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Nat Genet. 2019 Feb;51(2):230-236. doi: 10.1038/s41588-018-0327-1. Epub 2019 Jan 21.

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

Author information

1
Target Sciences-R&D, GSK Medicines Research Centre, Stevenage, UK.
2
Human Genetics, Wellcome Genome Campus, Wellcome Sanger Institute, Cambridge, UK.
3
Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
4
Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
5
MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK.
6
Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
7
Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
8
5th Psychiatric Department, Dromokaiteio Psychiatric Hospital, Haidari, Athens, Greece.
9
Cancer Research Division, Cancer Council NSW, Woolloomooloo, New South Wales, Australia.
10
Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.
11
Target Sciences-R&D, GSK, King of Prussia, PA, USA.
12
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, UK.
13
Human Genetics, Wellcome Genome Campus, Wellcome Sanger Institute, Cambridge, UK. eleftheria.zeggini@helmholtz-muenchen.de.
14
Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. eleftheria.zeggini@helmholtz-muenchen.de.

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.

PMID:
30664745
PMCID:
PMC6400267
[Available on 2019-08-01]
DOI:
10.1038/s41588-018-0327-1

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