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Hatzikotoulas, K. ; Southam, L. ; Stefansdottir, L.* ; Boer, C.G.* ; McDonald, M.L.* ; Pett, J.P.* ; Park, Y.-C. ; Tuerlings, M.* ; Mulders, R.* ; Barysenka, A. ; Arruda, A.L. ; Tragante, V.* ; Rocco, A.* ; Bittner, N. ; Chen, S. ; Horn, S. ; Srinivasasainagendra, V.* ; To, K.* ; Katsoula, G. ; Kreitmaier, P. ; Tenghe, A.M.M.* ; Gilly, A.* ; Arbeeva, L.* ; Chen, L.G.* ; de Pins, A.M.* ; Dochtermann, D.* ; Henkel, C.* ; Höijer, J.* ; Ito, S.* ; Lind, P.A.* ; Lukusa-Sawalena, B.* ; Minn, A.K.K.* ; Mola-Caminal, M.* ; Narita, A.* ; Nguyen, C.* ; Reimann, E.* ; Silberstein, M.D.* ; Skogholt, A.H.* ; Tiwari, H.K.* ; Yau, M.S.* ; Yue, M.* ; Zhao, W.* ; Zhou, J.J.* ; Alexiadis, G.* ; Banasik, K.* ; Brunak, S.* ; Campbell, A.* ; Cheung, J.T.S.* ; Dowsett, J.* ; Faquih, T.O.* ; Faul, J.D.* ; Fei, L.* ; Fenstad, A.M.* ; Funayama, T.* ; Gabrielsen, M.E.* ; Gocho, C.* ; Gromov, K.* ; Hansen, T.* ; Hudjashov, G.* ; Ingvarsson, T.* ; Johnson, J.S.* ; Jonsson, H.* ; Kakehi, S.* ; Karjalainen, J.* ; Kasbohm, E.* ; Lemmelä, S.* ; Lin, K.* ; Liu, X.* ; Loef, M.* ; Mangino, M.* ; McCartney, D.L.* ; Millwood, I.Y.* ; Richman, J.* ; Roberts, M.B.* ; Ryan, K.A.* ; Samartzis, D.* ; Shivakumar, M.* ; Skou, S.T.* ; Sugimoto, S.* ; Suzuki, K.* ; Takuwa, H.* ; Teder-Laving, M.* ; Thomas, L.* ; Tomizuka, K.* ; Turman, C.* ; Weiss, S.* ; Wu, T.T.* ; Zengini, E.* ; Zhang, Y.* ; Ferreira, M.A.R.* ; Babis, G.C.* ; Baras, A.* ; Barker, T.* ; Carey, D.J.* ; Cheah, K.S.E.* ; Chen, Z.* ; Cheung, J.P.Y.* ; Daly, M.* ; de Mutsert, R.* ; Eaton, C.B.* ; Erikstrup, C.* ; Furnes, O.N.* ; Golightly, Y.M.* ; Gudbjartsson, D.F.* ; Hailer, N.P.* ; Hayward, C.* ; Hochberg, M.C.* ; Homuth, G.* ; Huckins, L.M.* ; Hveem, K.* ; Ikegawa, S.* ; Ishijima, M.* ; Isomura, M.* ; Jones, M.* ; Kang, J.H.* ; Kardia, S.L.R.* ; Kloppenburg, M.* ; Kraft, P.* ; Kumahashi, N.* ; Kuwata, S.* ; Lee, M.T.M.* ; Lee, P.H.* ; Lerner, R.* ; Li, L.* ; Lietman, S.A.* ; Lotta, L.A.* ; Lupton, M.K.* ; Mägi, R.* ; Martin, N.G.* ; McAlindon, T.E.* ; Medland, S.E.* ; Michaëlsson, K.* ; Mitchell, B.D.* ; Mook-Kanamori, D.O.* ; Morris, A.P. ; Nabika, T.* ; Nagami, F.* ; Nelson, A.E.* ; Ostrowski, S.R.* ; Palotie, A.* ; Pedersen, O.B.* ; Rosendaal, F.R.* ; Sakurai-Yageta, M.* ; Schmidt, C.O.* ; Sham, P.C.* ; Singh, J.A.* ; Smelser, D.T.* ; Smith, J.A.* ; Song, Y.Q.* ; Sørensen, E.* ; Tamiya, G.* ; Tamura, Y.* ; Terao, C.* ; Thorleifsson, G.* ; Troelsen, A.* ; Tsezou, A.* ; Uchio, Y.* ; Uitterlinden, A.G.* ; Ullum, H.* ; Valdes, A.M.* ; van Heel, D.A.* ; Walters, R.G.* ; Weir, D.R.* ; Wilkinson, J.M.* ; Winsvold, B.S.* ; Yamamoto, M.* ; Zwart, J.A.* ; Stefansson, K.* ; Meulenbelt, I.* ; Teichmann, S.A.* ; van Meurs, J.B.J.* ; Styrkarsdottir, U.* ; Zeggini, E.

Translational genomics of osteoarthritis in 1,962,069 individuals.

Nature, 26 (2025)

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	Open Access Gold (Paid Option)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Rhythmic Variations; Wide Association; Metaanalysis; Mutations; Variants; Pain; Progression; Genetics; Haploreg; Site

ISSN (print) / ISBN 0028-0836

e-ISSN 1476-4687

Journal Nature

Quellenangaben Pages: 26

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Translational Genomics (ITG)

Grants Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH)