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1. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

Author

Zheng, H.-F. (Hou-Feng), Forgetta, V. (Vincenzo), Hsu, Y.-H. (Yi-Hsiang), Estrada Gil, K. (Karol), Rosello-Diez, A. (Alberto), Leo, P.J. (Paul), Dahia, C.L. (Chitra L.), Park-Min, K.H. (Kyung Hyun), Tobias, J.H. (Jon), Kooperberg, C. (Charles), Kleinman, A. (Aaron), Styrkarsdottir, U. (Unnur), Liu, C.-T. (Ching-Ti), Uggla, C. (Charlotta), Evans, D.S. (Daniel), Nielson, C. (Carrie), Walter, K. (Klaudia), Pettersson-Kymmer, U. (Ulrika), McCarthy, S. (Shane), Eriksson, J. (Joel), Kwan, T. (Tony), Jhamai, M. (Mila), Trajanoska, K. (Katerina), Memari, Y. (Yasin), Min, J.L. (Josine L.), Huang, J. (Jie), Danecek, P. (Petr), Wilmot, B. (Beth), Li, R. (Rui), Chou, W.-C. (Wen-Chi), Mokry, L.E. (Lauren E.), Moayyeri, A. (Alireza), Claussnitzer, M. (Melina), Cheng, C.-H. (Chia-Ho), Cheung, W. (Warren), Medina-Gomez, M.C. (Carolina), Ge, B. (Bing), Chen, S.-H. (Shu-Huang), Choi, K. (Kunho), Oei, L. (Ling), Fraser, J. (James), Kraaij, R. (Robert), Hibbs, M.A. (Matthew A.), Gregson, C.L. (Celia L.), Paquette, D. (Denis), Hofman, A. (Albert), Wibom, C. (Carl), Tranah, G.J. (Gregory), Marshall, M. (Mhairi), Gardiner, B.B. (Brooke B.), Cremin, K. (Katie), Auer, P. (Paul), Hsu, L. (Li), Ring, S. (Susan), Tung, J.Y. (Joyce Y.), Thorleifsson, G. (Gudmar), Enneman, A.W. (Anke), Schoor, N.M. (Natasja) van, Groot, L.C.P.G.M. (Lisette) de, Velde, N. (Nathalie) van der, Melin, B. (Beatrice), Kemp, J.P. (John), Christiansen, C., Sayers, I. (Ian), Zhou, Y. (Yanhua), Calderari, S. (Sophie), Rooij, J.G.J. (Jeroen) van, Carlson, C. (Chris), Peters, U. (Ulrike), Berlivet, S. (Soizik), Dostie, J. (Josée), Uitterlinden, A.G. (André), Williams, S.R. (Stephen R.), Farber, C. (Charles), Grinberg, D. (Daniel), LaCroix, A.Z. (Andrea), Haessler, J. (Jeff), Chasman, D.I. (Daniel), Giulianini, F. (Franco), Rose, L.M. (Lynda M.), Ridker, P.M. (Paul), Eisman, J.A. (John), Nguyen, T.V. (Tuan), Center, J.R. (Jacqueline), Nogues, X. (Xavier), Garcia-Giralt, N. (Natàlia), Launer, L.J. (Lenore), Gudnason, V. (Vilmunder), Mellström, D. (Dan), Vandenput, L. (Liesbeth), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Karlsson, M. (Magnus), Ljunggren, O. (Östen), Svensson, O. (Olle), Hallmans, G. (Göran), Rousseau, M.F. (Francois), Giroux, S. (Sylvie), Bussière, J. (Johanne), Arp, P.P. (Pascal), Koromani, F. (Fjorda), Prince, R.L. (Richard L.), Lewis, J.R. (Joshua), Langdahl, B.L. (Bente), Hermann, A.P. (A. Pernille), Jensen, J.-E.B. (Jens-Erik B.), Kaptoge, S. (Stephen), Khaw, K.T., Reeve, J. (Jonathan), Formosa, M.M. (Melissa M.), Xuereb-Anastasi, A. (Angela), Åkesson, K. (Kristina), McGuigan, F.E., Garg, G. (Gaurav), Olmos, D. (David), Zarrabeitia, M.T. (María), Riancho, J.A. (José), Ralston, S.H. (Stuart), Alonso, N. (Nerea), Jiang, X. (Xi), Goltzman, D. (David), Pastinen, T. (Tomi), Grundberg, E. (Elin), Gauguier, D. (Dominique), Orwoll, E.S. (Eric), Karasik, D. (David), Smith, A.V. (Davey), Siggeirsdottir, K. (Kristin), Harris, T.B. (Tamara), Zillikens, M.C. (Carola), Meurs, J.B.J. (Joyce) van, Thorsteinsdottir, U. (Unnur), Maurano, M.T. (Matthew T.), Timpson, N.J. (Nicholas), Soranzo, N. (Nicole), Durbin, R. (Richard), Wilson, S.G. (Scott), Ntzani, E.E. (Evangelia), Brown, M.A. (Matthew), Zwart, J-A. (John-Anker), Hinds, D.A. (David A.), Spector, T.D. (Timothy), Cupples, L.A. (Adrienne), Ohlsson, C. (Claes), Greenwood, C.M.T. (Celia), Jackson, R.D. (Rebecca), Rowe, D.W. (David W.), Loomis, C.A. (Cynthia A.), Evans, D.M. (David M.), Ackert-Bicknell, C.L. (Cheryl), Joyner, A.L. (Alexandra L.), Duncan, E.L. (Emma), Kiel, D.P. (Douglas P.), Rivadeneira Ramirez, F. (Fernando), Richards, J.B. (Brent), Zheng, H.