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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 Kemp, John P.
Estrada, Karol
Styrkarsdottir, Unnur
Evangelou, Evangelos
Hsu, Yi-Hsiang
Duncan, Emma L.
Ntzani, Evangelia E.
Oei, Ling
Albagha, Omar M. E.
Amin, Najaf
Kemp, John P.
Author
Estrada, Karol
Styrkarsdottir, Unnur
Evangelou, Evangelos
Hsu, Yi-Hsiang
Duncan, Emma L.
Ntzani, Evangelia E.
Oei, Ling
Albagha, Omar M. E.
Amin, Najaf
Kemp, John P.
Koller, Daniel L.
Li, Guo
Liu, Ching-Ti
Minster, Ryan L.
Moayyeri, Alireza
Vandenput, Liesbeth
Willner, Dana
Xiao, Su-Mei
Yerges-Armstrong, Laura M.
Zheng, Hou-Feng
Alonso, Nerea
Eriksson, Joel
Kammerer, Candace M.
Kaptoge, Stephen K.
Leo, Paul J.
Thorleifsson, Gudmar
Wilson, Scott G.
Wilson, James F.
Aalto, Ville
Alen, Markku
Aragaki, Aaron K.
Aspelund, Thor
Center, Jacqueline R.
Dailiana, Zoe
Duggan, David J.
Garcia, Melissa
Garcia-Giralt, Natàlia
Giroux, Sylvie
Hallmans, Göran
Hocking, Lynne J.
Husted, Lise Bjerre
Jameson, Karen A.
Khusainova, Rita
Kim, Ghi Su
Kooperberg, Charles
Koromila, Theodora
Kruk, Marcin
Laaksonen, Marika
Lacroix, Andrea Z.
Lee, Seung Hun
Leung, Ping C.
Lewis, Joshua R.
Masi, Laura
Mencej-Bedrac, Simona
Nguyen, Tuan V.
Nogues, Xavier
Patel, Millan S.
Prezelj, Janez
Rose, Lynda M.
Scollen, Serena
Siggeirsdottir, Kristin
Smith, Albert V.
Svensson, Olle
Trompet, Stella
Trummer, Olivia
van Schoor, Natasja M.
Woo, Jean
Zhu, Kun
Balcells, Susana
Brandi, Maria Luisa
Buckley, Brendan M.
Cheng, Sulin
Christiansen, Claus
Cooper, Cyrus
Dedoussis, George
Ford, Ian
Frost, Morten
Goltzman, David
González-Macías, Jesús
Kähönen, Mika
Karlsson, Magnus
Khusnutdinova, Elza
Koh, Jung-Min
Kollia, Panagoula
Langdahl, Bente Lomholt
Leslie, William D.
Lips, Paul
Ljunggren, Östen
Lorenc, Roman S.
Marc, Janja
Mellström, Dan
Barbara Obermayer-Pietsch
Olmos, José M.
Pettersson-Kymmer, Ulrika
Reid, David M.
Riancho, José A.
Ridker, Paul M.
Rousseau, François
lagboom, P. Eline S.
Tang, Nelson L. S.
Urreizti, Roser
Hul, Wim Van
Viikari, Jorma
Zarrabeitia, María T.
Aulchenko, Yurii S.
Castano-Betancourt, Martha
Grundberg, Elin
Herrera, Lizbeth
Ingvarsson, Thorvaldur
Johannsdottir, Hrefna
Kwan, Tony
Li, Rui
Luben, Robert
Medina-Gómez, Carolina
Palsson, Stefan Th
Reppe, Sjur
Rotter, Jerome I.
Sigurdsson, Gunnar
van Meurs, Joyce B. J.
Verlaan, Dominique
Williams, Frances M. K.
Wood, Andrew R.
Zhou, Yanhua
Gautvik, Kaare M.
Pastinen, Tomi
Raychaudhuri, Soumya
Cauley, Jane A.
Chasman, Daniel I.
Clark, Graeme R.
Cummings, Steven R.
Danoy, Patrick
Dennison, Elaine M.
Eastell, Richard
Eisman, John A.
Gudnason, Vilmundur
Hofman, Albert
Jackson, Rebecca D.
Jones, Graeme
Jukema, J. Wouter
Khaw, Kay-Tee
Lehtimäki, Terho
Liu, Yongmei
Lorentzon, Mattias
McCloskey, Eugene
Mitchell, Braxton D.
Nandakumar, Kannabiran
Nicholson, Geoffrey C.
Oostra, Ben A.
Peacock, Munro
Pols, Huibert A. P.
Prince, Richard L.
Raitakari, Olli
Reid, Ian R.
Robbins, John
Sambrook, Philip N.
Sham, Pak Chung
Shuldiner, Alan R.
Tylavsky, Frances A.
van Duijn, Cornelia M.
Wareham, Nick J.
Cupples, L. Adrienne
Econs, Michael J.
Evans, David M.
Harris, Tamara B.
Kung, Annie Wai Chee
Psaty, Bruce M.
Reeve, Jonathan
Spector, Timothy D.
Streeten, Elizabeth A.
Zillikens, M. Carola
Thorsteinsdottir, Unnur
Ohlsson, Claes
Karasik, David
Richards, J. Brent
Brown, Matthew A.
Stefansson, Kari
Uitterlinden, André G.
Ralston, Stuart H.
Ioannidis, John P. A.
Kiel, Douglas P.
