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

Hatzikotoulas K, Southam L, Stefansdottir L, Boer CG, McDonald ML, Pett JP, Park YC, Tuerlings M, Mulders R, Barysenka A, Arruda AL, Tragante V, Rocco A, Bittner N, Chen S, Horn S, Srinivasasainagendra V, To K, Katsoula G, Kreitmaier P, Tenghe AMM, Gilly A, Arbeeva L, Chen LG, de Pins AM, Dochtermann D, Henkel C, Höijer J, Ito S, Lind PA, Lukusa-Sawalena B, Minn AKK, Mola-Caminal M, Narita A, Nguyen C, Reimann E, Silberstein MD, Skogholt AH, Tiwari HK, Yau MS, Yue M, Zhao W, Zhou JJ, Alexiadis G, Banasik K, Brunak S, Campbell A, Cheung JTS, Dowsett J, Faquih T, Faquih T, Faul JD, Fei L, Fenstad AM, Fenstad AM, Funayama T, Funayama T, Gabrielsen ME, Gabrielsen ME, Gocho C, Gocho C, Gromov K, Gromov K, Hansen T, Hansen T, Hudjashov G, Hudjashov G, Ingvarsson T, Ingvarsson T, Johnson JS, Johnson JS, Jonsson H, Jonsson H, Kakehi S, Kakehi S, Karjalainen J, Karjalainen J, Kasbohm E, Kasbohm E, Lemmelä S, Lemmelä S, Lin K, Lin K, Liu X, Liu X, Loef M, Loef M, Mangino M, Mangino M, McCartney D, McCartney D, Millwood IY, Millwood IY, Richman J, Richman J, Roberts MB, Roberts MB, Ryan KA, Ryan KA, Samartzis D, Samartzis D, Shivakumar M, Shivakumar M, Skou ST, Skou ST, Sugimoto S, Sugimoto S, Suzuki K, Suzuki K, Takuwa H, Takuwa H, Teder-Laving M, Teder-Laving M, Thomas L, Thomas L, Tomizuka K, Tomizuka K, Turman C, Turman C, Weiss S, Wu TT, Wu TT, Zengini E, Zhang Y, arcOGEN Consortium , arcOGEN Consortium , arcOGEN Consortium , ARGO Consortium , ARGO Consortium , ARGO Consortium , DBDS Genomic Consortium , DBDS Genomic Consortium , Estonian Biobank Research Team , Estonian Biobank Research Team , FinnGen , FinnGen , FinnGen , Genes & Health Research Team , Genes & Health Research Team , HUNT All-In Pain , HUNT All-In Pain , Million Veteran Program , Million Veteran Program , Regeneron Genetics Center , Regeneron Genetics Center , Ferreira MAR, Ferreira MAR, Babis G, Babis G, Baras A, Baras A, Barker T, Barker T, Carey DJ, Carey DJ, Cheah KSE, Cheah KSE, Chen Z, Chen Z, Cheung JP, Cheung JP, Daly M, Daly M, de Mutsert R, de Mutsert R, Eaton CB, Eaton CB, Erikstrup C, Erikstrup C, Furnes ON, Furnes ON, Erikstrup C, Golightly YM, Golightly YM, Golightly YM, Furnes ON, Gudbjartsson DF, Gudbjartsson DF, Gudbjartsson DF, Hailer NP, Hailer NP, Hailer NP, Hayward C, Hayward C, Hayward C, Hochberg MC, Hochberg MC, Hochberg MC, Homuth G, Homuth G, Homuth G, Huckins LM, Huckins LM, Huckins LM, Hveem K, Hveem K, Hveem K, Ikegawa S, Ikegawa S, Ikegawa S, Ishijima M, Ishijima M, Ishijima M, Isomura M, Isomura M, Isomura M, Jones M, Jones M, Jones M, Kang JH, Kang JH, Kang JH, Kardia SLR, Kardia SLR, Kardia SLR, Kloppenburg M, Kloppenburg M, Kloppenburg M, Kraft P, Kraft P, Kraft P, Kumahashi N, Kumahashi N, Kumahashi N, Kuwata S, Kuwata S, Kuwata S, Lee MTM, Lee MTM, Lee MTM, Lee PH, Lee PH, Lee PH, Lerner R, Lerner