-F. (Hou-Feng), Forgetta, V. (Vincenzo), Hsu, Y.-H. (Yi-Hsiang), Estrada Gil, K. (Karol), Rosello-Diez, A. (Alberto), Leo, P.J. (Paul), Dahia, C.L. (Chitra L.), Park-Min, K.H. (Kyung Hyun), Tobias, J.H. (Jon), Kooperberg, C. (Charles), Kleinman, A. (Aaron), Styrkarsdottir, U. (Unnur), Liu, C.-T. (Ching-Ti), Uggla, C. (Charlotta), Evans, D.S. (Daniel), Nielson, C. (Carrie), Walter, K. (Klaudia), Pettersson-Kymmer, U. (Ulrika), McCarthy, S. (Shane), Eriksson, J. (Joel), Kwan, T. (Tony), Jhamai, M. (Mila), Trajanoska, K. (Katerina), Memari, Y. (Yasin), Min, J.L. (Josine L.), Huang, J. (Jie), Danecek, P. (Petr), Wilmot, B. (Beth), Li, R. (Rui), Chou, W.-C. (Wen-Chi), Mokry, L.E. (Lauren E.), Moayyeri, A. (Alireza), Claussnitzer, M. (Melina), Cheng, C.-H. (Chia-Ho), Cheung, W. (Warren), Medina-Gomez, M.C. (Carolina), Ge, B. (Bing), Chen, S.-H. (Shu-Huang), Choi, K. (Kunho), Oei, L. (Ling), Fraser, J. (James), Kraaij, R. (Robert), Hibbs, M.A. (Matthew A.), Gregson, C.L. (Celia L.), Paquette, D. (Denis), Hofman, A. (Albert), Wibom, C. (Carl), Tranah, G.J. (Gregory), Marshall, M. (Mhairi), Gardiner, B.B. (Brooke B.), Cremin, K. (Katie), Auer, P. (Paul), Hsu, L. (Li), Ring, S. (Susan), Tung, J.Y. (Joyce Y.), Thorleifsson, G. (Gudmar), Enneman, A.W. (Anke), Schoor, N.M. (Natasja) van, Groot, L.C.P.G.M. (Lisette) de, Velde, N. (Nathalie) van der, Melin, B. (Beatrice), Kemp, J.P. (John), Christiansen, C., Sayers, I. (Ian), Zhou, Y. (Yanhua), Calderari, S. (Sophie), Rooij, J.G.J. (Jeroen) van, Carlson, C. (Chris), Peters, U. (Ulrike), Berlivet, S. (Soizik), Dostie, J. (Josée), Uitterlinden, A.G. (André), Williams, S.R. (Stephen R.), Farber, C. (Charles), Grinberg, D. (Daniel), LaCroix, A.Z. (Andrea), Haessler, J. (Jeff), Chasman, D.I. (Daniel), Giulianini, F. (Franco), Rose, L.M. (Lynda M.), Ridker, P.M. (Paul), Eisman, J.A. (John), Nguyen, T.V. (Tuan), Center, J.R. (Jacqueline), Nogues, X. (Xavier), Garcia-Giralt, N. (Natàlia), Launer, L.J. (Lenore), Gudnason, V. (Vilmunder), Mellström, D. (Dan), Vandenput, L. (Liesbeth), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Karlsson, M. (Magnus), Ljunggren, O. (Östen), Svensson, O. (Olle), Hallmans, G. (Göran), Rousseau, M.F. (Francois), Giroux, S. (Sylvie), Bussière, J. (Johanne), Arp, P.P. (Pascal), Koromani, F. (Fjorda), Prince, R.L. (Richard L.), Lewis, J.R. (Joshua), Langdahl, B.L. (Bente), Hermann, A.P. (A. Pernille), Jensen, J.-E.B. (Jens-Erik B.), Kaptoge, S. (Stephen), Khaw, K.T., Reeve, J. (Jonathan), Formosa, M.M. (Melissa M.), Xuereb-Anastasi, A. (Angela), Åkesson, K. (Kristina), McGuigan, F.E., Garg, G. (Gaurav), Olmos, D. (David), Zarrabeitia, M.T. (María), Riancho, J.A. (José), Ralston, S.H. (Stuart), Alonso, N. (Nerea), Jiang, X. (Xi), Goltzman, D. (David), Pastinen, T. (Tomi), Grundberg, E. (Elin), Gauguier, D. (Dominique), Orwoll, E.S. (Eric), Karasik, D. (David), Smith, A.V. (Davey), Siggeirsdottir, K. (Kristin), Harris, T.B. (Tamara), Zillikens, M.C. (Carola), Meurs, J.B.J. (Joyce) van, Thorsteinsdottir, U. (Unnur), Maurano, M.T. (Matthew T.), Timpson, N.J. (Nicholas), Soranzo, N. (Nicole), Durbin, R. (Richard), Wilson, S.G. (Scott), Ntzani, E.E. (Evangelia), Brown, M.A. (Matthew), Zwart, J-A. (John-Anker), Hinds, D.A. (David A.), Spector, T.D. (Timothy), Cupples, L.A. (Adrienne), Ohlsson, C. (Claes), Greenwood, C.M.T. (Celia), Jackson, R.D. (Rebecca), Rowe, D.W. (David W.), Loomis, C.A. (Cynthia A.), Evans, D.M. (David M.), Ackert-Bicknell, C.L. (Cheryl), Joyner, A.L. (Alexandra L.), Duncan, E.L. (Emma), Kiel, D.P. (Douglas P.), Rivadeneira Ramirez, F. (Fernando), and Richards, J.B. (Brent)

