Translational genomics of osteoarthritis in 1,962,069 individuals

• 成果类型: Article
• 署名作者: Hatzikotoulas, Konstantinos; Southam, Lorraine; Stefansdottir, Lilja; Boer, Cindy G.; Mcdonald, Merry-Lynn; Pett, J. Patrick; Park, Young-Chan; Tuerlings, Margo; Mulders, Rick; Barysenka, Andrei; Arruda, Ana Luiza; Tragante, Vinicius; Rocco, Alison; Bittner, Norbert; Chen, Shibo; Horn, Susanne; Srinivasasainagendra, Vinodh; To, Ken; Katsoula, Georgia; Kreitmaier, Peter; Tenghe, Amabel M. M.; Gilly, Arthur; Arbeeva, Liubov; Chen, Lane G.; de Pins, Agathe M.; Dochtermann, Daniel; Henkel, Cecilie; Hoeijer, Jonas; Ito, Shuji; Lind, Penelope A.; Lukusa-Sawalena, Bitota; Minn, Aye Ko Ko; Mola-Caminal, Marina; Narita, Akira; Nguyen, Chelsea; Reimann, Ene; Silberstein, Micah D.; Skogholt, Anne-Heidi; Tiwari, Hemant K.; Yau, Michelle S.; Yue, Ming; Zhao, Wei; Zhou, Jin J.; Alexiadis, George; Banasik, Karina; Brunak, Soren; Campbell, Archie; Cheung, Jackson T. S.; Dowsett, Joseph; Faquih, Tariq; Faul, Jessica D.; Fei, Lijiang; Fenstad, Anne Marie; Funayama, Takamitsu; Gabrielsen, Maiken E.; Gocho, Chinatsu; Gromov, Kirill; Hansen, Thomas; Hudjashov, Georgi; Ingvarsson, Thorvaldur; Johnson, Jessica S.; Jonsson, Helgi; Kakehi, Saori; Karjalainen, Juha; Kasbohm, Elisa; Lemmelae, Susanna; Lin, Kuang; Liu, Xiaoxi; Loef, Marieke; Mangino, Massimo; Mccartney, Daniel; Millwood, Iona Y.; Richman, Joshua; Roberts, Mary B.; Ryan, Kathleen A.; Samartzis, Dino; Shivakumar, Manu; Skou, Soren T.; Sugimoto, Sachiyo; Suzuki, Ken; Takuwa, Hiroshi; Teder-Laving, Maris; Thomas, Laurent; Tomizuka, Kohei; Turman, Constance; Weiss, Stefan; Wu, Tian T.; Zengini, Eleni; Zhang, Yanfei; Babis, George; van Heel, David A.; Winsvold, Bendik; Gabrielsen, Maiken; Ferreira, Manuel Allen Revez; Baras, Aris; Barker, Tyler; Carey, David J.; Cheah, Kathryn S. E.; Chen, Zhengming; Cheung, Jason Pui-Yin; Daly, Mark; de Mutsert, Renee; Eaton, Charles B.; Erikstrup, Christian; Furnes, Ove Nord; Golightly, Yvonne M.; Gudbjartsson, Daniel F.; Hailer, Nils P.; Hayward, Caroline; Hochberg, Marc C.; Homuth, Georg; Huckins, Laura M.; Hveem, Kristian; Ikegawa, Shiro; Ishijima, Muneaki; Isomura, Minoru; Jones, Marcus; Kang, Jae H.; Kardia, Sharon L. R.; Kloppenburg, Margreet; Kraft, Peter; Kumahashi, Nobuyuki; Kuwata, Suguru; Lee, Ming Ta Michael; Lee, Phil H.; Lerner, Robin; Li, Liming; Lietman, Steve A.; Lotta, Luca; Lupton, Michelle K.; Maegi, Reedik; Martin, Nicholas G.; Mcalindon, Timothy E.; Medland, Sarah E.; Michaelsson, Karl; Mitchell, Braxton D.; Mook-Kanamori, Dennis O.; Morris, Andrew P.; Nabika, Toru; Nagami, Fuji; Nelson, Amanda E.; Ostrowski, Sisse Rye; Palotie, Aarno; Pedersen, Ole Birger; Rosendaal, Frits R.; Sakurai-Yageta, Mika; Schmidt, Carsten Oliver; Sham, Pak Chung; Singh, Jasvinder A.; Smelser, Diane T.; Smith, Jennifer A.; Song, You-qiang; Sorensen, Erik; Tamiya, Gen; Tamura, Yoshifumi; Terao, Chikashi; Thorleifsson, Gudmar; Troelsen, Anders; Tsezou, Aspasia; Uchio, Yuji; Uitterlinden, A. G.; Ullum, Henrik; Valdes, Ana M.; Walters, Robin G.; Weir, David R.; Wilkinson, J. Mark; Winsvold, Bendik S.; Yamamoto, Masayuki; Zwart, John-Anker; Stefansson, Kari; Meulenbelt, Ingrid; Teichmann, Sarah A.; van Meurs, Joyce B. J.; Styrkarsdottir, Unnur; Zeggini, Eleftheria
• 署名单位: Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Decode Genetics; Erasmus University Rotterdam; Erasmus MC; University of Alabama System; University of Alabama Birmingham; University of Alabama System; University of Alabama Birmingham; University of Alabama System; University of Alabama Birmingham; University of Alabama System; University of Alabama Birmingham; Wellcome Trust Sanger Institute; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); University of Alabama System; University of Alabama Birmingham; University of Cambridge; University of Cambridge; Eberhard Karls University of Tubingen; Regeneron; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of Hong Kong; Icahn School of Medicine at Mount Sinai; University of Copenhagen; Uppsala University; Shimane University; RIKEN; RIKEN; QIMR Berghofer Medical Research Institute; University of Queensland; Queensland University of Technology (QUT); Tohoku University; Tohoku University; University of Tartu; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Norwegian University of Science & Technology (NTNU); Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Hebrew SeniorLife; University of Hong Kong; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of California System; University of California Los Angeles; University of Copenhagen; University of Edinburgh; Imperial College London; Rigshospitalet; University of Copenhagen; Copenhagen University Hospital; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard Medical School; University of Bergen; Haukeland University Hospital; University of Copenhagen; University of Iceland; Icahn School of Medicine at Mount Sinai; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; Juntendo University; University of Helsinki; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Universitat Greifswald; Greifswald Medical School; University of Oxford; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; University of London; King's College London; University of Alabama System; University of Alabama Birmingham; Brown University; University System of Maryland; University of Maryland Baltimore; University of Hong Kong; Rush University; University of Pennsylvania; University of Southern Denmark; Naestved Hospital; University of Manchester; University of Tokyo; University of Osaka; Norwegian University of Science & Technology (NTNU); Harvard University; Harvard T.H. Chan School of Public Health; Universitat Greifswald; Greifswald Medical School; Geisinger Health System; National & Kapodistrian University of Athens; University System of Ohio; Ohio State University; Utah System of Higher Education; University of Utah; Brown University; Brown University; Aarhus University; Aarhus University; University of Bergen; University of Nebraska System; University of Nebraska Medical Center; University of Iceland; Uppsala University; University of Edinburgh; University System of Maryland; University of Maryland Baltimore; Yale University; Norwegian University of Science & Technology (NTNU); Juntendo University; Shimane University; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; University of London; Queen Mary University London; Peking University; Peking University; QIMR Berghofer Medical Research Institute; Queensland University of Technology (QUT); QIMR Berghofer Medical Research Institute; Tufts Medical Center; University of Queensland; University of Queensland; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Shimane University; University of Copenhagen; University of Hong Kong; University of Alabama System; University of Alabama Birmingham; Baylor College of Medicine; RIKEN; Juntendo University; Shizuoka General Hospital; University of Shizuoka; University of Copenhagen; University of Thessaly; Statens Serum Institut; University of Nottingham; University of Sheffield; University of Oslo; University of Oslo; University of Oslo; University of Cambridge; Technical University of Munich
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2552
• DOI: 10.1038/s41586-025-08771-z
• 发表日期: 2025-05-29
• 关键词: rhythmic variations; wide association; metaanalysis; mutations; variants; pain; progression; genetics; haploreg; site

摘要

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 (TGF beta, 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.