Translational genomics of osteoarthritis in 1,962,069 individuals

Abstract

Osteoarthritis is the third most rapidly growing health condition associated with disability, after dementia and diabetes1. By 2050, the total number of patients with osteoarthritis is estimated to reach 1 billion worldwide2. As no disease-modifying treatments exist for osteoarthritis, a better understanding of disease aetiopathology is urgently needed. Here we perform a genome-wide association study meta-analyses across up to 489,975 cases and 1,472,094 controls, establishing 962 independent associations, 513 of which have not been previously reported. Using single-cell multiomics data, we identify signal enrichment in embryonic skeletal development pathways. We integrate orthogonal lines of evidence, including transcriptome, proteome and epigenome profiles of primary joint tissues, and implicate 700 effector genes. Within these, we find rare coding-variant burden associations with effect sizes that are consistently higher than common frequency variant associations. We highlight eight biological processes in which we find convergent involvement of multiple effector genes, including the circadian clock, glial-cell-related processes and pathways with an established role in osteoarthritis (TGFβ, FGF, WNT, BMP and retinoic acid signalling, and extracellular matrix organization). We find that 10% of the effector genes express a protein that is the target of approved drugs, offering repurposing opportunities, which can accelerate translation.

Metadata

Item Type:	Article
Authors/Creators:	Hatzikotoulas, K. https://orcid.org/0000-0002-4699-3672 Southam, L. Stefansdottir, L. Boer, C.G. McDonald, M.-L. Pett, J.P. https://orcid.org/0000-0002-5249-444X Park, Y.-C. Tuerlings, M. Mulders, R. https://orcid.org/0000-0002-6151-0595 Barysenka, A. Arruda, A.L. Tragante, V. https://orcid.org/0000-0002-8223-8957 Rocco, A. Bittner, N. https://orcid.org/0000-0002-8588-185X Chen, S. Horn, S. https://orcid.org/0000-0002-2902-0377 Srinivasasainagendra, V. To, K. Katsoula, G. Kreitmaier, P. Tenghe, A.M.M. https://orcid.org/0000-0002-3799-1907 Gilly, A. Arbeeva, L. https://orcid.org/0000-0001-5004-419X Chen, L.G. https://orcid.org/0000-0002-7761-2334 de Pins, A.M. https://orcid.org/0000-0001-9988-8967 Dochtermann, D. https://orcid.org/0000-0001-9513-5124 Henkel, C. https://orcid.org/0000-0002-4219-5374 Höijer, J. Ito, S. Lind, P.A. https://orcid.org/0000-0002-3887-2598 Lukusa-Sawalena, B. Minn, A.K.K. Mola-Caminal, M. https://orcid.org/0000-0003-0122-9096 Narita, A. https://orcid.org/0000-0002-9076-0710 Nguyen, C. https://orcid.org/0000-0003-0674-7423 Reimann, E. Silberstein, M.D. Skogholt, A.-H. https://orcid.org/0000-0001-7466-0405 Tiwari, H.K. Yau, M.S. Yue, M. https://orcid.org/0000-0002-4052-818X Zhao, W. https://orcid.org/0000-0001-7388-0692 Zhou, J.J. Alexiadis, G. Banasik, K. Brunak, S. https://orcid.org/0000-0003-0316-5866 Campbell, A. https://orcid.org/0000-0003-0198-5078 Cheung, J.T.S. Dowsett, J. https://orcid.org/0000-0001-5381-2633 Faquih, T. Faul, J.D. Fei, L. Fenstad, A.M. Funayama, T. Gabrielsen, M.E. Gocho, C. Gromov, K. Hansen, T. https://orcid.org/0000-0001-6703-7762 Hudjashov, G. Ingvarsson, T. Johnson, J.S. Jonsson, H. Kakehi, S. https://orcid.org/0000-0002-1280-2882 Karjalainen, J. Kasbohm, E. https://orcid.org/0000-0001-5261-538X Lemmelä, S. Lin, K. Liu, X. Loef, M. Mangino, M. https://orcid.org/0000-0002-2167-7470 McCartney, D. Millwood, I.Y. Richman, J. Roberts, M.B. Ryan, K.A. Samartzis, D. Shivakumar, M. https://orcid.org/0000-0003-4733-7375 Skou, S.T. https://orcid.org/0000-0003-4336-7059 Sugimoto, S. Suzuki, K. Takuwa, H. Teder-Laving, M. https://orcid.org/0000-0002-5872-1850 Thomas, L. https://orcid.org/0000-0003-0548-2486 Tomizuka, K. Turman, C. https://orcid.org/0000-0002-7790-8311 Weiss, S. https://orcid.org/0000-0002-3553-4315 Wu, T.T. Zengini, E. Zhang, Y. Babis, G. van Heel, D.A. Winsvold, B. Gabrielsen, M. Ferreira, M.A.R. https://orcid.org/0000-0001-9059-1825 Babis, G. Baras, A. https://orcid.org/0000-0002-6830-3396 Barker, T. Carey, D.J. Cheah, K.S.E. https://orcid.org/0000-0003-0802-8799 Chen, Z. https://orcid.org/0000-0001-6423-105X Cheung, J.P.