Abstract

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10-14), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10-11; ncases = 98,742 and n controls = 409,511). Using an En1 cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10-11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation

Published
2015
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2. Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

Author

Reppe, S. (Sjur), Wang, Y. (Yunpeng), Thompson, W.K. (Wesley K.), McEvoy, L.K. (Linda K.), Schork, N.J. (Nicholas), Zuber, V. (Verena), Leblanc, M. (Marissa), Bettella, F. (Francesco), Mills, I.G. (Ian G.), Desikan, R.S. (Rahul S.), Djurovic, S. (Srdjan), Gautvik, K.M. (Kaare), Dale, A.M. (Anders), Andreassen, O.A. (Ole), Estrada Gil, K. (Karol), Styrkarsdottir, U. (Unnur), Evangelou, E. (Evangelos), Hsu, Y.-H. (Yi-Hsiang), Duncan, E.L. (Emma), Ntzani, E.E. (Evangelia), Oei, L. (Ling), Albagha, O.M.E. (Omar M.), Amin, N. (Najaf), Kemp, J.P. (John), Koller, D.L. (Daniel), Li, G. (Guo), Liu, C.-T. (Ching-Ti), Minster, R.L. (Ryan), Moayyeri, A. (Alireza), Vandenput, L. (Liesbeth), Willner, D. (Dana), Xiao, S.-M. (Su-Mei), Yerges-Armstrong, L.M. (Laura), Zheng, H.-F. (Hou-Feng), Alonso, N. (Nerea), Eriksson, J. (Joel), Kammerer, C.M. (Candace), Kaptoge, S. (Stephen), Leo, P.J. (Paul), Thorleifsson, G. (Gudmar), Wilson, S.G. (Scott), Wilson, J.F. (James F), Aalto, V. (Ville), Alen, M. (Markku), Aragaki, A.K. (Aaron), Aspelund, T. (Thor), Center, J.R. (Jacqueline), Dailiana, Z. (Zoe), Duggan, C., Garcia, M. (Melissa), Garcia-Giralt, N. (Natàlia), Giroux, S. (Sylvie), Hallmans, G. (Göran), Hocking, L.J. (Lynne), Husted, L.B. (Lise Bjerre), Jameson, K. (Karen), Khusainova, R. (Rita), Kim, G.S. (Ghi Su), Kooperberg, C. (Charles), Koromila, T. (Theodora), Kruk, M. (Marcin), Laaksonen, M. (Marika), Lacroix, A.Z. (Andrea Z.), Lee, S.H. (Seung Hun), Leung, P.C. (Ping C.), Lewis, J.R. (Joshua), Masi, L. (Laura), Mencej-Bedrac, S. (Simona), Nguyen, T.V. (Tuan), Nogues, X. (Xavier), Patel, M.S. (Millan), Prezelj, J. (Janez), Rose, L.M. (Lynda), Scollen, S. (Serena), Siggeirsdottir, K. (Kristin), Smith, A.V. (Davey), Svensson, O. (Olle), Trompet, S. (Stella), Trummer, O. (Olivia), Schoor, N.M. (Natasja) van, Woo, J. (Jean), Zhu, K. (Kun), Balcells, S. (Susana), Brandi, M.L., Buckley, B.M. (Brendan M.), Cheng, S. (Sulin), Christiansen, C., Cooper, C. (Charles), Dedoussis, G.V. (George), Ford, I. (Ian), Frost, M. (Morten), Goltzman, D. (David), González-Macías, J. (Jesús), Kähönen, M. (Mika), Karlsson, M. (Magnus), Khusnutdinova, E.K. (Elza), Koh, J.-M. (Jung-Min), Kollia, P. (Panagoula), Langdahl, B.L. (Bente), Leslie, W.D. (William D.), Lips, P. (Paul), Ljunggren, O. (Östen), Lorenc, R. (Roman), Marc, J. (Janja), Mellström, D. (Dan), Obermayer-Pietsch, B. (Barbara), Olmos, D. (David), Pettersson-Kymmer, U. (Ulrika), Reid, D.M. (David), Riancho, J.A. (José), Ridker, P.M. (Paul), Rousseau, M.F. (Francois), Slagboom, P.E. (Eline), Tang, N.L.S. (Nelson L.S.), Urreizti, R. (Roser), Van Hul, W. (Wim), Viikari, J. (Jorma), Zarrabeitia, M.T. (María), Aulchenko, Y.S. (Yurii), Castaño Betancourt, M.C. (Martha), Grundberg, E. (Elin), Herrera, L. (Lizbeth), Ingvarsson, T. (Torvaldur), Johannsdottir, H. (Hrefna), Kwan, T. (Tony), Li, R. (Rui), Luben, R.N. (Robert), Medina-Gomez, M.C. (Carolina), Palsson, S.T. (Stefan Th), Rotter, J.I. (Jerome I.), Sigurdsson, G. (Gunnar), Meurs, J.B.J. (Joyce) van, Verlaan, D.J. (Dominique), Williams, F.M. (Frances), Wood, A.R. (Andrew), Zhou, Y. (Yanhua), Pastinen, T. (Tomi), Raychaudhuri, S. (Soumya), Cauley, J.A. (Jane), Chasman, D.I. (Daniel), Clark, G.R. (Graeme), Cummings, S.R. (Steven R.), Danoy, P. (Patrick), Dennison, E.M. (Elaine), Eastell, R. (Richard), Eisman, J.A. (John), Gudnason, V. (Vilmundur), Hofman, A. (Albert), Jackson, R.D. (Rebecca), Jones, G. (Graeme), Jukema, J.W. (Jan Wouter), Khaw, K.T., Lehtimäki, T. (Terho), Liu, Y. (YongMei), Lorentzon, M. (Mattias), McCloskey, E.V. (Eugene), Mitchell, B.D. (Braxton), Nandakumar, K. (Kannabiran), Nicholson, G.C. (Geoffrey), Oostra, B.A. (Ben), Peacock, M. (Munro), Pols, H.A.P. (Huib), Prince, R.L. (Richard), Raitakari, O. (Olli), Reid, I.R. (Ian), Robbins, J. (John), Sambrook, P.N. (Philip), Sham, P.C. (Pak Chung), Shuldiner, A.R. (Alan), Tylavsky, F.A. (Frances), Duijn, C.M. (Cornelia) van, Wareham, N.J. (Nicholas J.), Cupples, L.A. (Adrienne), Econs, M.J. (Michael), Evans, D.M. (David), Harris, T.B. (Tamara B.), Kung, A.W.C. (Annie Wai Chee), Psaty, B.M. (Bruce), Reeve, J. (Jonathan), Spector, T.D. (Timothy), Streeten, E.A. (Elizabeth), Zillikens, M.C. (Carola), Thorsteinsdottir, U. (Unnur), Ohlsson, C. (Claes), Karasik, D. (David), Richards, J.B. (Brent), Brown, M.A. (Matthew), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Ralston, S.H. (Stuart), Ioannidis, J.P.A. (John P.A.), Kiel, D.P. (Douglas P.), Rivadeneira Ramirez, F. (Fernando), Reppe, S. (Sjur), Wang, Y. (Yunpeng), Thompson, W.K. (Wesley K.), McEvoy, L.K. (Linda K.), Schork, N.J. (Nicholas), Zuber, V. (Verena), Leblanc, M. (Marissa), Bettella, F. (Francesco), Mills, I.G. (Ian G.), Desikan, R.S. (Rahul S.), Djurovic, S. (Srdjan), Gautvik, K.M. (Kaare), Dale, A.M. (Anders), Andreassen, O.A. (Ole), Estrada Gil, K. (Karol), Styrkarsdottir, U. (Unnur), Evangelou, E. (Evangelos), Hsu, Y.