Translational genomics of osteoarthritis in 1,962,069 individuals.
Hatzikotoulas K., Southam L., Stefansdottir L., Boer CG., McDonald M-L., Pett JP., Park Y-C., 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 A-H., Tiwari HK., Yau MS., Yue M., Zhao W., Zhou JJ., Alexiadis G., Banasik K., Brunak S., Campbell A., Cheung JTS., Dowsett J., Faquih T., Faul JD., Fei L., Fenstad AM., Funayama T., Gabrielsen ME., Gocho C., Gromov K., Hansen T., Hudjashov G., Ingvarsson T., Johnson JS., Jonsson H., Kakehi S., Karjalainen J., Kasbohm E., Lemmelä S., Lin K., Liu X., Loef M., Mangino M., McCartney D., Millwood IY., Richman J., Roberts MB., Ryan KA., Samartzis D., Shivakumar M., Skou ST., Sugimoto S., Suzuki K., Takuwa H., Teder-Laving M., Thomas L., Tomizuka K., Turman C., Weiss S., Wu TT., Zengini E., Zhang Y., arcOGEN Consortium None., ARGO Consortium None., DBDS Genomic Consortium None., Estonian Biobank Research Team None., FinnGen None., Genes & Health Research Team None., HUNT All-In Pain None., Million Veteran Program None., Regeneron Genetics Center None., Ferreira MAR., Babis G., Baras A., Barker T., Carey DJ., Cheah KSE., Chen Z., Cheung JP-Y., Daly M., de Mutsert R., Eaton CB., Erikstrup C., Furnes ON., Golightly YM., Gudbjartsson DF., Hailer NP., Hayward C., Hochberg MC., Homuth G., Huckins LM., Hveem K., Ikegawa S., Ishijima M., Isomura M., Jones M., Kang JH., Kardia SLR., Kloppenburg M., Kraft P., Kumahashi N., Kuwata S., Lee MTM., Lee PH., Lerner R., Li L., Lietman SA., Lotta L., Lupton MK., Mägi R., Martin NG., McAlindon TE., Medland SE., Michaëlsson K., Mitchell BD., Mook-Kanamori DO., Morris AP., Nabika T., Nagami F., Nelson AE., Ostrowski SR., Palotie A., Pedersen OB., Rosendaal FR., Sakurai-Yageta M., Schmidt CO., Sham PC., Singh JA., Smelser DT., Smith JA., Song Y-Q., Sørensen E., Tamiya G., Tamura Y., Terao C., Thorleifsson G., Troelsen A., Tsezou A., Uchio Y., Uitterlinden AG., Ullum H., Valdes AM., van Heel DA., Walters RG., Weir DR., Wilkinson JM., Winsvold BS., Yamamoto M., Zwart J-A., Stefansson K., Meulenbelt I., Teichmann SA., van Meurs JBJ., Styrkarsdottir U., Zeggini E.
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.