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Nature · 2025

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

СтатьяМетаанализПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПоддержка службы здравоохранения СШАНазвание и аннотация: Перевод в очереди
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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, Höijer 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 Søren, 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, Lemmelä 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 Søren 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, 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, Ferreira Manuel Allen Revez, Babis George, Baras Aris, Barker Tyler, Carey David J, Cheah Kathryn S E, Chen Zhengming, Cheung Jason Pui-Yin, Daly Mark, de Mutsert Renée, 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, Mägi Reedik, Martin Nicholas G, McAlindon Timothy E, Medland Sarah E, Michaëlsson 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, Sørensen Erik, Tamiya Gen, Tamura Yoshifumi, Terao Chikashi, Thorleifsson Gudmar, Troelsen Anders, Tsezou Aspasia, Uchio Yuji, Uitterlinden A G, Ullum Henrik, Valdes Ana M, van Heel David A, 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

Аннотация

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.

Предметные рубрики MeSH

ИП Урсолов Владлен Сергеевич

ИНН 500118482352 · ОГРНИП 314500117700049

Реквизиты и контакты