-H. (Yi-Hsiang), Duncan, E.L. (Emma), Ntzani, E.E. (Evangelia), Oei, L. (Ling), Albagha, O.M.E. (Omar M.), Amin, N. (Najaf), Kemp, J.P. (John), Koller, D.L. (Daniel), Li, G. (Guo), Liu, C.-T. (Ching-Ti), Minster, R.L. (Ryan), Moayyeri, A. (Alireza), Vandenput, L. (Liesbeth), Willner, D. (Dana), Xiao, S.-M. (Su-Mei), Yerges-Armstrong, L.M. (Laura), Zheng, H.-F. (Hou-Feng), Alonso, N. (Nerea), Eriksson, J. (Joel), Kammerer, C.M. (Candace), Kaptoge, S. (Stephen), Leo, P.J. (Paul), Thorleifsson, G. (Gudmar), Wilson, S.G. (Scott), Wilson, J.F. (James F), Aalto, V. (Ville), Alen, M. (Markku), Aragaki, A.K. (Aaron), Aspelund, T. (Thor), Center, J.R. (Jacqueline), Dailiana, Z. (Zoe), Duggan, C., Garcia, M. (Melissa), Garcia-Giralt, N. (Natàlia), Giroux, S. (Sylvie), Hallmans, G. (Göran), Hocking, L.J. (Lynne), Husted, L.B. (Lise Bjerre), Jameson, K. (Karen), Khusainova, R. (Rita), Kim, G.S. (Ghi Su), Kooperberg, C. (Charles), Koromila, T. (Theodora), Kruk, M. (Marcin), Laaksonen, M. (Marika), Lacroix, A.Z. (Andrea Z.), Lee, S.H. (Seung Hun), Leung, P.C. (Ping C.), Lewis, J.R. (Joshua), Masi, L. (Laura), Mencej-Bedrac, S. (Simona), Nguyen, T.V. (Tuan), Nogues, X. (Xavier), Patel, M.S. (Millan), Prezelj, J. (Janez), Rose, L.M. (Lynda), Scollen, S. (Serena), Siggeirsdottir, K. (Kristin), Smith, A.V. (Davey), Svensson, O. (Olle), Trompet, S. (Stella), Trummer, O. (Olivia), Schoor, N.M. (Natasja) van, Woo, J. (Jean), Zhu, K. (Kun), Balcells, S. (Susana), Brandi, M.L., Buckley, B.M. (Brendan M.), Cheng, S. (Sulin), Christiansen, C., Cooper, C. (Charles), Dedoussis, G.V. (George), Ford, I. (Ian), Frost, M. (Morten), Goltzman, D. (David), González-Macías, J. (Jesús), Kähönen, M. (Mika), Karlsson, M. (Magnus), Khusnutdinova, E.K. (Elza), Koh, J.-M. (Jung-Min), Kollia, P. (Panagoula), Langdahl, B.L. (Bente), Leslie, W.D. (William D.), Lips, P. (Paul), Ljunggren, O. (Östen), Lorenc, R. (Roman), Marc, J. (Janja), Mellström, D. (Dan), Obermayer-Pietsch, B. (Barbara), Olmos, D. (David), Pettersson-Kymmer, U. (Ulrika), Reid, D.M. (David), Riancho, J.A. (José), Ridker, P.M. (Paul), Rousseau, M.F. (Francois), Slagboom, P.E. (Eline), Tang, N.L.S. (Nelson L.S.), Urreizti, R. (Roser), Van Hul, W. (Wim), Viikari, J. (Jorma), Zarrabeitia, M.T. (María), Aulchenko, Y.S. (Yurii), Castaño Betancourt, M.C. (Martha), Grundberg, E. (Elin), Herrera, L. (Lizbeth), Ingvarsson, T. (Torvaldur), Johannsdottir, H. (Hrefna), Kwan, T. (Tony), Li, R. (Rui), Luben, R.N. (Robert), Medina-Gomez, M.C. (Carolina), Palsson, S.T. (Stefan Th), Rotter, J.I. (Jerome I.), Sigurdsson, G. (Gunnar), Meurs, J.B.J. (Joyce) van, Verlaan, D.J. (Dominique), Williams, F.M. (Frances), Wood, A.R. (Andrew), Zhou, Y. (Yanhua), Pastinen, T. (Tomi), Raychaudhuri, S. (Soumya), Cauley, J.A. (Jane), Chasman, D.I. (Daniel), Clark, G.R. (Graeme), Cummings, S.R. (Steven R.), Danoy, P. (Patrick), Dennison, E.M. (Elaine), Eastell, R. (Richard), Eisman, J.A. (John), Gudnason, V. (Vilmundur), Hofman, A. (Albert), Jackson, R.D. (Rebecca), Jones, G. (Graeme), Jukema, J.W. (Jan Wouter), Khaw, K.T., Lehtimäki, T. (Terho), Liu, Y. (YongMei), Lorentzon, M. (Mattias), McCloskey, E.V. (Eugene), Mitchell, B.D. (Braxton), Nandakumar, K. (Kannabiran), Nicholson, G.C. (Geoffrey), Oostra, B.A. (Ben), Peacock, M. (Munro), Pols, H.A.P. (Huib), Prince, R.L. (Richard), Raitakari, O. (Olli), Reid, I.R. (Ian), Robbins, J. (John), Sambrook, P.N. (Philip), Sham, P.C. (Pak Chung), Shuldiner, A.R. (Alan), Tylavsky, F.A. (Frances), Duijn, C.M. (Cornelia) van, Wareham, N.J. (Nicholas J.), Cupples, L.A. (Adrienne), Econs, M.J. (Michael), Evans, D.M. (David), Harris, T.B. (Tamara B.), Kung, A.W.C. (Annie Wai Chee), Psaty, B.M. (Bruce), Reeve, J. (Jonathan), Spector, T.D. (Timothy), Streeten, E.A. (Elizabeth), Zillikens, M.C. (Carola), Thorsteinsdottir, U. (Unnur), Ohlsson, C. (Claes), Karasik, D. (David), Richards, J.B. (Brent), Brown, M.A. (Matthew), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Ralston, S.H. (Stuart), Ioannidis, J.P.A. (John P.A.), Kiel, D.P. (Douglas P.), and Rivadeneira Ramirez, F. (Fernando)

