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

Estrada, Karol; Styrkarsdottir, Unnur; Evangelou, Evangelos; Hsu, Yi-Hsiang; Duncan, Emma L.; Ntzani, Evangelia E.; Oei, Ling; Albagha, Omar M. E.; Amin, Najaf and Kemp, John P., et al. (2012) In Nature Genetics 44(5). p.491-491
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 x 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways.... (More)
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 x 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 x 10(-4), Bonferroni corrected), of which six reached P < 5 x 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. (Less)
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Nature Genetics
volume
44
issue
5
pages
491 - 491
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Nature Publishing Group
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  • wos:000303416300007
  • scopus:84860331458
ISSN
1546-1718
DOI
10.1038/ng.2249
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English
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2012-07-03 10:24:37
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2017-11-12 03:50:07
@article{9dc40d40-ba91-4bb7-af5b-36be7f6d81ae,
  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 &lt; 5 x 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 &lt; 5 x 10(-4), Bonferroni corrected), of which six reached P &lt; 5 x 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.},
  author       = {Estrada, Karol and Styrkarsdottir, Unnur and Evangelou, Evangelos and Hsu, Yi-Hsiang and Duncan, Emma L. and Ntzani, Evangelia E. and Oei, Ling and Albagha, Omar M. E. and Amin, Najaf and Kemp, John P. and Koller, Daniel L. and Li, Guo and Liu, Ching-Ti and Minster, Ryan L. and Moayyeri, Alireza and Vandenput, Liesbeth and Willner, Dana and Xiao, Su-Mei and Yerges-Armstrong, Laura M. and Zheng, Hou-Feng and Alonso, Nerea and Eriksson, Joel and Kammerer, Candace M. and Kaptoge, Stephen K. and Leo, Paul J. and Thorleifsson, Gudmar and Wilson, Scott G. and Wilson, James F. and Aalto, Ville and Alen, Markku and Aragaki, Aaron K. and Aspelund, Thor and Center, Jacqueline R. and Dailiana, Zoe and Duggan, David J. and Garcia, Melissa and Garcia-Giralt, Natalia and Giroux, Sylvie and Hallmans, Goran and Hocking, Lynne J. and Husted, Lise Bjerre and Jameson, Karen A. and Khusainova, Rita and Kim, Ghi Su and Kooperberg, Charles and Koromila, Theodora and Kruk, Marcin and Laaksonen, Marika and Lacroix, Andrea Z. and Lee, Seung Hun and Leung, Ping C. and Lewis, Joshua R. and Masi, Laura and Mencej-Bedrac, Simona and Nguyen, Tuan V. and Nogues, Xavier and Patel, Millan S. and Prezelj, Janez and Rose, Lynda M. and Scollen, Serena and Siggeirsdottir, Kristin and Smith, Albert V. and Svensson, Olle and Trompet, Stella and Trummer, Olivia and van Schoor, Natasja M. and Woo, Jean and Zhu, Kun and Balcells, Susana and Brandi, Maria Luisa and Buckley, Brendan M. and Cheng, Sulin and Christiansen, Claus and Cooper, Cyrus and Dedoussis, George and Ford, Ian and Frost, Morten and Goltzman, David and Gonzalez-Macias, Jesus and Kahonen, Mika and Karlsson, Magnus and Khusnutdinova, Elza and Koh, Jung-Min and Kollia, Panagoula and Langdahl, Bente Lomholt and Leslie, William D. and Lips, Paul and Ljunggren, Osten and Lorenc, Roman S. and Marc, Janja and Mellstrom, Dan and Obermayer-Pietsch, Barbara and Olmos, Jose M. and Pettersson-Kymmer, Ulrika and Reid, David M. and Riancho, Jose A. and Ridker, Paul M. and Rousseau, Francois and Slagboom, P. Eline and Tang, Nelson L. S. and Urreizti, Roser and Van Hul, Wim and Viikari, Jorma and Zarrabeitia, Maria T. and Aulchenko, Yurii S. and Castano-Betancourt, Martha and Grundberg, Elin and Herrera, Lizbeth and Ingvarsson, Thorvaldur and Johannsdottir, Hrefna and Kwan, Tony and Li, Rui and Luben, Robert and Medina-Gomez, Carolina and Palsson, Stefan Th and Reppe, Sjur and Rotter, Jerome I. and Sigurdsson, Gunnar and van Meurs, Joyce B. J. and Verlaan, Dominique and Williams, Frances M. K. and Wood, Andrew R. and Zhou, Yanhua and Gautvik, Kaare M. and Pastinen, Tomi and Raychaudhuri, Soumya and Cauley, Jane A. and Chasman, Daniel I. and Clark, Graeme R. and Cummings, Steven R. and Danoy, Patrick and Dennison, Elaine M. and Eastell, Richard and Eisman, John A. and Gudnason, Vilmundur and Hofman, Albert and Jackson, Rebecca D. and Jones, Graeme and Jukema, J. Wouter and Khaw, Kay-Tee and Lehtimaki, Terho and Liu, Yongmei and Lorentzon, Mattias and McCloskey, Eugene and Mitchell, Braxton D. and Nandakumar, Kannabiran and Nicholson, Geoffrey C. and Oostra, Ben A. and Peacock, Munro and Pols, Huibert A. P. and Prince, Richard L. and Raitakari, Olli and Reid, Ian R. and Robbins, John and Sambrook, Philip N. and Sham, Pak Chung and Shuldiner, Alan R. and Tylavsky, Frances A. and van Duijn, Cornelia M. and Wareham, Nick J. and Cupples, L. Adrienne and Econs, Michael J. and Evans, David M. and Harris, Tamara B. and Kung, Annie Wai Chee and Psaty, Bruce M. and Reeve, Jonathan and Spector, Timothy D. and Streeten, Elizabeth A. and Zillikens, M. Carola and Thorsteinsdottir, Unnur and Ohlsson, Claes and Karasik, David and Richards, J. Brent and Brown, Matthew A. and Stefansson, Kari and Uitterlinden, Andre G. and Ralston, Stuart H. and Ioannidis, John P. A. and Kiel, Douglas P. and Rivadeneira, Fernando},
  issn         = {1546-1718},
  language     = {eng},
  number       = {5},
  pages        = {491--491},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture},
  url          = {http://dx.doi.org/10.1038/ng.2249},
  volume       = {44},
  year         = {2012},
}