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

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 & 161 others 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, Natalia Garcia-Giralt, Sylvie Giroux, Goran 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, Jesus Gonzalez-Macias, Mika Kahonen, Magnus Karlsson, Elza Khusnutdinova, Jung-Min Koh, Panagoula Kollia, Bente Lomholt Langdahl, William D. Leslie, Paul Lips, Osten Ljunggren, Roman S. Lorenc, Janja Marc, Dan Mellstrom, Barbara Obermayer-Pietsch, Jose M. Olmos, Ulrika Pettersson-Kymmer, David M. Reid, Jose A. Riancho, Paul M. Ridker, Francois Rousseau, P. Eline Slagboom, Nelson L. S. Tang, Roser Urreizti, Wim Van Hul, Jorma Viikari, Maria T. Zarrabeitia, Yurii S. Aulchenko, Martha Castano-Betancourt, Elin Grundberg, Lizbeth Herrera, Thorvaldur Ingvarsson, Hrefna Johannsdottir, Tony Kwan, Rui Li, Robert Luben, Carolina Medina-Gomez, 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 Lehtimaki, 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, Andre G. Uitterlinden, Stuart H. Ralston, John P. A. Ioannidis, Douglas P. Kiel, Fernando Rivadeneira

Research output: Contribution to journalArticle

608 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)491-501
Number of pages11
JournalNature Genetics
Volume44
Issue number5
Early online date15 Apr 2012
DOIs
Publication statusPublished - May 2012

Keywords

  • osteoporotic fractures
  • gene-expression
  • imputed data
  • variants
  • disease
  • women
  • LRP5
  • population
  • imputation
  • patterns

Cite this

Estrada, K., Styrkarsdottir, U., Evangelou, E., Hsu, Y-H., Duncan, E. L., Ntzani, E. E., ... Rivadeneira, F. (2012). Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nature Genetics, 44(5), 491-501. https://doi.org/10.1038/ng.2249

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, Natalia; Giroux, Sylvie; Hallmans, Goran; 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; Gonzalez-Macias, Jesus; Kahonen, Mika; Karlsson, Magnus; Khusnutdinova, Elza; Koh, Jung-Min; Kollia, Panagoula; Langdahl, Bente Lomholt; Leslie, William D.; Lips, Paul; Ljunggren, Osten; Lorenc, Roman S.; Marc, Janja; Mellstrom, Dan; Obermayer-Pietsch, Barbara; Olmos, Jose M.; Pettersson-Kymmer, Ulrika; Reid, David M.; Riancho, Jose A.; Ridker, Paul M.; Rousseau, Francois; Slagboom, P. Eline; Tang, Nelson L. S.; Urreizti, Roser; Van Hul, Wim; Viikari, Jorma; Zarrabeitia, Maria T.; Aulchenko, Yurii S.; Castano-Betancourt, Martha; Grundberg, Elin; Herrera, Lizbeth; Ingvarsson, Thorvaldur; Johannsdottir, Hrefna; Kwan, Tony; Li, Rui; Luben, Robert; Medina-Gomez, 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; Lehtimaki, 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, Andre G.; Ralston, Stuart H.; Ioannidis, John P. A.; Kiel, Douglas P.; Rivadeneira, Fernando.

In: Nature Genetics, Vol. 44, No. 5, 05.2012, p. 491-501.