R, Lerner R, Li L, Li L, Li L, Lietman SA, Lietman SA, Lietman SA, Lotta L, Lotta L, Lotta L, Lupton MK, Lupton MK, Lupton MK, Mägi R, Mägi R, Mägi R, Martin NG, Martin NG, Martin NG, McAlindon TE, McAlindon TE, Martin NG, McAlindon TE, Medland SE, McAlindon TE, Medland SE, Medland SE, Michaëlsson K, Medland SE, Michaëlsson K, Michaëlsson K, Mitchell BD, Mitchell BD, Michaëlsson K, Mitchell BD, Mook-Kanamori DO, Mook-Kanamori DO, Mook-Kanamori DO, Mitchell BD, Morris AP, Morris AP, Mook-Kanamori DO, Morris AP, Nabika T, Morris AP, Nabika T, Nabika T, Nagami F, Nagami F, Nagami F, Nabika T, Nelson AE, Nelson AE, Nagami F, Nelson AE, Ostrowski SR, Nelson AE, Ostrowski SR, Ostrowski SR, Palotie A, Palotie A, Ostrowski SR, Palotie A, Pedersen OB, Pedersen OB, Pedersen OB, Palotie A, Rosendaal FR, Rosendaal FR, Rosendaal FR, Pedersen OB, Rosendaal FR, Sakurai-Yageta M, Sakurai-Yageta M, Sakurai-Yageta M, Schmidt CO, Schmidt CO, Schmidt CO, Sakurai-Yageta M, Sham PC, Sham PC, Sham PC, Schmidt CO, Sham PC, Singh JA, Singh JA, Singh JA, Smelser DT, Smelser DT, Smelser DT, Singh JA, Smith JA, Smith JA, Smith JA, Smelser DT, Song YQ, Song YQ, Smith JA, Song YQ, Song YQ, Sørensen E, Sørensen E, Sørensen E, Tamiya G, Tamiya G, Sørensen E, Tamiya G, Tamiya G, Tamura Y, Tamura Y, Tamura Y, Terao C, Tamura Y, Terao C, Terao C, Thorleifsson G, Thorleifsson G, Terao C, Thorleifsson G, Thorleifsson G, Troelsen A, Troelsen A, Troelsen A, Troelsen A, Tsezou A, Tsezou A, Tsezou A, Uchio Y, Uchio Y, Uchio Y, Tsezou A, Uchio Y, Uitterlinden AG, Uitterlinden AG, Uitterlinden AG, Ullum H, Uitterlinden AG, Ullum H, Ullum H, Valdes AM, Valdes AM, Ullum H, Valdes AM, van Heel DA, van Heel DA, van Heel DA, Valdes AM, Walters RG, Walters RG, Walters RG, van Heel DA, Weir DR, Weir DR, Weir DR, Walters RG, Wilkinson JM, Wilkinson JM, Wilkinson JM, Weir DR, Winsvold BS, Wilkinson JM, Winsvold BS, Winsvold BS, Yamamoto M, Yamamoto M, Winsvold BS, Yamamoto M, Zwart JA, Yamamoto M, Zwart JA, Zwart JA, Stefansson K, Stefansson K, Stefansson K, Zwart JA, Meulenbelt I, Meulenbelt I, Meulenbelt I, Stefansson K, Teichmann SA, Teichmann SA, Teichmann SA, Meulenbelt I, van Meurs JBJ, Teichmann SA, van Meurs JBJ, van Meurs JBJ, Styrkarsdottir U, Styrkarsdottir U, van Meurs JBJ, Styrkarsdottir U, Styrkarsdottir U, Zeggini E, Zeggini E, Zeggini E, Zeggini E. Translational genomics of osteoarthritis in 1,962,069 individuals. Nature. 2025 May 1; 641(8065):1217-1224, DOI: 10.1038/s41586-025-08771-z.

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Abstract:

Osteoarthritis is the third most rapidly growing health condition associated with disability, after dementia and diabetes. By 2050, the total number of patients with osteoarthritis is estimated to reach 1 billion worldwide. 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 (TGF , 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.