Rivadeneira, Fernando
Styrkarsdottir, Unnur
Evangelou, Evangelos
Hsu, Yi-Hsiang
Duncan, Emma L.
Ntzani, Evangelia E.
Oei, Ling
Albagha, Omar M. E.
Amin, Najaf
Kemp, John P.
Koller, Daniel L.
Li, Guo
Liu, Ching-Ti
Minster, Ryan L.
Moayyeri, Alireza
Vandenput, Liesbeth
Willner, Dana
Xiao, Su-Mei
Yerges-Armstrong, Laura M.
Zheng, Hou-Feng
Alonso, Nerea
Eriksson, Joel
Kammerer, Candace M.
Kaptoge, Stephen K.
Leo, Paul J.
Thorleifsson, Gudmar
Wilson, Scott G.
Wilson, James F.
Aalto, Ville
Alen, Markku
Aragaki, Aaron K.
Aspelund, Thor
Center, Jacqueline R.
Dailiana, Zoe
Duggan, David J.
Garcia, Melissa
Garcia-Giralt, Natàlia
Giroux, Sylvie
Hallmans, Göran
Hocking, Lynne J.
Husted, Lise Bjerre
Jameson, Karen A.
Khusainova, Rita
Kim, Ghi Su
Kooperberg, Charles
Koromila, Theodora
Kruk, Marcin
Laaksonen, Marika
Lacroix, Andrea Z.
Lee, Seung Hun
Leung, Ping C.
Lewis, Joshua R.
Masi, Laura
Mencej-Bedrac, Simona
Nguyen, Tuan V.
Nogues, Xavier
Patel, Millan S.
Prezelj, Janez
Rose, Lynda M.
Scollen, Serena
Siggeirsdottir, Kristin
Smith, Albert V.
Svensson, Olle
Trompet, Stella
Trummer, Olivia
van Schoor, Natasja M.
Woo, Jean
Zhu, Kun
Balcells, Susana
Brandi, Maria Luisa
Buckley, Brendan M.
Cheng, Sulin
Christiansen, Claus
Cooper, Cyrus
Dedoussis, George
Ford, Ian
Frost, Morten
Goltzman, David
González-Macías, Jesús
Kähönen, Mika
Karlsson, Magnus
Khusnutdinova, Elza
Koh, Jung-Min
Kollia, Panagoula
Langdahl, Bente Lomholt
Leslie, William D.
Lips, Paul
Ljunggren, Östen
Lorenc, Roman S.
Marc, Janja
Mellström, Dan
Barbara Obermayer-Pietsch
Olmos, José M.
Pettersson-Kymmer, Ulrika
Reid, David M.
Riancho, José A.
Ridker, Paul M.
Rousseau, François
lagboom, P. Eline S.
Tang, Nelson L. S.
Urreizti, Roser
Hul, Wim Van
Viikari, Jorma
Zarrabeitia, María T.
Aulchenko, Yurii S.
Castano-Betancourt, Martha
Grundberg, Elin
Herrera, Lizbeth
Ingvarsson, Thorvaldur
Johannsdottir, Hrefna
Kwan, Tony
Li, Rui
Luben, Robert
Medina-Gómez, Carolina
Palsson, Stefan Th
Reppe, Sjur
Rotter, Jerome I.
Sigurdsson, Gunnar
van Meurs, Joyce B. J.
Verlaan, Dominique
Williams, Frances M. K.
Wood, Andrew R.
Zhou, Yanhua
Gautvik, Kaare M.
Pastinen, Tomi
Raychaudhuri, Soumya
Cauley, Jane A.
Chasman, Daniel I.
Clark, Graeme R.
Cummings, Steven R.
Danoy, Patrick
Dennison, Elaine M.
Eastell, Richard
Eisman, John A.
Gudnason, Vilmundur
Hofman, Albert
Jackson, Rebecca D.
Jones, Graeme
Jukema, J. Wouter
Khaw, Kay-Tee
Lehtimäki, Terho
Liu, Yongmei
Lorentzon, Mattias
McCloskey, Eugene
Mitchell, Braxton D.
Nandakumar, Kannabiran
Nicholson, Geoffrey C.
Oostra, Ben A.
Peacock, Munro
Pols, Huibert A. P.
Prince, Richard L.
Raitakari, Olli
Reid, Ian R.
Robbins, John
Sambrook, Philip N.
Sham, Pak Chung
Shuldiner, Alan R.
Tylavsky, Frances A.
van Duijn, Cornelia M.
Wareham, Nick J.
Cupples, L. Adrienne
Econs, Michael J.
Evans, David M.
Harris, Tamara B.
Kung, Annie Wai Chee
Psaty, Bruce M.
Reeve, Jonathan
Spector, Timothy D.
Streeten, Elizabeth A.
Zillikens, M. Carola
Thorsteinsdottir, Unnur
Ohlsson, Claes
Karasik, David
Richards, J. Brent
Brown, Matthew A.
Stefansson, Kari
Uitterlinden, André G.
Ralston, Stuart H.
Ioannidis, John P. A.
Kiel, Douglas P.
Rivadeneira, Fernando
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.
Keywords
Date
2012
Type
Journal article
Journal
Nature Genetics
Book
Volume
44
Issue
5
Page Range
491-503
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
Collections
Relation URI
DOI
Source URL
Event URL
Open Access Status
License
All rights reserved
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Controlled