-Y. https://orcid.org/0000-0002-7052-0875 Daly, M. de Mutsert, R. Eaton, C.B. Erikstrup, C. https://orcid.org/0000-0001-6551-6647 Furnes, O.N. https://orcid.org/0000-0001-8223-2515 Golightly, Y.M. Gudbjartsson, D.F. https://orcid.org/0000-0002-5222-9857 Hailer, N.P. Hayward, C. https://orcid.org/0000-0002-9405-9550 Hochberg, M.C. Homuth, G. https://orcid.org/0000-0001-6839-0605 Huckins, L.M. https://orcid.org/0000-0002-5369-6502 Hveem, K. Ikegawa, S. https://orcid.org/0000-0003-0316-2147 Ishijima, M. Isomura, M. Jones, M. Kang, J.H. Kardia, S.L.R. Kloppenburg, M. https://orcid.org/0000-0002-9294-2307 Kraft, P. Kumahashi, N. Kuwata, S. https://orcid.org/0009-0009-3176-1906 Lee, M.T.M. Lee, P.H. https://orcid.org/0000-0003-1770-3100 Lerner, R. Li, L. https://orcid.org/0000-0001-5873-7089 Lietman, S.A. Lotta, L. Lupton, M.K. Mägi, R. https://orcid.org/0000-0002-2964-6011 Martin, N.G. https://orcid.org/0000-0003-4069-8020 McAlindon, T.E. Medland, S.E. https://orcid.org/0000-0003-1382-380X Michaëlsson, K. https://orcid.org/0000-0003-2815-1217 Mitchell, B.D. https://orcid.org/0000-0003-4920-4744 Mook-Kanamori, D.O. Morris, A.P. https://orcid.org/0000-0002-6805-6014 Nabika, T. Nagami, F. Nelson, A.E. https://orcid.org/0000-0002-9344-7877 Ostrowski, S.R. https://orcid.org/0000-0001-5288-3851 Palotie, A. https://orcid.org/0000-0002-2527-5874 Pedersen, O.B. https://orcid.org/0000-0003-2312-5976 Rosendaal, F.R. https://orcid.org/0000-0003-2558-7496 Sakurai-Yageta, M. Schmidt, C.O. https://orcid.org/0000-0001-5266-9396 Sham, P.C. https://orcid.org/0000-0002-2533-7270 Singh, J.A. Smelser, D.T. Smith, J.A. https://orcid.org/0000-0002-3575-5468 Song, Y.-Q. https://orcid.org/0000-0001-9407-2256 Sørensen, E. https://orcid.org/0000-0002-5002-9077 Tamiya, G. Tamura, Y. https://orcid.org/0000-0002-1685-7821 Terao, C. https://orcid.org/0000-0002-6452-4095 Thorleifsson, G. https://orcid.org/0000-0003-4623-9087 Troelsen, A. Tsezou, A. Uchio, Y. https://orcid.org/0000-0002-5858-9861 Uitterlinden, A.G. https://orcid.org/0000-0002-7276-3387 Ullum, H. Valdes, A.M. https://orcid.org/0000-0003-1141-4471 van Heel, D.A. https://orcid.org/0000-0002-0637-2265 Walters, R.G. https://orcid.org/0000-0002-9179-0321 Weir, D.R. https://orcid.org/0000-0002-1661-2402 Wilkinson, J.M. https://orcid.org/0000-0001-5577-3674 Winsvold, B.S. https://orcid.org/0000-0003-4171-8919 Yamamoto, M. https://orcid.org/0000-0002-9073-9436 Zwart, J.-A. https://orcid.org/0000-0001-5721-0154 Stefansson, K. Meulenbelt, I. https://orcid.org/0000-0001-7786-7081 Teichmann, S.A. https://orcid.org/0000-0002-6294-6366 van Meurs, J.B.J. Styrkarsdottir, U. https://orcid.org/0000-0001-8146-8278 Zeggini, E. https://orcid.org/0000-0003-4238-659X
Copyright, Publisher and Additional Information:	© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	arcOGEN Consortium; ARGO Consortium; DBDS Genomic Consortium; Estonian Biobank Research Team; FinnGen; Genes & Health Research Team; HUNT All-In Pain; Million Veteran Program; Regeneron Genetics Center
Dates:	Submitted: 17 July 2024 Accepted: 11 February 2025 Published (online): 9 April 2025 Published: 9 April 2025
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Depositing User:	Symplectic Sheffield
Date Deposited:	11 Apr 2025 15:31
Last Modified:	11 Apr 2025 15:31
Status:	Published online
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41586-025-08771-z
Related URLs:	PubMed URL Dataset
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:225424