Abstract

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.

Published
2015
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3. Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome-wide association studies

Author

Rodriguez-Fontenla, C. (Cristina), Calaza, M. (Manuel), Evangelou, E. (Evangelos), Valdes, A.M. (Ana Maria), Arden, N.K. (Nigel), Blanco, F.J., Carr, A.J. (Andrew Jonathan), Chapman, K. (Kay), Deloukas, P. (Panagiotis), Doherty, M. (Michael), Esko, T. (Tõnu), Garcés Aletá, C.M. (Carlos), Gomez-Reino Carnota, J.J. (Juan), Helgadottir, H.T. (Hafdis), Hofman, A. (Albert), Jonsdottir, I. (Ingileif), Kerkhof, J.M. (Hanneke), Kloppenburg, M. (Margreet), McCaskie, A. (Andrew), Ntzani, E.E. (Evangelia), Ollier, W.E.R. (William), Oreiro, N. (Natividad), Panoutsopoulou, K. (Kalliope), Ralston, S.H. (Stuart), Ramos, Y.F.M. (Yolande), Riancho, J.A. (José), Rivadeneira Ramirez, F. (Fernando), Slagboom, P.E. (Eline), Styrkarsdottir, U. (Unnur), Thorsteinsdottir, U. (Unnur), Thorleifsson, G. (Gudmar), Tsezou, A. (Aspasia), Uitterlinden, A.G. (André), Wallis, G.A. (Gillian), Wilkinson, J.M. (Mark), Zhai, G. (Guangju), Zhu, Y. (Yanyan), Felson, D., Ioannidis, J.P.A. (John), Loughlin, J. (John), Metspalu, A. (Andres), Meulenbelt, I. (Ingrid), Zwart, J-A. (John-Anker), Meurs, J.B.J. (Joyce) van, Zeggini, E. (Eleftheria), Spector, T.D. (Timothy), Gonzalez, A. (Antonio), Rodriguez-Fontenla, C. (Cristina), Calaza, M. (Manuel), Evangelou, E. (Evangelos), Valdes, A.M. (Ana Maria), Arden, N.K. (Nigel), Blanco, F.J., Carr, A.J. (Andrew Jonathan), Chapman, K. (Kay), Deloukas, P. (Panagiotis), Doherty, M. (Michael), Esko, T. (Tõnu), Garcés Aletá, C.M. (Carlos), Gomez-Reino Carnota, J.J. (Juan), Helgadottir, H.T. (Hafdis), Hofman, A. (Albert), Jonsdottir, I. (Ingileif), Kerkhof, J.M. (Hanneke), Kloppenburg, M. (Margreet), McCaskie, A. (Andrew), Ntzani, E.E. (Evangelia), Ollier, W.E.R. (William), Oreiro, N. (Natividad), Panoutsopoulou, K. (Kalliope), Ralston, S.H. (Stuart), Ramos, Y.F.M. (Yolande), Riancho, J.A. (José), Rivadeneira Ramirez, F. (Fernando), Slagboom, P.E. (Eline), Styrkarsdottir, U. (Unnur), Thorsteinsdottir, U. (Unnur), Thorleifsson, G. (Gudmar), Tsezou, A. (Aspasia), Uitterlinden, A.G. (André), Wallis, G.A. (Gillian), Wilkinson, J.M. (Mark), Zhai, G. (Guangju), Zhu, Y. (Yanyan), Felson, D., Ioannidis, J.P.A. (John), Loughlin, J. (John), Metspalu, A. (Andres), Meulenbelt, I. (Ingrid), Zwart, J-A. (John-Anker), Meurs, J.B.J. (Joyce) van, Zeggini, E. (Eleftheria), Spector, T.D. (Timothy), and Gonzalez, A. (Antonio)

Abstract

Objective To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA. Methods A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10-5 were considered significant. Results SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10-5, odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06-1.17) and rs1241164 (P = 1.47 × 10-5, OR 0.82, 95% CI 0.74-0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10-5, OR 0.87, 95% CI 0.82-0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10-5, OR 0.85, 95% CI 0.79-0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened. Conclusion Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated. Copyright

Published
2014
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4. A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip

Author

Evangelou, E. (Evangelos), Kerkhof, J.M. (Hanneke), Styrkarsdottir, U. (Unnur), Ntzani, E.E. (Evangelia), Bos, S.D. (Steffan), Esko, T. (Tõnu), Evans, D.S. (Daniel), Metrustry, S. (Sarah), Panoutsopoulou, K. (Kalliope), Ramos, Y.F.M. (Yolande), Thorleifsson, G. (Gudmar), Tsilidis, K.K. (Konstantinos), Arden, N.K. (Nigel), Aslam, N. (Nadim), Bellamy, N. (Nicholas), Birrell, F. (Fraser), Blanco, F.J., Carr, A.J. (Andrew Jonathan), Chapman, K. (Kay), Day-Williams, A.G. (Aaron), Deloukas, P. (Panagiotis), Doherty, M. (Michael), Engström, G., Helgadottir, H.T. (Hafdis), Hofman, A. (Albert), Ingvarsson, T. (Torvaldur), Jonsson, H. (Helgi), Keis, A. (Aime), Keurentjes, J.C. (J. Christiaan), Kloppenburg, M. (Margreet), Lind, P.A. (Penelope), McCaskie, A. (Andrew), Martin, N.G. (Nicholas), Milani, A.L. (Alfredo), Montgomery, G.W., Nelissen, R.G.H.H. (Rob), Nevitt, M.C. (Michael), Nilsson, P. (Peter), Ollier, W.E.R. (William), Parimi, N. (Neeta), Rai, A. (Ashok), Ralston, S.H., Reed, M.R. (Mike), Riancho, J.A. (José), Rivadeneira Ramirez, F. (Fernando), Rodriguez-Fontenla, C. (Cristina), Southam, L. (Lorraine), Thorsteinsdottir, U. (Unnur), Tsezou, A. (Aspasia), Wallis, G.A. (Gillian), Wilkinson, J.M. (Mark), Gonzalez, A. (Antonio), Lane, N.E., Lohmander, L.S. (Stefan), Loughlin, J. (John), Metspalu, A. (Andres), Uitterlinden, A.G. (André), Jonsdottir, I. (Ingileif), Zwart, J-A. (John-Anker), Slagboom, P.E. (Eline), Zeggini, E. (Eleftheria), Meulenbelt, I. (Ingrid), Ioannidis, J.P.A. (John), Spector, T.D. (Timothy), Meurs, J.B.J. (Joyce) van, Valdes, A.M. (Ana Maria), Evangelou, E. (Evangelos), Kerkhof, J.M. (Hanneke), Styrkarsdottir, U. (Unnur), Ntzani, E.E. (Evangelia), Bos, S.D. (Steffan), Esko, T. (Tõnu), Evans, D.S. (Daniel), Metrustry, S. (Sarah), Panoutsopoulou, K. (Kalliope), Ramos, Y.F.M. (Yolande), Thorleifsson, G. (Gudmar), Tsilidis, K.K. (Konstantinos), Arden, N.K. (Nigel), Aslam, N. (Nadim), Bellamy, N. (Nicholas), Birrell, F. (Fraser), Blanco, F.J., Carr, A.J. (Andrew Jonathan), Chapman, K. (Kay), Day-Williams, A.G. (Aaron), Deloukas, P. (Panagiotis), Doherty, M. (Michael), Engström, G., Helgadottir, H.T. (Hafdis), Hofman, A. (Albert), Ingvarsson, T. (Torvaldur), Jonsson, H. (Helgi), Keis, A. (Aime), Keurentjes, J.C. (J. Christiaan), Kloppenburg, M. (Margreet), Lind, P.A. (Penelope), McCaskie, A. (Andrew), Martin, N.G. (Nicholas), Milani, A.L. (Alfredo), Montgomery, G.W., Nelissen, R.G.H.H. (Rob), Nevitt, M.C. (Michael), Nilsson, P. (Peter), Ollier, W.E.R. (William), Parimi, N. (Neeta), Rai, A. (Ashok), Ralston, S.H., Reed, M.R. (Mike), Riancho, J.A. (José), Rivadeneira Ramirez, F. (Fernando), Rodriguez-Fontenla, C. (Cristina), Southam, L. (Lorraine), Thorsteinsdottir, U. (Unnur), Tsezou, A. (Aspasia), Wallis, G.A. (Gillian), Wilkinson, J.M. (Mark), Gonzalez, A. (Antonio), Lane, N.E., Lohmander, L.S. (Stefan), Loughlin, J. (John), Metspalu, A. (Andres), Uitterlinden, A.G. (André), Jonsdottir, I. (Ingileif), Zwart, J-A. (John-Anker), Slagboom, P.E. (Eline), Zeggini, E. (Eleftheria), Meulenbelt, I. (Ingrid), Ioannidis, J.P.A. (John), Spector, T.D. (Timothy), Meurs, J.B.J. (Joyce) van, and Valdes, A.M. (Ana Maria)

