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Boer, C.G.* ; Yau, M.S.* ; Rice, S.J.* ; de Almeida, R.C.* ; Cheung, K.* ; Styrkarsdottir, U.* ; Southam, L. ; Broer, L.* ; Wilkinson, J.M.* ; Uitterlinden, A.G.* ; Zeggini, E. ; Felson, D.* ; Loughlin, J.* ; Young, M.* ; Capellini, T.D.* ; Meulenbelt, I.* ; van Meurs, J.B.J.*

Genome-wide association of phenotypes based on clustering patterns of hand osteoarthritis identify WNT9A as novel osteoarthritis gene.

Ann. Rheum. Dis. 80, 367–375 (2021)
Verlagsversion DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Background Despite recent advances in the understanding of the genetic architecture of osteoarthritis (OA), only two genetic loci have been identified for OA of the hand, in part explained by the complexity of the different hand joints and heterogeneity of OA pathology. Methods We used data from the Rotterdam Study (RSI, RSII and RSIII) to create three hand OA phenotypes based on clustering patterns of radiographic OA severity to increase power in our modest discovery genome-wide association studies in the RS (n=8700), and sought replication in an independent cohort, the Framingham Heart Study (n=1203). We used multiple approaches that leverage different levels of information and functional data to further investigate the underlying biological mechanisms and candidate genes for replicated loci. We also attempted to replicate known OA loci at other joint sites, including the hips and knees. Results We found two novel genome-wide significant loci for OA in the thumb joints. We identified WNT9A as a possible novel causal gene involved in OA pathogenesis. Furthermore, several previously identified genetic loci for OA seem to confer risk for OA across multiple joints: TGFa, RUNX2, COL27A1, ASTN2, IL11 and GDF5 loci. Conclusions We identified a robust novel genetic locus for hand OA on chromosome 1, of which WNT9A is the most likely causal gene. In addition, multiple genetic loci were identified to be associated with OA across multiple joints. Our study confirms the potential for novel insight into the genetic architecture of OA by using biologically meaningful stratified phenotypes.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 0003-4967
e-ISSN 1468-2060
Quellenangaben Band: 80, Heft: 3, Seiten: 367–375 Artikelnummer: , Supplement: ,
Verlag BMJ Publishing Group
Verlagsort British Med Assoc House, Tavistock Square, London Wc1h 9jr, England
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Translational Genomics (ITG)
Förderungen Harvard University
Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA)
Research Institute for Diseases in the Elderly
Genetic Laboratory of the Department of Internal Medicine, Erasmus MC
Netherlands Organisation of Scientific Research NWO Investments
Municipality of Rotterdam
European Commission (DG XII)
Ministry for Health, Welfare and Sports
Ministry of Education, Culture and Science
Research Institute for Diseases in the Elderly (RIDE)
Netherlands Organization for the Health Research and Development (ZonMw)
Dutch Arthritis Association
European Union
Arthritis Research UK as part of the MRC-Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA)
Medical Research Council
Arthritis
National Institute on Aging (NIA)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Affymetrix, Inc.
National Institutes of Health
Erasmus Medical Center and Erasmus University, Rotterdam