Research output: Contribution to journalArticle

Estrada, K, Styrkarsdottir, U, Evangelou, E, Hsu, Y-H, Duncan, EL, Ntzani, EE, Oei, L, Albagha, OME, Amin, N, Kemp, JP, Koller, DL, Li, G, Liu, C-T, Minster, RL, Moayyeri, A, Vandenput, L, Willner, D, Xiao, S-M, Yerges-Armstrong, LM, Zheng, H-F, Alonso, N, Eriksson, J, Kammerer, CM, Kaptoge, SK, Leo, PJ, Thorleifsson, G, Wilson, SG, Wilson, JF, Aalto, V, Alen, M, Aragaki, AK, Aspelund, T, Center, JR, Dailiana, Z, Duggan, DJ, Garcia, M, Garcia-Giralt, N, Giroux, S, Hallmans, G, Hocking, LJ, Husted, LB, Jameson, KA, Khusainova, R, Kim, GS, Kooperberg, C, Koromila, T, Kruk, M, Laaksonen, M, Lacroix, AZ, Lee, SH, Leung, PC, Lewis, JR, Masi, L, Mencej-Bedrac, S, Nguyen, TV, Nogues, X, Patel, MS, Prezelj, J, Rose, LM, Scollen, S, Siggeirsdottir, K, Smith, AV, Svensson, O, Trompet, S, Trummer, O, van Schoor, NM, Woo, J, Zhu, K, Balcells, S, Brandi, ML, Buckley, BM, Cheng, S, Christiansen, C, Cooper, C, Dedoussis, G, Ford, I, Frost, M, Goltzman, D, Gonzalez-Macias, J, Kahonen, M, Karlsson, M, Khusnutdinova, E, Koh, J-M, Kollia, P, Langdahl, BL, Leslie, WD, Lips, P, Ljunggren, O, Lorenc, RS, Marc, J, Mellstrom, D, Obermayer-Pietsch, B, Olmos, JM, Pettersson-Kymmer, U, Reid, DM, Riancho, JA, Ridker, PM, Rousseau, F, Slagboom, PE, Tang, NLS, Urreizti, R, Van Hul, W, Viikari, J, Zarrabeitia, MT, Aulchenko, YS, Castano-Betancourt, M, Grundberg, E, Herrera, L, Ingvarsson, T, Johannsdottir, H, Kwan, T, Li, R, Luben, R, Medina-Gomez, C, Palsson, ST, Reppe, S, Rotter, JI, Sigurdsson, G, van Meurs, JBJ, Verlaan, D, Williams, FMK, Wood, AR, Zhou, Y, Gautvik, KM, Pastinen, T, Raychaudhuri, S, Cauley, JA, Chasman, DI, Clark, GR, Cummings, SR, Danoy, P, Dennison, EM, Eastell, R, Eisman, JA, Gudnason, V, Hofman, A, Jackson, RD, Jones, G, Jukema, JW, Khaw, K-T, Lehtimaki, T, Liu, Y, Lorentzon, M, McCloskey, E, Mitchell, BD, Nandakumar, K, Nicholson, GC, Oostra, BA, Peacock, M, Pols, HAP, Prince, RL, Raitakari, O, Reid, IR, Robbins, J, Sambrook, PN, Sham, PC, Shuldiner, AR, Tylavsky, FA, van Duijn, CM, Wareham, NJ, Cupples, LA, Econs, MJ, Evans, DM, Harris, TB, Kung, AWC, Psaty, BM, Reeve, J, Spector, TD, Streeten, EA, Zillikens, MC, Thorsteinsdottir, U, Ohlsson, C, Karasik, D, Richards, JB, Brown, MA, Stefansson, K, Uitterlinden, AG, Ralston, SH, Ioannidis, JPA, Kiel, DP & Rivadeneira, F 2012, 'Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture', Nature Genetics, vol. 44, no. 5, pp. 491-501. https://doi.org/10.1038/ng.2249
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, Natalia ; Giroux, Sylvie ; Hallmans, Goran ; 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 ; Gonzalez-Macias, Jesus ; Kahonen, Mika ; Karlsson, Magnus ; Khusnutdinova, Elza ; Koh, Jung-Min ; Kollia, Panagoula ; Langdahl, Bente Lomholt ; Leslie, William D. ; Lips, Paul ; Ljunggren, Osten ; Lorenc, Roman S. ; Marc, Janja ; Mellstrom, Dan ; Obermayer-Pietsch, Barbara ; Olmos, Jose M. ; Pettersson-Kymmer, Ulrika ; Reid, David M. ; Riancho, Jose A. ; Ridker, Paul M. ; Rousseau, Francois ; Slagboom, P. Eline ; Tang, Nelson L. S. ; Urreizti, Roser ; Van Hul, Wim ; Viikari, Jorma ; Zarrabeitia, Maria T. ; Aulchenko, Yurii S. ; Castano-Betancourt, Martha ; Grundberg, Elin ; Herrera, Lizbeth ; Ingvarsson, Thorvaldur ; Johannsdottir, Hrefna ; Kwan, Tony ; Li, Rui ; Luben, Robert ; Medina-Gomez, 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 ; Lehtimaki, 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, Andre G. ; Ralston, Stuart H. ; Ioannidis, John P. A. ; Kiel, Douglas P. ; Rivadeneira, Fernando. / Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. In: Nature Genetics. 2012 ; Vol. 44, No. 5. pp. 491-501.
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title = "Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture",
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. 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.",
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author = "Karol Estrada and Unnur Styrkarsdottir and Evangelos Evangelou and Yi-Hsiang Hsu and Duncan, {Emma L.} and Ntzani, {Evangelia E.} and Ling Oei and Albagha, {Omar M. E.} and Najaf Amin and Kemp, {John P.} and Koller, {Daniel L.} and Guo Li and Ching-Ti Liu and Minster, {Ryan L.} and Alireza Moayyeri and Liesbeth Vandenput and Dana Willner and Su-Mei Xiao and Yerges-Armstrong, {Laura M.} and Hou-Feng Zheng and Nerea Alonso and Joel Eriksson and Kammerer, {Candace M.} and Kaptoge, {Stephen K.} and Leo, {Paul J.} and Gudmar Thorleifsson and Wilson, {Scott G.} and Wilson, {James F.} and Ville Aalto and Markku Alen and Aragaki, {Aaron K.} and Thor Aspelund and Center, {Jacqueline R.} and Zoe Dailiana and Duggan, {David J.} and Melissa Garcia and Natalia Garcia-Giralt and Sylvie Giroux and Goran Hallmans and Hocking, {Lynne J.} and Husted, {Lise Bjerre} and Jameson, {Karen A.} and Rita Khusainova and Kim, {Ghi Su} and Charles Kooperberg and Theodora Koromila and Marcin Kruk and Marika Laaksonen and Lacroix, {Andrea Z.} and Lee, {Seung Hun} and Leung, {Ping C.} and Lewis, {Joshua R.} and Laura Masi and Simona Mencej-Bedrac and Nguyen, {Tuan V.} and Xavier Nogues and Patel, {Millan S.} and Janez Prezelj and Rose, {Lynda M.} and Serena Scollen and Kristin Siggeirsdottir and Smith, {Albert V.} and Olle Svensson and Stella Trompet and Olivia Trummer and {van Schoor}, {Natasja M.} and Jean Woo and Kun Zhu and Susana Balcells and Brandi, {Maria Luisa} and Buckley, {Brendan M.} and Sulin Cheng and Claus Christiansen and Cyrus Cooper and George Dedoussis and Ian Ford and Morten Frost and David Goltzman and Jesus Gonzalez-Macias and Mika Kahonen and Magnus Karlsson and Elza Khusnutdinova and Jung-Min Koh and Panagoula Kollia and Langdahl, {Bente Lomholt} and Leslie, {William D.} and Paul Lips and Osten Ljunggren and Lorenc, {Roman S.} and Janja Marc and Dan Mellstrom and Barbara Obermayer-Pietsch and Olmos, {Jose M.} and Ulrika Pettersson-Kymmer and Reid, {David M.} and Riancho, {Jose A.} and Ridker, {Paul M.} and Francois Rousseau and Slagboom, {P. Eline} and Tang, {Nelson L. S.} and Roser Urreizti and {Van Hul}, Wim and Jorma Viikari and Zarrabeitia, {Maria T.} and Aulchenko, {Yurii S.} and Martha Castano-Betancourt and Elin Grundberg and Lizbeth Herrera and Thorvaldur Ingvarsson and Hrefna Johannsdottir and Tony Kwan and Rui Li and Robert Luben and Carolina Medina-Gomez and Palsson, {Stefan Th} and Sjur Reppe and Rotter, {Jerome I.} and Gunnar Sigurdsson and {van Meurs}, {Joyce B. J.} and Dominique Verlaan and Williams, {Frances M. K.} and Wood, {Andrew R.} and Yanhua Zhou and Gautvik, {Kaare M.} and Tomi Pastinen and Soumya Raychaudhuri and Cauley, {Jane A.} and Chasman, {Daniel I.} and Clark, {Graeme R.} and Cummings, {Steven R.} and Patrick Danoy and Dennison, {Elaine M.} and Richard Eastell and Eisman, {John A.} and Vilmundur Gudnason and Albert Hofman and Jackson, {Rebecca D.} and Graeme Jones and Jukema, {J. Wouter} and Kay-Tee Khaw and Terho Lehtimaki and Yongmei Liu and Mattias Lorentzon and Eugene McCloskey and Mitchell, {Braxton D.} and Kannabiran Nandakumar and Nicholson, {Geoffrey C.} and Oostra, {Ben A.} and Munro Peacock and Pols, {Huibert A. P.} and Prince, {Richard L.} and Olli Raitakari and Reid, {Ian R.} and John Robbins 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 Jonathan Reeve and Spector, {Timothy D.} and Streeten, {Elizabeth A.} and Zillikens, {M. Carola} and Unnur Thorsteinsdottir and Claes Ohlsson and David Karasik and Richards, {J. Brent} and Brown, {Matthew A.} and Kari Stefansson and Uitterlinden, {Andre G.} and Ralston, {Stuart H.} and Ioannidis, {John P. A.} and Kiel, {Douglas P.} and Fernando Rivadeneira",
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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, Natalia

