @CecilieHenkel, @ProfTroelsen

    • OBP, KS and AT contributed equally.

    • Collaborators DBDS Genomic Consortium: Steffen Andersen, Karina Banasik, Søren Brunak, Kristoffer Burgdorf, Maria Didriksen, Khoa Manh Dinh, Christian Erikstrup, Daniel Gudbjartsson, Thomas Folkmann Hansen, Henrik Hjalgrim, Gregor Jemec, Poul Jennum, Pär Ingemar Johansson, Margit Anita Hørup Larsen, Susan Mikkelsen, Kasper René Nielsen, Mette Nyegaard, Sisse Rye Ostrowski, Ole Birger Pedersen, Kári Stefánsson, Hreinn Stefánsson, Susanne Sækmose, Erik Sørensen, Unnur Þorsteinsdóttir, Mie Topholm Brun, Henrik Ullum, Thomas Werge.

    • Contributors CH, US, OBP and AT designed the study. CH, KB, SB, CE, KMD, TFH, KRN, MTB, JD, TB, DBDS GC, KG, MPB, HU, SRO, OBP and AT contributed to the acquisition of the Danish data. US, GB, TET and KS contributed to the acquisition of the Icelandic data. US, GB and KS were responsible for the UK Biobank data. Osteoarthritis phenotypes were handled by CH for the Danish data, GT for the British data, and US for the Icelandic data. GB and TET were responsible for the pain phenotypes. CH, US, GT and LS performed statistical analyses. CH, US, OBP and AT interpreted the results. The manuscript was drafted by CH and critically revised by all authors. All authors approved the manuscript for publication. OBP, KS and AT contributed equally to this paper and are responsible for the overall content as guarantors.

    • Funding The study was supported financially by the Candys Foundation (ref. no. 2019-314), Greater Copenhagen Health Science Partners, and Copenhagen University Hospital Hvidovre. For the pain GWAS, financial support from the European Commission to the painFACT project (H2020-2020- 848099) is acknowledged. Authors KB and SB acknowledge the Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001).

    • Disclaimer None of the funding sources had influence on the study regarding design, analysis, interpretation or dissemination of the results.

    • Competing interests The authors US, GT, LS, GB, TET and KS are employed by deCODE genetics/Amgen Inc.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.