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Cited by 516Osteoarthritis Treatment and MechanismsGenetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and Animals

Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data

Open access
arcOGEN Consortium, Tachmazidou, Ioanna, Hatzikotoulas, Konstantinos, Southam, Lorraine, Esparza-Gordillo, Jorge, Haberland, Valeriia, Zheng, Jie, Johnson, Toby +14 more·2019·Nature Genetics
DOI 10.1038/s41588-018-0327-1PMC PMC6400267

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Abstract

Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we performed a genome-wide association study for osteoarthritis (77,052 cases and 378,169 controls), analyzing four phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discovered 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine-mapped to a single variant. We identified putative effector genes by integrating expression quantitative trait loci (eQTL) colocalization, fine-mapping, and human rare-disease, animal-model, and osteoarthritis tissue expression data. We found enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organization biological pathways. Ten of the likely effector genes, including TGFB1 (transforming growth factor beta 1), FGF18 (fibroblast growth factor 18), CTSK (cathepsin K), and IL11 (interleukin 11), have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.

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Authors
arcOGEN Consortium, Tachmazidou, I., Hatzikotoulas, K., Southam, L., Esparza-Gordillo, J., Haberland, V., Zheng, J., Johnson, T., Koprulu, M., Zengini, E., Steinberg, J., Wilkinson, J. M., Bhatnagar, S., Hoffman, J. D., Buchan, N., Süveges, D., Yerges-Armstrong, L., Smith, G. D., Gaunt, T. R., Scott, R. A., McCarthy, L. C., & Zeggini, E.
Affiliations
  • GlaxoSmithKline (United Kingdom) (GB)
  • Wellcome Sanger Institute (GB)
  • Centre for Human Genetics (GB)
  • University of Bristol (GB)
  • University of Cambridge (GB)
  • University of Sheffield (GB)
  • McGill University (CA)
  • GlaxoSmithKline (United States) (US)
  • European Bioinformatics Institute (GB)
Corresponding author
Zeggini, Eleftheria
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2019-01-21
Volume
51
Issue
2
Pages
230-236
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-018-0327-1
PMC
PMC6400267
OpenAlex
W2950103694
Cited by
516
References
10
Citations by year
2026: 42 · 2025: 48 · 2024: 115 · 2023: 90 · 2022: 73 · 2021: 69 · 2020: 50 · 2019: 28
FWCI
41.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed (publishedVersion)
  • Explore Bristol Research (publishedVersion, other-oa)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Bristol Research (University of Bristol) (submittedVersion, other-oa)
  • Brunel University Research Archive (BURA) (Brunel University London) (submittedVersion)
  • Site cant be reached (submittedVersion, other-oa)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
  • The Sydney eScholarship Repository (The University of Sydney) (submittedVersion)
  • UEA Digital Repository (University of East Anglia) (submittedVersion)
Funders
  • University of Essex
  • Wellcome Trust (MC_UU_00011/1, MC_UU_00011/4, WT 098051, 213422/Z/18/Z, 206194)
  • Understanding Society
  • National Institute for Health and Care Research (206194, MC_UU_00011/4, MC_UU_00011/1, WT098051)
  • Versus Arthritis (18030)
  • Medical Research Council (MC_UU_00011/4, MR/N01104X/1, MR/N01104X/2, MC_PC_17228, WT098051, MC_UU_00011/1, MC_UU_00011/1 and MC_UU_00011/4, MC_UU_00011)
  • Economic and Social Research Council (ES/H029745/1, ES/S008349/1)
  • NIHR Cambridge Biomedical Research Centre
Topics
  • Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
osteoarthritis, knee osteoarthritis, hip osteoarthritis, genetic susceptibility loci, therapeutic target, effector genes, expression quantitative trait loci, colocalization, collagen synthesis, extracellular matrix, TGF-β1, FGF18, cathepsin K, interleukin-11, animal models
MeSH terms
Adult, Aged, Female, United Kingdom, Humans, Male, Middle Aged, Osteoarthritis, Hip, Case-Control Studies, Biological Specimen Banks, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study

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