Translational genomics of osteoarthritis in 1,962,069 individuals

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. 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, 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 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. 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. Meurs, Unnur Styrkarsdottir and Eleftheria Zeggini ()
Additional contact information
Konstantinos Hatzikotoulas: German Research Center for Environmental Health
Lorraine Southam: German Research Center for Environmental Health
Lilja Stefansdottir: deCODE Genetics/Amgen
Cindy G. Boer: Erasmus MC Medical Center
Merry-Lynn McDonald: Birmingham Veterans Affairs Healthcare System (BVAHS)
J. Patrick Pett: Wellcome Genome Campus
Young-Chan Park: German Research Center for Environmental Health
Margo Tuerlings: Leiden University Medical Center
Rick Mulders: Leiden University Medical Center
Andrei Barysenka: German Research Center for Environmental Health
Ana Luiza Arruda: German Research Center for Environmental Health
Vinicius Tragante: deCODE Genetics/Amgen
Alison Rocco: Birmingham Veterans Affairs Healthcare System (BVAHS)
Norbert Bittner: German Research Center for Environmental Health
Shibo Chen: German Research Center for Environmental Health
Susanne Horn: German Research Center for Environmental Health
Vinodh Srinivasasainagendra: Birmingham Veterans Affairs Healthcare System (BVAHS)
Ken To: Wellcome Genome Campus
Georgia Katsoula: German Research Center for Environmental Health
Peter Kreitmaier: German Research Center for Environmental Health
Amabel M. M. Tenghe: University of Tubingen
Arthur Gilly: Regeneron Genetics Center
Liubov Arbeeva: University of North Carolina at Chapel Hill
Lane G. Chen: The University of Hong Kong
Agathe M. Pins: Icahn School of Medicine at Mount Sinai
Daniel Dochtermann: Birmingham Veterans Affairs Healthcare System (BVAHS)
Cecilie Henkel: Copenhagen University Hospital Hvidovre
Jonas Höijer: Uppsala University
Shuji Ito: Shimane University Faculty of Medicine
Penelope A. Lind: QIMR Berghofer Medical Research Institute
Bitota Lukusa-Sawalena: Birmingham Veterans Affairs Healthcare System (BVAHS)
Aye Ko Ko Minn: Tohoku University Graduate School of Medicine
Marina Mola-Caminal: Uppsala University
Akira Narita: Tohoku University
Chelsea Nguyen: Birmingham Veterans Affairs Healthcare System (BVAHS)
Ene Reimann: University of Tartu
Micah D. Silberstein: Massachusetts General Hospital
Anne-Heidi Skogholt: Norwegian University of Science and Technology
Hemant K. Tiwari: UAB
Michelle S. Yau: Harvard Medical School
Ming Yue: The University of Hong Kong
Wei Zhao: University of Michigan
Jin J. Zhou: UCLA Fielding School of Public Health
George Alexiadis: KAT General Hospital
Karina Banasik: University of Copenhagen
Søren Brunak: University of Copenhagen
Archie Campbell: University of Edinburgh
Jackson T. S. Cheung: University College London
Joseph Dowsett: Copenhagen University Hospital—Rigshospitalet
Tariq Faquih: Leiden University Medical Center
Jessica D. Faul: University of Michigan
Lijiang Fei: Wellcome Genome Campus
Anne Marie Fenstad: Haukeland University Hospital
Takamitsu Funayama: Tohoku University
Maiken E. Gabrielsen: Norwegian University of Science and Technology
Chinatsu Gocho: Tohoku University
Kirill Gromov: Copenhagen University Hospital Hvidovre
Thomas Hansen: Rigshospitalet – Glostrup
Georgi Hudjashov: University of Tartu
Thorvaldur Ingvarsson: Akureyri Hospital
Jessica S. Johnson: Icahn School of Medicine at Mount Sinai
Helgi Jonsson: University of Iceland
Saori Kakehi: Juntendo University
Juha Karjalainen: University of Helsinki
Elisa Kasbohm: University Medicine Greifswald
Susanna Lemmelä: University of Helsinki
Kuang Lin: University of Oxford
Xiaoxi Liu: RIKEN Center for Integrative Medical Sciences
Marieke Loef: Leiden University Medical Center
Massimo Mangino: Kings College London
Daniel McCartney: University of Edinburgh
Iona Y. Millwood: University of Oxford
Joshua Richman: Birmingham Veterans Affairs Healthcare System (BVAHS)
Mary B. Roberts: Brown University
Kathleen A. Ryan: University of Maryland School of Medicine
Dino Samartzis: The University of Hong Kong
Manu Shivakumar: University of Pennsylvania
Søren T. Skou: University of Southern Denmark
Sachiyo Sugimoto: Tohoku University
Ken Suzuki: University of Manchester
Hiroshi Takuwa: Shimane University Faculty of Medicine
Maris Teder-Laving: University of Tartu
Laurent Thomas: Norwegian University of Science and Technology