Abstract

Objectives: Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. Methods: We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. Results: We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10-9and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10-8) and follow-up studies (p=7.3×10-4). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10-7, OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10-6, OR=1.27 in male specific analysis). Conclusions: Novel genetic loci for hip OA were found in this meta-analysis of GWAS.

Published
2014
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5. A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus

Author

Oei, L. (Ling), Hsu, Y.-H. (Yi-Hsiang), Styrkarsdottir, U. (Unnur), Eussen, H.J.F.M.M. (Bert), Klein, J.E.M.M. (Annelies) de, Peters, M.J. (Marjolein), Halldorsson, B.V. (Bjarni), Liu, C.-T. (Ching-Ti), Alonso, N. (Nerea), Kaptoge, S. (Stephen), Thorleifsson, G. (Gudmar), Hallmans, G. (Göran), Hocking, L.J. (Lynne), Husted, L.B. (Lise Bjerre), Jameson, K. (Karen), Kingdom, M.K. (Marcin KrUnited), Lewis, J.R. (Joshua), Patel, M.S. (Millan), Scollen, S. (Serena), Svensson, O. (Olle), Trompet, S. (Stella), Schoor, N.M. (Natasja) van, Zhu, K. (Kun), Buckley, B.M. (Brendan M.), Cooper, C. (Charles), Ford, I. (Ian), Goltzman, D. (David), González-Macías, J. (Jesús), Langdahl, B.L. (Bente), Leslie, W.D. (William), Lips, P. (Paul), Lorenc, R. (Roman), Olmos, D. (David), Pettersson-Kymmer, U. (Ulrika), Reid, D.M. (David), Riancho, J.A. (José), Slagboom, P.E. (Eline), Garcia-Ibarbia, C. (Carmen), Ingvarsson, T. (Torvaldur), Johannsdottir, H. (Hrefna), Luben, R.N. (Robert), Medina-Gomez, M.C. (Carolina), Arp, P.P. (Pascal), Nandakumar, K. (Kannabiran), Palsson, S.T. (Stefan Th), Sigurdsson, G. (Gunnar), Meurs, J.B.J. (Joyce) van, Zhou, Y. (Yanhua), Hofman, A. (Albert), Jukeme, J.W. (J. Wouter), Pols, H.A.P. (Huib), Prince, R.L. (Richard), Cupples, L.A. (Adrienne), Marshall, C.R. (Christian), Pinto, D. (Duane), Sato, D.K. (DaisUnited Kingdome), Scherer, S.W. (Stephen), Reeve, J. (Jonathan), Thorsteinsdottir, U. (Unnur), Karasik, D. (David), Richards, J.B. (Brent), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Ralston, S.H. (Stuart), Ioannidis, J.P.A. (John), Kiel, D.P. (Douglas), Rivadeneira Ramirez, F. (Fernando), Estrada Gil, K. (Karol), Oei, L. (Ling), Hsu, Y.-H. (Yi-Hsiang), Styrkarsdottir, U. (Unnur), Eussen, H.J.F.M.M. (Bert), Klein, J.E.M.M. (Annelies) de, Peters, M.J. (Marjolein), Halldorsson, B.V. (Bjarni), Liu, C.-T. (Ching-Ti), Alonso, N. (Nerea), Kaptoge, S. (Stephen), Thorleifsson, G. (Gudmar), Hallmans, G. (Göran), Hocking, L.J. (Lynne), Husted, L.B. (Lise Bjerre), Jameson, K. (Karen), Kingdom, M.K. (Marcin KrUnited), Lewis, J.R. (Joshua), Patel, M.S. (Millan), Scollen, S. (Serena), Svensson, O. (Olle), Trompet, S. (Stella), Schoor, N.M. (Natasja) van, Zhu, K. (Kun), Buckley, B.M. (Brendan M.), Cooper, C. (Charles), Ford, I. (Ian), Goltzman, D. (David), González-Macías, J. (Jesús), Langdahl, B.L. (Bente), Leslie, W.D. (William), Lips, P. (Paul), Lorenc, R. (Roman), Olmos, D. (David), Pettersson-Kymmer, U. (Ulrika), Reid, D.M. (David), Riancho, J.A. (José), Slagboom, P.E. (Eline), Garcia-Ibarbia, C. (Carmen), Ingvarsson, T. (Torvaldur), Johannsdottir, H. (Hrefna), Luben, R.N. (Robert), Medina-Gomez, M.C. (Carolina), Arp, P.P. (Pascal), Nandakumar, K. (Kannabiran), Palsson, S.T. (Stefan Th), Sigurdsson, G. (Gunnar), Meurs, J.B.J. (Joyce) van, Zhou, Y. (Yanhua), Hofman, A. (Albert), Jukeme, J.W. (J. Wouter), Pols, H.A.P. (Huib), Prince, R.L. (Richard), Cupples, L.A. (Adrienne), Marshall, C.R. (Christian), Pinto, D. (Duane), Sato, D.K. (DaisUnited Kingdome), Scherer, S.W. (Stephen), Reeve, J. (Jonathan), Thorsteinsdottir, U. (Unnur), Karasik, D. (David), Richards, J.B. (Brent), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Ralston, S.H. (Stuart), Ioannidis, J.P.A. (John), Kiel, D.P. (Douglas), Rivadeneira Ramirez, F. (Fernando), and Estrada Gil, K. (Karol)

