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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2012-05

AUTHORS

Karol Estrada, Unnur Styrkarsdottir, Evangelos Evangelou, Yi-Hsiang Hsu, Emma L Duncan, Evangelia E Ntzani, Ling Oei, Omar M E Albagha, Najaf Amin, John P Kemp, Daniel L Koller, Guo Li, Ching-Ti 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 J Leo, Gudmar Thorleifsson, Scott G Wilson, James F Wilson, Ville Aalto, Markku Alen, Aaron K Aragaki, Thor Aspelund, Jacqueline R Center, Zoe Dailiana, David J Duggan, Melissa Garcia, Natàlia Garcia-Giralt, Sylvie Giroux, Göran Hallmans, Lynne J Hocking, Lise Bjerre Husted, Karen A Jameson, Rita Khusainova, Ghi Su Kim, Charles Kooperberg, Theodora Koromila, Marcin Kruk, Marika Laaksonen, Andrea Z Lacroix, Seung Hun Lee, Ping C Leung, Joshua R Lewis, Laura Masi, Simona Mencej-Bedrac, Tuan V Nguyen, Xavier Nogues, Millan S Patel, Janez Prezelj, Lynda M Rose, Serena Scollen, Kristin Siggeirsdottir, 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 Karlsson, Elza Khusnutdinova, Jung-Min Koh, Panagoula Kollia, Bente Lomholt Langdahl, William D Leslie, Paul Lips, Östen Ljunggren, Roman S Lorenc, Janja Marc, Dan Mellström, Barbara Obermayer-Pietsch, José M Olmos, Ulrika Pettersson-Kymmer, David M Reid, José A Riancho, Paul M Ridker, François Rousseau, P Eline S lagboom, Nelson L S Tang, Roser Urreizti, Wim Van Hul, Jorma Viikari, María T Zarrabeitia, Yurii S Aulchenko, Martha Castano-Betancourt, Elin Grundberg, Lizbeth Herrera, Thorvaldur Ingvarsson, Hrefna Johannsdottir, Tony Kwan, Rui Li, Robert Luben, Carolina Medina-Gómez, Stefan Th Palsson, Sjur Reppe, Jerome I Rotter, Gunnar Sigurdsson, Joyce B J van Meurs, Dominique 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 M Dennison, Richard Eastell, John A Eisman, Vilmundur Gudnason, Albert Hofman, Rebecca D Jackson, Graeme Jones, J Wouter Jukema, Kay-Tee Khaw, Terho Lehtimäki, Yongmei Liu, Mattias Lorentzon, Eugene 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 Robbins, Philip N Sambrook, Pak Chung Sham, Alan R Shuldiner, Frances A Tylavsky, Cornelia M van Duijn, Nick J Wareham, L Adrienne Cupples, Michael J Econs, David M Evans, Tamara B Harris, Annie Wai Chee Kung, Bruce M Psaty, Jonathan Reeve, Timothy D Spector, Elizabeth A Streeten, M Carola Zillikens, Unnur Thorsteinsdottir, Claes Ohlsson, David Karasik, J Brent Richards, Matthew A Brown, Kari Stefansson, André G Uitterlinden, Stuart H Ralston, John P A Ioannidis, Douglas P Kiel, Fernando Rivadeneira

ABSTRACT

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. More... »

PAGES

491

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  • Journal

    TITLE

    Nature Genetics

    ISSUE

    5

    VOLUME

    44

    Author Affiliations

  • Netherlands Consortium for Healthy Ageing
  • deCODE Genetics (Iceland)
  • University of Ioannina
  • Harvard University
  • Royal Brisbane and Women's Hospital
  • University of Edinburgh
  • Erasmus University Medical Center
  • University of Bristol
  • Indiana University – Purdue University Indianapolis
  • University of Washington
  • Boston University
  • University of Pittsburgh
  • King's College London
  • University of Gothenburg
  • University of Queensland
  • Queen Mary Hospital
  • University of Maryland, Baltimore
  • University of Cambridge
  • Sir Charles Gairdner Hospital
  • University of Turku
  • Fred Hutchinson Cancer Research Center
  • University of Iceland
  • St Vincent's Hospital Sydney
  • University Of Thessaly
  • Translational Genomics Research Institute
  • National Institute on Aging
  • Centre Hospitalier Universitaire de Québec
  • University of Aberdeen
  • Aarhus University Hospital
  • University of Southampton
  • Bashkir State University
  • Asan Medical Center
  • National and Kapodistrian University of Athens
  • Children's Memorial Health Institute
  • University of Helsinki
  • Chinese University of Hong Kong
  • University of Florence
  • University of Ljubljana
  • UNSW Australia
  • University of British Columbia
  • Ljubljana University Medical Centre
  • Brigham and Women's Hospital
  • Icelandic Heart Association
  • Leiden University Medical Center
  • Medical University of Graz
  • VU University Medical Center
  • University of Barcelona
  • University College Cork
  • Kuopio University Hospital
  • Center for Clinical & Basic Research
  • Harokopio University
  • University of Glasgow
  • University of Southern Denmark
  • McGill University
  • Marqués de Valdecilla University Hospital
  • University of Tampere
  • Lund University
  • University of Manitoba
  • Uppsala University
  • Umeå University
  • Université Laval
  • University of Antwerp
  • Turku University Hospital
  • University of Cantabria
  • Wellcome Sanger Institute
  • University of Akureyri
  • McGill University and Génome Québec Innovation Centre
  • Oslo University Hospital
  • Cedars-Sinai Medical Center
  • National University Hospital of Iceland
  • University of Exeter
  • Lovisenberg Diakonale Sykehus
  • McGill University Health Centre
  • Broad Institute
  • California Pacific Medical Center
  • University of Sheffield
  • The Ohio State University
  • University of Tasmania
  • Netherlands Heart Institute
  • Wake Forest University
  • University of Auckland
  • University of California System
  • University of Sydney
  • University of Hong Kong
  • Baltimore VA Medical Center
  • University of Tennessee Health Science Center
  • MRC Centre
  • Group Health Cooperative
  • Stanford University
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/ng.2249

    DOI

    http://dx.doi.org/10.1038/ng.2249

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1052981137

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/22504420


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