Kohei Tomizuka: RIKEN Center for Integrative Medical Sciences
Constance Turman: Harvard T.H. Chan School of Public Health
Stefan Weiss: University Medicine Greifswald
Tian T. Wu: The University of Hong Kong
Eleni Zengini: Haidari
Yanfei Zhang: Geisinger Health System
Manuel Allen Revez Ferreira: Regeneron Genetics Center
George Babis: ‘Konstantopouleio’ Hospital
Aris Baras: Regeneron Genetics Center
Tyler Barker: The Ohio State University Wexner Medical Center
David J. Carey: Geisinger
Kathryn S. E. Cheah: The University of Hong Kong
Zhengming Chen: University of Oxford
Jason Pui-Yin Cheung: The University of Hong Kong
Mark Daly: University of Helsinki
Renée Mutsert: Leiden University Medical Center
Charles B. Eaton: Brown University
Christian Erikstrup: Aarhus University Hospital
Ove Nord Furnes: Haukeland University Hospital
Yvonne M. Golightly: University of North Carolina at Chapel Hill
Daniel F. Gudbjartsson: deCODE Genetics/Amgen
Nils P. Hailer: Uppsala University
Caroline Hayward: University of Edinburgh
Marc C. Hochberg: University of Maryland School of Medicine
Georg Homuth: University Medicine Greifswald
Laura M. Huckins: Yale University
Kristian Hveem: Norwegian University of Science and Technology
Shiro Ikegawa: RIKEN Center for Integrative Medical Sciences
Muneaki Ishijima: Juntendo University Graduate School of Medicine
Minoru Isomura: Shimane University
Marcus Jones: Regeneron Genetics Center
Jae H. Kang: Brigham and Women’s Hospital
Sharon L. R. Kardia: University of Michigan
Margreet Kloppenburg: Leiden University Medical Center
Peter Kraft: Harvard T.H. Chan School of Public Health
Nobuyuki Kumahashi: Matsue Red Cross Hospital
Suguru Kuwata: Shimane University Faculty of Medicine
Ming Ta Michael Lee: Geisinger Health System
Phil H. Lee: Massachusetts General Hospital
Robin Lerner: Queen Mary University of London
Liming Li: Peking University
Steve A. Lietman: Geisinger
Luca Lotta: Regeneron Genetics Center
Michelle K. Lupton: University of Queensland
Reedik Mägi: University of Tartu
Nicholas G. Martin: QIMR Berghofer Medical Research Institute
Timothy E. McAlindon: Tufts Medical Center
Sarah E. Medland: QIMR Berghofer Medical Research Institute
Karl Michaëlsson: Uppsala University
Braxton D. Mitchell: University of Maryland School of Medicine
Dennis O. Mook-Kanamori: Leiden University Medical Center
Andrew P. Morris: German Research Center for Environmental Health
Toru Nabika: Shimane University School of Medicine
Fuji Nagami: Tohoku University
Amanda E. Nelson: University of North Carolina at Chapel Hill
Sisse Rye Ostrowski: Copenhagen University Hospital—Rigshospitalet
Aarno Palotie: University of Helsinki
Ole Birger Pedersen: University of Copenhagen
Frits R. Rosendaal: Leiden University Medical Center
Mika Sakurai-Yageta: Tohoku University
Carsten Oliver Schmidt: University Medicine Greifswald
Pak Chung Sham: The University of Hong Kong
Jasvinder A. Singh: Birmingham Veterans Affairs Healthcare System (BVAHS)
Diane T. Smelser: Geisinger
Jennifer A. Smith: University of Michigan
You-qiang Song: The University of Hong Kong
Erik Sørensen: Copenhagen University Hospital—Rigshospitalet
Gen Tamiya: Tohoku University Graduate School of Medicine
Yoshifumi Tamura: Juntendo University Graduate School of Medicine
Chikashi Terao: RIKEN Center for Integrative Medical Sciences
Gudmar Thorleifsson: deCODE Genetics/Amgen
Anders Troelsen: Copenhagen University Hospital Hvidovre
Aspasia Tsezou: University of Thessaly
Yuji Uchio: Shimane University Faculty of Medicine
A. G. Uitterlinden: Erasmus MC Medical Center
Henrik Ullum: Statens Serum Institute
Ana M. Valdes: University of Nottingham
David A. Heel: Queen Mary University of London
Robin G. Walters: University of Oxford
David R. Weir: University of Michigan
J. Mark Wilkinson: The University of Sheffield
Bendik S. Winsvold: Norwegian University of Science and Technology
Masayuki Yamamoto: Tohoku University Graduate School of Medicine
John-Anker Zwart: Norwegian University of Science and Technology
Kari Stefansson: deCODE Genetics/Amgen
Ingrid Meulenbelt: Leiden University Medical Center
Sarah A. Teichmann: University of Cambridge
Joyce B. J. Meurs: Erasmus MC Medical Center
Unnur Styrkarsdottir: deCODE Genetics/Amgen
Eleftheria Zeggini: German Research Center for Environmental Health

Nature, 2025, vol. 641, issue 8065, 1217-1224

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-025-08771-z

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