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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

2012; Nature Portfolio; Volume: 44; Issue: 5 Linguagem: Inglês

10.1038/ng.2249

1546-1718

Karol Estrada, Unnur Styrkársdóttir, Εvangelos Εvangelou, Yi‐Hsiang Hsu, Emma L. Duncan, Evangelia Ntzani, Ling Oei, Omar Albagha, Najaf Amin, John P. Kemp, Daniel L. Koller, Li Guo, Yongmei Liu, Ryan L. Minster, Alireza Moayyeri, Liesbeth Vandenput, Dana Willner, Su‐Mei Xiao, Laura M. Yerges-Armstrong, Hou‐Feng Zheng, Nerea Alonso, Joel Eriksson, Candace M. Kammerer, Stephen K. Kaptoge, Paul Leo, Guðmar Þorleifsson, Scott G. Wilson, James F. Wilson, Ville Aalto, Markku Alén, Aaron K. Aragaki, Thor Aspelund, Jacqueline R. Center, Zoe Dailiana, David Duggan, Melissa García, Natàlia Garcia‐Giralt, Sylvie Giroux, Göran Hallmans, Lynne J. Hocking, Lise B. Husted, Anthony James, Р. И. Хусаинова, Ghi Su Kim, Charles Kooperberg, Theodora Koromila, Marcin Kruk, Marika Laaksonen, Andrea Z. LaCroix, Seung Hun Lee, Ping‐Chung Leung, Joshua R. Lewis, Laura Masi, Simona Mencej-Bedrač, Tuan V. Nguyen, Xavier Nogués, Millan S. Patel, Janez Preželj, Lynda M. Rose, Serena Scollen, Kristín Siggeirsdóttir, Albert V. Smith, Olle Svensson, Stella Trompet, Olivia Trummer, Natasja M. van Schoor, Jean Woo, Kun Zhu, Susana Balcells, Maria Luisa Brandi, Brendan M. Buckley, Sulin Cheng, Claus Christiansen, Cyrus Cooper, George Dedoussis, Ian Ford, Morten Frost, David Goltzman, Jesús González‐Macías, Mika Kähönen, Magnus K. Karlsson, Э. К. Хуснутдинова, Jung‐Min Koh, Panagoula Κollia, Bente Langdahl, William D. Leslie, Paul Lips, Östen Ljunggren, R Lorenc, Janja Marc, Dan Mellström, Barbara Obermayer‐Pietsch, José M. Olmos, U. Pettersson, David M. Reid, José A. Riancho, Paul M. Ridker, François Rousseau, P. Eline Slagboom, Nelson L.S. Tang, Roser Urreizti, Wim Van Hul, Jorma Viikari, Marı́a T. Zarrabeitia, Yurii S. Aulchenko, Martha C. Castaño‐Betancourt, Elin Grundberg, Lizbeth Herrera, Þorvaldur Ingvarsson, Hrefna Johannsdottir, Tony Kwan, Rui Li, Robert Luben, Carolina Medina‐Gómez, Stefan Palsson, Sjur Reppe, Jerome I. Rotter, Gunnar Sigurðsson, Joyce B. J. van Meurs, Dominique J. Verlaan, Frances M. K. Williams, Andrew R. Wood, Yanhua Zhou, Kaare M. Gautvik, Tomi Pastinen, Soumya Raychaudhuri, Jane A. Cauley, Daniel I. Chasman, Graeme R. Clark, Steven R. Cummings, Patrick Danoy, Elaine Dennison, Richard Eastell, John A. Eisman, Vilmundur Guðnason, Albert Hofman, Rebecca D. Jackson, Graeme Jones, J. Wouter Jukema, Kay‐Tee Khaw, Terho Lehtimäki, Yongmei Liu, Mattias Lorentzon, Eugène McCloskey, Braxton D. Mitchell, Kannabiran Nandakumar, Geoffrey C. Nicholson, Ben A. Oostra, Munro Peacock, Huibert A. P. Pols, Richard L. Prince, Olli Raitakari, Ian R. Reid, John A. Robbins, Philip N. Sambrook, Pak C. Sham, Alan R. Shuldiner, Frances A. Tylavsky, Cornelia M. van Duijn, Nicholas J. Wareham, L. Adrienne Cupples, Michael J. Econs, David M. Evans, Tamara B. Harris, A W Kung, Bruce M. Psaty, J. Reeve, Timothy D. Spector, Elizabeth A. Streeten, M. Carola Zillikens, Unnur Þorsteinsdóttir, Claes Ohlsson, David Karasik, J. Brent Richards, Matthew A. Brown, Kári Stéfansson, André G. Uitterlinden, Stuart H. Ralston, John P. A. Ioannidis, Douglas P. Kiel, Fernando Rivadeneira,

Genetic Associations and Epidemiology

Fernando Rivadeneira and colleagues in the Genetic Factors for Osteoporosis Consortium report a large-scale meta-analysis identifying new loci associated with bone mineral density (BMD) and risk of fracture. Thirty-two new loci are found to be associated with BMD, and 6 loci confer higher risk for low-trauma bone fracture. Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10−4, Bonferroni corrected), of which six reached P < 5 × 10−8, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.