AU - Giroux, Sylvie

AU - Hallmans, Goran

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 - Gonzalez-Macias, Jesus

AU - Kahonen, Mika

AU - Karlsson, Magnus

AU - Khusnutdinova, Elza

AU - Koh, Jung-Min

AU - Kollia, Panagoula

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AU - Grundberg, Elin

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AU - Kwan, Tony

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AU - Luben, Robert

AU - Medina-Gomez, Carolina

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AU - Reppe, Sjur

AU - Rotter, Jerome I.

AU - Sigurdsson, Gunnar

AU - van Meurs, Joyce B. J.

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AU - Williams, Frances M. K.

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AU - Zhou, Yanhua

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AU - Pastinen, Tomi

AU - Raychaudhuri, Soumya

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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.

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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

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AU - Ralston, Stuart H.

AU - Ioannidis, John P. A.

AU - Kiel, Douglas P.

AU - Rivadeneira, Fernando

PY - 2012/5

Y1 - 2012/5

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 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.

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 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.

KW - osteoporotic fractures

KW - gene-expression

KW - imputed data

KW - variants

KW - disease

KW - women

KW - LRP5

KW - population

KW - imputation

KW - patterns

U2 - 10.1038/ng.2249

DO - 10.1038/ng.2249

M3 - Article

VL - 44

SP - 491

EP - 501

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 5

ER -