Abstract

Background Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. Aim To identify CNVs associated with osteoporotic bone fracture risk. Method We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. Results A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10−5). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. Conclusions These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

Published
2014
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6. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Author

Estrada Gil, K. (Karol), Styrkarsdottir, U. (Unnur), Evangelou, E. (Evangelos), Hsu, Y.-H. (Yi-Hsiang), Duncan, E.L. (Emma), Ntzani, E.E. (Evangelia), Oei, L. (Ling), Albagha, O.M.E. (Omar M.), Amin, N. (Najaf), Kemp, J.P. (John), Koller, D.L. (Daniel), Li, G. (Guo), Liu, C.-T. (Ching-Ti), Minster, R.L. (Ryan), Moayyeri, A. (Alireza), Vandenput, L. (Liesbeth), Willner, D. (Dana), Xiao, S.-M. (Su-Mei), Yerges-Armstrong, L.M. (Laura), Zheng, H.-F. (Hou-Feng), Alonso, N. (Nerea), Eriksson, J. (Joel), Kammerer, C.M. (Candace), Kaptoge, S. (Stephen), Leo, P.J. (Paul), Thorleifsson, G. (Gudmar), Wilson, S.G. (Scott), Wilson, J.F. (James), Aalto, V. (Ville), Alen, T.A. (Theo) van, Aragaki, A.K. (Aaron), Aspelund, T. (Thor), Center, J.R. (Jacqueline), Dailiana, Z. (Zoe), Duggan, C., Garcia, M. (Melissa), Garcia-Giralt, N. (Natàlia), Giroux, S. (Sylvie), Hallmans, G. (Göran), Hocking, L.J. (Lynne), Husted, L.B. (Lise Bjerre), Jameson, K. (Karen), Khusainova, R. (Rita), Kim, G.S. (Ghi Su), Kooperberg, C. (Charles), Koromila, T. (Theodora), Kruk, M. (Marcin), Laaksonen, M. (Marika), LaCroix, A.Z. (Andrea), Lee, S.U. (Seung), Leung, P.C. (Ping), Lewis, J.R. (Joshua), Masi, L. (Laura), Mencej-Bedrac, S. (Simona), Nguyen, T.V. (Tuan), Nogues, X. (Xavier), Patel, M.S. (Millan), Prezelj, J. (Janez), Rose, L.M. (Lynda), Scollen, S. (Serena), Siggeirsdottir, K. (Kristin), Smith, A.V. (Davey), Svensson, O. (Olle), Trompet, S. (Stella), Trummer, O. (Olivia), Schoor, N.M. (Natasja) van, Woo, M.M. (Margaret M.), Zhu, K. (Kun), Balcells, S. (Susana), Brandi, M.L., Buckley, B.M. (Brendan M.), Cheng, S. (Sulin), Christiansen, C., Cooper, C. (Charles), Dedoussis, G.V. (George), Ford, I. (Ian), Frost, M. (Morten), Goltzman, D. (David), González-Macías, J. (Jesús), Kähönen, M. (Mika), Karlsson, M. (Magnus), Khusnutdinova, E.K. (Elza), Koh, J.-M. (Jung-Min), Kollia, P. (Panagoula), Langdahl, B.L. (Bente), Leslie, W.D. (William), Lips, P. (Paul), Ljunggren, O. (Östen), Lorenc, R. (Roman), Marc, J. (Janja), Mellström, D. (Dan), Obermayer-Pietsch, B. (Barbara), Olmos, D. (David), Pettersson-Kymmer, U. (Ulrika), Reid, D.M. (David), Riancho, J.A. (José), Ridker, P.M. (Paul), Rousseau, M.F. (Francois), Slagboom, P.E. (Eline), Tang, N.L.S. (Nelson L.), Urreizti, R. (Roser), Van Hul, W. (Wim), Viikari, J. (Jorma), Zarrabeitia, M.T. (María), Aulchenko, Y.S. (Yurii), Castaño Betancourt, M.C. (Martha), Grundberg, E. (Elin), Herrera, L. (Lizbeth), Ingvarsson, T. (Torvaldur), Johannsdottir, H. (Hrefna), Kwan, T. (Tony), Li, R. (Rui), Luben, R.N. (Robert), Medina-Gomez, M.C. (Carolina), Palsson, S.T. (Stefan), Reppe, S. (Sjur), Rotter, J.I. (Jerome), Sigurdsson, G. (Gunnar), Meurs, J.B.J. (Joyce) van, Verlaan, D.J. (Dominique), Williams, F.M. (Frances), Wood, A.R. (Andrew), Zhou, Y. (Yanhua), Gautvik, K.M. (Kaare), Pastinen, T. (Tomi), Raychaudhuri, S. (Soumya), Cauley, J.A. (Jane), Chasman, D.I. (Daniel), Clark, G.R. (Graeme), Cummings, S., Danoy, P. (Patrick), Dennison, E.M. (Elaine), Eastell, R. (Richard), Eisman, J.A. (John), Gudnason, V. (Vilmundur), Hofman, A. (Albert), Jackson, R.D. (Rebecca), Jones, G. (Graeme), Jukema, J.W. (Jan Wouter), Khaw, K-T. (Kay-Tee), Lehtimäki, T. (Terho), Liu, Y. (YongMei), Lorentzon, M. (Mattias), McCloskey, E.V. (Eugene), Mitchell, B.D. (Braxton), Nandakumar, K. (Kannabiran), Nicholson, G.C. (Geoffrey), Oostra, B.A. (Ben), Peacock, M. (Munro), Pols, H.A.P. (Huib), Prince, R.L. (Richard), Raitakari, O. (Olli), Reid, I.R. (Ian), Robbins, J. (John), Sambrook, P.N. (Philip), Sham, P.C. (Pak), Shuldiner, A.R. (Alan), Tylavsky, F.A. (Frances), Duijn, C.M. (Cornelia) van, Wareham, N.J. (Nick), Cupples, L.A. (Adrienne), Econs, M.J. (Michael), Evans, D.M. (David), Harris, T.B. (Tamara), Kung, A.W.C. (Annie), Psaty, B.M. (Bruce), Reeve, J. (Jonathan), Spector, T.D. (Timothy), Streeten, E.A. (Elizabeth), Zillikens, M.C. (Carola), Thorsteinsdottir, U. (Unnur), Ohlsson, C. (Claes), Karasik, D. (David), Richards, J.B. (Brent), Brown, M.A. (Matthew), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Ralston, S.H. (Stuart), Ioannidis, J.P.A. (John), Kiel, D.P. (Douglas), Rivadeneira Ramirez, F. (Fernando), Estrada Gil, K. (Karol), Styrkarsdottir, U. (Unnur), Evangelou, E. (Evangelos), Hsu, Y.