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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.
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.
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