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.
| Original language | English |
|---|---|
| Pages (from-to) | 491-501 |
| Number of pages | 11 |
| Journal | Nature Genetics |
| Volume | 44 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 1 May 2012 |
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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.; 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, Østen; Lorenc, Roman S.; Marc, Janja; Mellström, Dan; Obermayer-Pietsch, Barbara; 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; Van Hul, Wim; 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; Th Palsson, Stefan; 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.
In: Nature Genetics, Vol. 44, No. 5, 01.05.2012, p. 491-501.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture
AU - Estrada, Karol
AU - Styrkarsdottir, Unnur
AU - Evangelou, Evangelos
AU - Hsu, Yi Hsiang
AU - Duncan, Emma L.
AU - Ntzani, Evangelia E.
AU - Oei, Ling
AU - Albagha, Omar M.E.
AU - Amin, Najaf
AU - Kemp, John P.
AU - Koller, Daniel L.
AU - Li, Guo
AU - Liu, Ching Ti
AU - Minster, Ryan L.
AU - Moayyeri, Alireza
AU - Vandenput, Liesbeth
AU - Willner, Dana
AU - Xiao, Su Mei
AU - Yerges-Armstrong, Laura M.
AU - Zheng, Hou Feng
AU - Alonso, Nerea
AU - Eriksson, Joel
AU - Kammerer, Candace M.
AU - Kaptoge, Stephen K.
AU - Leo, Paul J.
AU - Thorleifsson, Gudmar
AU - Wilson, Scott G.
AU - Wilson, James F.
AU - Aalto, Ville
AU - Alen, Markku
AU - Aragaki, Aaron K.
AU - Aspelund, Thor
AU - Center, Jacqueline R.
AU - Dailiana, Zoe
AU - Duggan, David J.
AU - Garcia, Melissa
AU - Garcia-Giralt, Natàlia
AU - Giroux, Sylvie
AU - Hallmans, Göran
AU - Hocking, Lynne J.
AU - Husted, Lise Bjerre
AU - Jameson, Karen A.
AU - Khusainova, Rita
AU - Kim, Ghi Su
AU - Kooperberg, Charles
AU - Koromila, Theodora
AU - Kruk, Marcin
AU - Laaksonen, Marika
AU - Lacroix, Andrea Z.
AU - Lee, Seung Hun
AU - Leung, Ping C.
AU - Lewis, Joshua R.
AU - Masi, Laura
AU - Mencej-Bedrac, Simona
AU - Nguyen, Tuan V.
AU - Nogues, Xavier
AU - Patel, Millan S.
AU - Prezelj, Janez
AU - Rose, Lynda M.
AU - Scollen, Serena
AU - Siggeirsdottir, Kristin
AU - Smith, Albert V.
AU - Svensson, Olle
AU - Trompet, Stella
AU - Trummer, Olivia
AU - Van Schoor, Natasja M.
AU - Woo, Jean
AU - Zhu, Kun
AU - Balcells, Susana
AU - Brandi, Maria Luisa
AU - Buckley, Brendan M.
AU - Cheng, Sulin
AU - Christiansen, Claus
AU - Cooper, Cyrus
AU - Dedoussis, George
AU - Ford, Ian
AU - Frost, Morten
AU - Goltzman, David
AU - González-Macías, Jesús
AU - Kähönen, Mika
AU - Karlsson, Magnus
AU - Khusnutdinova, Elza
AU - Koh, Jung Min
AU - Kollia, Panagoula
AU - Langdahl, Bente Lomholt
AU - Leslie, William D.
AU - Lips, Paul
AU - Ljunggren, Østen
AU - Lorenc, Roman S.
AU - Marc, Janja
AU - Mellström, Dan
AU - Obermayer-Pietsch, Barbara
AU - Olmos, José M.
AU - Pettersson-Kymmer, Ulrika
AU - Reid, David M.
AU - Riancho, José A.
AU - Ridker, Paul M.
AU - Rousseau, François
AU - Lagboom, P. Eline S.
AU - Tang, Nelson L.S.
AU - Urreizti, Roser
AU - Van Hul, Wim
AU - Viikari, Jorma
AU - Zarrabeitia, María T.
AU - Aulchenko, Yurii S.
AU - Castano-Betancourt, Martha
AU - Grundberg, Elin
AU - Herrera, Lizbeth
AU - Ingvarsson, Thorvaldur
AU - Johannsdottir, Hrefna
AU - Kwan, Tony
AU - Li, Rui
AU - Luben, Robert
AU - Medina-Gómez, Carolina
AU - Th Palsson, Stefan
AU - Reppe, Sjur
AU - Rotter, Jerome I.
AU - Sigurdsson, Gunnar
AU - Van Meurs, Joyce B.J.
AU - Verlaan, Dominique
AU - Williams, Frances M.K.
AU - Wood, Andrew R.
AU - Zhou, Yanhua
AU - Gautvik, Kaare M.
AU - Pastinen, Tomi
AU - Raychaudhuri, Soumya
AU - Cauley, Jane A.
AU - Chasman, Daniel I.
AU - Clark, Graeme R.
AU - Cummings, Steven R.
AU - Danoy, Patrick
AU - Dennison, Elaine M.
AU - Eastell, Richard
AU - Eisman, John A.
AU - Gudnason, Vilmundur
AU - Hofman, Albert
AU - Jackson, Rebecca D.
AU - Jones, Graeme
AU - Jukema, J. Wouter
AU - Khaw, Kay Tee
AU - Lehtimäki, Terho
AU - Liu, Yongmei
AU - Lorentzon, Mattias
AU - Mccloskey, Eugene
AU - Mitchell, Braxton D.
AU - Nandakumar, Kannabiran
AU - Nicholson, Geoffrey C.
AU - Oostra, Ben A.
AU - Peacock, Munro
AU - Pols, Huibert A.P.
AU - Prince, Richard L.
AU - Raitakari, Olli
AU - Reid, Ian R.
AU - Robbins, John
AU - Sambrook, Philip N.
AU - Sham, Pak Chung
AU - Shuldiner, Alan R.
AU - Tylavsky, Frances A.
AU - Van Duijn, Cornelia M.
AU - Wareham, Nick J.
AU - Cupples, L. Adrienne
AU - Econs, Michael J.
AU - Evans, David M.
AU - Harris, Tamara B.
AU - Kung, Annie Wai Chee
AU - Psaty, Bruce M.
AU - Reeve, Jonathan
AU - Spector, Timothy D.
AU - Streeten, Elizabeth A.
AU - Zillikens, M. Carola
AU - Thorsteinsdottir, Unnur
AU - Ohlsson, Claes
AU - Karasik, David
AU - Richards, J. Brent
AU - Brown, Matthew A.
AU - Stefansson, Kari
AU - Uitterlinden, André G.
AU - Ralston, Stuart H.
AU - Ioannidis, John P.A.
AU - Kiel, Douglas P.
AU - Rivadeneira, Fernando
PY - 2012/5/1
Y1 - 2012/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84860331458&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84860331458&partnerID=8YFLogxK
U2 - 10.1038/ng.2249
DO - 10.1038/ng.2249
M3 - Article
C2 - 22504420
AN - SCOPUS:84860331458
VL - 44
SP - 491
EP - 501
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 5
ER -