-H. (Yi-Hsiang), Duncan, E.L. (Emma), Ntzani, E.E. (Evangelia), Oei, L. (Ling), Albagha, O.M.E. (Omar M.), Amin, N. (Najaf), Kemp, J.P. (John), Koller, D.L. (Daniel), Li, G. (Guo), Liu, C.-T. (Ching-Ti), Minster, R.L. (Ryan), Moayyeri, A. (Alireza), Vandenput, L. (Liesbeth), Willner, D. (Dana), Xiao, S.-M. (Su-Mei), Yerges-Armstrong, L.M. (Laura), Zheng, H.-F. (Hou-Feng), Alonso, N. (Nerea), Eriksson, J. (Joel), Kammerer, C.M. (Candace), Kaptoge, S. (Stephen), Leo, P.J. (Paul), Thorleifsson, G. (Gudmar), Wilson, S.G. (Scott), Wilson, J.F. (James), Aalto, V. (Ville), Alen, T.A. (Theo) van, Aragaki, A.K. (Aaron), Aspelund, T. (Thor), Center, J.R. (Jacqueline), Dailiana, Z. (Zoe), Duggan, C., Garcia, M. (Melissa), Garcia-Giralt, N. (Natàlia), Giroux, S. (Sylvie), Hallmans, G. (Göran), Hocking, L.J. (Lynne), Husted, L.B. (Lise Bjerre), Jameson, K. (Karen), Khusainova, R. (Rita), Kim, G.S. (Ghi Su), Kooperberg, C. (Charles), Koromila, T. (Theodora), Kruk, M. (Marcin), Laaksonen, M. (Marika), LaCroix, A.Z. (Andrea), Lee, S.U. (Seung), Leung, P.C. (Ping), Lewis, J.R. (Joshua), Masi, L. (Laura), Mencej-Bedrac, S. (Simona), Nguyen, T.V. (Tuan), Nogues, X. (Xavier), Patel, M.S. (Millan), Prezelj, J. (Janez), Rose, L.M. (Lynda), Scollen, S. (Serena), Siggeirsdottir, K. (Kristin), Smith, A.V. (Davey), Svensson, O. (Olle), Trompet, S. (Stella), Trummer, O. (Olivia), Schoor, N.M. (Natasja) van, Woo, M.M. (Margaret M.), Zhu, K. (Kun), Balcells, S. (Susana), Brandi, M.L., Buckley, B.M. (Brendan M.), Cheng, S. (Sulin), Christiansen, C., Cooper, C. (Charles), Dedoussis, G.V. (George), Ford, I. (Ian), Frost, M. (Morten), Goltzman, D. (David), González-Macías, J. (Jesús), Kähönen, M. (Mika), Karlsson, M. (Magnus), Khusnutdinova, E.K. (Elza), Koh, J.-M. (Jung-Min), Kollia, P. (Panagoula), Langdahl, B.L. (Bente), Leslie, W.D. (William), Lips, P. (Paul), Ljunggren, O. (Östen), Lorenc, R. (Roman), Marc, J. (Janja), Mellström, D. (Dan), Obermayer-Pietsch, B. (Barbara), Olmos, D. (David), Pettersson-Kymmer, U. (Ulrika), Reid, D.M. (David), Riancho, J.A. (José), Ridker, P.M. (Paul), Rousseau, M.F. (Francois), Slagboom, P.E. (Eline), Tang, N.L.S. (Nelson L.), Urreizti, R. (Roser), Van Hul, W. (Wim), Viikari, J. (Jorma), Zarrabeitia, M.T. (María), Aulchenko, Y.S. (Yurii), Castaño Betancourt, M.C. (Martha), Grundberg, E. (Elin), Herrera, L. (Lizbeth), Ingvarsson, T. (Torvaldur), Johannsdottir, H. (Hrefna), Kwan, T. (Tony), Li, R. (Rui), Luben, R.N. (Robert), Medina-Gomez, M.C. (Carolina), Palsson, S.T. (Stefan), Reppe, S. (Sjur), Rotter, J.I. (Jerome), Sigurdsson, G. (Gunnar), Meurs, J.B.J. (Joyce) van, Verlaan, D.J. (Dominique), Williams, F.M. (Frances), Wood, A.R. (Andrew), Zhou, Y. (Yanhua), Gautvik, K.M. (Kaare), Pastinen, T. (Tomi), Raychaudhuri, S. (Soumya), Cauley, J.A. (Jane), Chasman, D.I. (Daniel), Clark, G.R. (Graeme), Cummings, S., Danoy, P. (Patrick), Dennison, E.M. (Elaine), Eastell, R. (Richard), Eisman, J.A. (John), Gudnason, V. (Vilmundur), Hofman, A. (Albert), Jackson, R.D. (Rebecca), Jones, G. (Graeme), Jukema, J.W. (Jan Wouter), Khaw, K-T. (Kay-Tee), Lehtimäki, T. (Terho), Liu, Y. (YongMei), Lorentzon, M. (Mattias), McCloskey, E.V. (Eugene), Mitchell, B.D. (Braxton), Nandakumar, K. (Kannabiran), Nicholson, G.C. (Geoffrey), Oostra, B.A. (Ben), Peacock, M. (Munro), Pols, H.A.P. (Huib), Prince, R.L. (Richard), Raitakari, O. (Olli), Reid, I.R. (Ian), Robbins, J. (John), Sambrook, P.N. (Philip), Sham, P.C. (Pak), Shuldiner, A.R. (Alan), Tylavsky, F.A. (Frances), Duijn, C.M. (Cornelia) van, Wareham, N.J. (Nick), Cupples, L.A. (Adrienne), Econs, M.J. (Michael), Evans, D.M. (David), Harris, T.B. (Tamara), Kung, A.W.C. (Annie), Psaty, B.M. (Bruce), Reeve, J. (Jonathan), Spector, T.D. (Timothy), Streeten, E.A. (Elizabeth), Zillikens, M.C. (Carola), Thorsteinsdottir, U. (Unnur), Ohlsson, C. (Claes), Karasik, D. (David), Richards, J.B. (Brent), Brown, M.A. (Matthew), Zwart, J-A. (John-Anker), Uitterlinden, A.G. (André), Ralston, S.H. (Stuart), Ioannidis, J.P.A. (John), Kiel, D.P. (Douglas), and Rivadeneira Ramirez, F. (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.

Published
2012
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