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Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations

2021; Cell Press; Volume: 184; Issue: 18 Linguagem: Inglês

10.1016/j.cell.2021.07.038

1097-4172

Cindy G. Boer, Konstantinos Hatzikotoulas, Lorraine Southam, Lilja Stefánsdóttir, Yanfei Zhang, Rodrigo Coutinho de Almeida, Tian Wu, Jie Zheng, April Hartley, Maris Teder‐Laving, Anne Heidi Skogholt, Chikashi Terao, Eleni Zengini, George Alexiadis, Andrei Barysenka, Gyða Björnsdóttir, Maiken E. Gabrielsen, Arthur Gilly, Þorvaldur Ingvarsson, Marianne Bakke Johnsen, Helgi Jónsson, M. Kloppenburg, Almut Luetge, Sigrún H. Lund, Reedik Mägi, Massimo Mangino, Rob G. H. H. Nelissen, Manu Shivakumar, Julia Steinberg, Hiroshi Takuwa, Laurent F. Thomas, Margo Tuerlings, George C. Babis, Jason Pui Yin Cheung, Jae H. Kang, Peter Kraft, Steven A. Lietman, Dino Samartzis, P. Eline Slagboom, Hreinn Stefánsson, Unnur Þorsteinsdóttir, Jonathan H. Tobias, André G. Uitterlinden, Bendik S. Winsvold, John‐Anker Zwart, George Davey Smith, Pak C. Sham, Guðmar Þorleifsson, Tom R. Gaunt, Andrew P. Morris, Ana M. Valdes, Aspasia Tsezou, Kathryn S.E. Cheah, Shiro Ikegawa, Kristian Hveem, Tõnu Esko, J. Mark Wilkinson, Ingrid Meulenbelt, Ming Ta Michael Lee, Joyce B. J. van Meurs, Unnur Styrkársdóttir, Eleftheria Zeggini, John Loughlin, Nigel Arden, Fraser Birrell, Andrew Carr, Panos Deloukas, Michael Doherty, Andrew W. McCaskie, William Ollier, Ashok Rai, Stuart H. Ralston, Tim D. Spector, Gillian A. Wallis, Amy E. Martinsen, Cristen J. Willer, Egil A. Fors, Ingunn Mundal, Knut Hagen, Kristian Bernhard Nilsen, Marie Udnesseter Lie, Sigrid Børte, Ben Brumpton, Jonas B. Nielsen, Lars G. Fritsche, Wei Zhou, Ingrid Heuch, Kjersti Storheim, Evangelos Tyrpenou, A. Koukakis, Dimitrios Chytas, Dimitrios Stergios Evangelopoulos, Chronopoulos Efstathios, Spiros G. Pneumaticos, Vasileios S. Nikolaou, Κonstantinos Ν. Malizos, Lydia Anastasopoulou, Gonçalo R. Abecasis, Aris Baras, Michael Cantor, Giovanni Coppola, Andrew Deubler, Aris N. Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan R. Shuldiner, Katia Karalis, Katherine Siminovitch, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Xiaodong Bai, Suganthi Balasubramanian, Boris Boutkov, Gisu Eom, Lukas Habegger, Alicia Hawes, Olga Krasheninina, Rouel Lanche, Adam J. Mansfield, Evan K. Maxwell, Mona Nafde, Sean O’Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, William Salerno, Jeffrey Staples, Dadong Li, Deepika Sharma, Ilanjana Banerjee, Jonas Bovijn, Adam E. Locke, Niek Verweij, Mary E. Haas, George Hindy, Tanima De, Parsa Akbari, Olukayode Sosina, Manuel A. R. Ferreira, Marcus B. Jones, Jason Mighty, Michelle G. LeBlanc, Lyndon J. Mitnaul,

Inflammatory mediators and NSAID effects

Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.