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<p>Osteoarthritis is the third most rapidly growing health condition associated with disability, after dementia and diabetes<sup><CitationRef CitationID="CR1">1</CitationRef></sup>. By 2050, the total number of patients with osteoarthritis is estimated to reach 1 billion worldwide<sup><CitationRef CitationID="CR2">2</CitationRef></sup>. 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.</p>

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Translational genomics of osteoarthritis in 1,962,069 individuals

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月9日

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  • Konstantinos Hatzikotoulas,
  • Lorraine Southam,
  • Lilja Stefansdottir,
  • Cindy G. Boer,
  • Merry-Lynn McDonald,
  • J. Patrick Pett,
  • Young-Chan Park,
  • Margo Tuerlings,
  • Rick Mulders,
  • Andrei Barysenka,
  • Ana Luiza Arruda,
  • Vinicius Tragante,
  • Alison Rocco,
  • Norbert Bittner,
  • Shibo Chen,
  • Susanne Horn,
  • Vinodh Srinivasasainagendra,
  • Ken To,
  • Georgia Katsoula,
  • Peter Kreitmaier,
  • Amabel M. M. Tenghe,
  • Arthur Gilly,
  • Liubov Arbeeva,
  • Lane G. Chen,
  • Agathe M. de Pins,
  • Daniel Dochtermann,
  • Cecilie Henkel,
  • Jonas Höijer,
  • Shuji Ito,
  • Penelope A. Lind,
  • Bitota Lukusa-Sawalena,
  • Aye Ko Ko Minn,
  • Marina Mola-Caminal,
  • Akira Narita,
  • Chelsea Nguyen,
  • Ene Reimann,
  • Micah D. Silberstein,
  • Anne-Heidi Skogholt,
  • Hemant K. Tiwari,
  • Michelle S. Yau,
  • Ming Yue,
  • Wei Zhao,
  • Jin J. Zhou,
  • George Alexiadis,
  • Karina Banasik,
  • Søren Brunak,
  • Archie Campbell,
  • Jackson T. S. Cheung,
  • Joseph Dowsett,
  • Tariq Faquih,
  • Jessica D. Faul,
  • Lijiang Fei,
  • Anne Marie Fenstad,
  • Takamitsu Funayama,
  • Maiken E. Gabrielsen,
  • Chinatsu Gocho,
  • Kirill Gromov,
  • Thomas Hansen,
  • Georgi Hudjashov,
  • Thorvaldur Ingvarsson,
  • Jessica S. Johnson,
  • Helgi Jonsson,
  • Saori Kakehi,
  • Juha Karjalainen,
  • Elisa Kasbohm,
  • Susanna Lemmelä,
  • Kuang Lin,
  • Xiaoxi Liu,
  • Marieke Loef,
  • Massimo Mangino,
  • Daniel McCartney,
  • Iona Y. Millwood,
  • Joshua Richman,
  • Mary B. Roberts,
  • Kathleen A. Ryan,
  • Dino Samartzis,
  • Manu Shivakumar,
  • Søren T. Skou,
  • Sachiyo Sugimoto,
  • Ken Suzuki,
  • Hiroshi Takuwa,
  • Maris Teder-Laving,
  • Laurent Thomas,
  • Kohei Tomizuka,
  • Constance Turman,
  • Stefan Weiss,
  • Tian T. Wu,
  • Eleni Zengini,
  • Yanfei Zhang,
  • George Babis,
  • David A. van Heel,
  • Bendik Winsvold,
  • Maiken Gabrielsen,
  • Manuel Allen Revez Ferreira,
  • George Babis,
  • Aris Baras,
  • Tyler Barker,
  • David J. Carey,
  • Kathryn S. E. Cheah,
  • Zhengming Chen,
  • Jason Pui-Yin Cheung,
  • Mark Daly,
  • Renée de Mutsert,
  • Charles B. Eaton,
  • Christian Erikstrup,
  • Ove Nord Furnes,
  • Yvonne M. Golightly,
  • Daniel F. Gudbjartsson,
  • Nils P. Hailer,
  • Caroline Hayward,
  • Marc C. Hochberg,
  • Georg Homuth,
  • Laura M. Huckins,
  • Kristian Hveem,
  • Shiro Ikegawa,
  • Muneaki Ishijima,
  • Minoru Isomura,
  • Marcus Jones,
  • Jae H. Kang,
  • Sharon L. R. Kardia,
  • Margreet Kloppenburg,
  • Peter Kraft,
  • Nobuyuki Kumahashi,
  • Suguru Kuwata,
  • Ming Ta Michael Lee,
  • Phil H. Lee,
  • Robin Lerner,
  • Liming Li,
  • Steve A. Lietman,
  • Luca Lotta,
  • Michelle K. Lupton,
  • Reedik Mägi,
  • Nicholas G. Martin,
  • Timothy E. McAlindon,
  • Sarah E. Medland,
  • Karl Michaëlsson,
  • Braxton D. Mitchell,
  • Dennis O. Mook-Kanamori,
  • Andrew P. Morris,
  • Toru Nabika,
  • Fuji Nagami,
  • Amanda E. Nelson,
  • Sisse Rye Ostrowski,
  • Aarno Palotie,
  • Ole Birger Pedersen,
  • Frits R. Rosendaal,
  • Mika Sakurai-Yageta,
  • Carsten Oliver Schmidt,
  • Pak Chung Sham,
  • Jasvinder A. Singh,
  • Diane T. Smelser,
  • Jennifer A. Smith,
  • You-qiang Song,
  • Erik Sørensen,
  • Gen Tamiya,
  • Yoshifumi Tamura,
  • Chikashi Terao,
  • Gudmar Thorleifsson,
  • Anders Troelsen,
  • Aspasia Tsezou,
  • Yuji Uchio,
  • A. G. Uitterlinden,
  • Henrik Ullum,
  • Ana M. Valdes,
  • David A. van Heel,
  • Robin G. Walters,
  • David R. Weir,
  • J. Mark Wilkinson,
  • Bendik S. Winsvold,
  • Masayuki Yamamoto,
  • John-Anker Zwart,
  • Kari Stefansson,
  • Ingrid Meulenbelt,
  • Sarah A. Teichmann,
  • Joyce B. J. van Meurs,
  • Unnur Styrkarsdottir,
  • Eleftheria Zeggini

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 (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.