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

Citation

Estrada, K and Styrkarsdottir, U and Evangelou, E and Hsu, Y-H and Duncan, EL and Ntzani, EE and Oei, L and Albagha, OME and Amin, N and Kemp, JP and Koller, DL and Li, G and Liu, C-T and Minster, RL and Moayyeri, A and Vandenput, L and Willner, D and Xiao, S-M and Yerges-Armstrong, LM and Zheng, H-F and Alonso, N and Eriksson, J and Kammerer, CM and Kaptoge, SK and Leo, PJ and Thorleifsson, G and Wilson, SG and Wilson, JF and Aalto, V and Alen, M and Aragaki, AK and Aspelund, T and Center, JR and Dailiana, Z and Duggan, DJ and Garcia, M and Garcia-Giralt, N and Giroux, S and Hallmans, G and Hocking, LJ and Husted, LB and Jameson, KA and Khusainova, R and Kim, GS and Kooperberg, C and Koromila, T and Kruk, M and Laaksonen, M and Lacroix, AZ and Lee, SH and Leung, PC and Lewis, JR and Masi, L and Mencej-Bedrac, S and Nguyen, TV and Nogues, X and Patel, MS and Prezelj, J and Rose, LM and Scollen, S and Siggeirsdottir, K and Smith, AV and Svensson, O and Trompet, S and Trummer, O and van Schoor, NM and Woo, J and Zhu, K and Balcells, S and Brandi, ML and Buckley, BM and Cheng, S and Christiansen, C and Cooper, C and Dedoussis, G and Ford, I and Frost, M and Goltzman, D and Gonzalez-Macias, J and Kahonen, M and Karlsson, M and Khusnutdinova, E and Koh, J-M and Kollia, P and Langdahl, BL and Leslie, WD and Lips, P and Ljunggren, O and Lorenc, RS and Marc, J and Mellstrom, D and Obermayer-Pietsch, B and Olmos, JM and Pettersson-Kymmer, U and Reid, DM and Riancho, JA and Ridker, PM and Rousseau, F and Slagboom, PE and Tang, NLS and Urreizti, R and Van Hul, W and Viikari, J and Zarrabeitia, MT and Aulchenko, YS and Castano-Betancourt, M and Grundberg, E and Herrera, L and Ingvarsson, T and Johannsdottir, H and Kwan, T and Li, R and Luben, R and Medina-Gomez, C and Palsson, ST and Reppe, S and Rotter, JI and Sigurdsson, G and van Meurs, JBJ and Verlaan, D and Williams, FMK and Wood, AR and Zhou, Y and Gautvik, KM and Pastinen, T and Raychaudhuri, S and Cauley, JA and Chasman, DI and Clark, GR and Cummings, SR and Danoy, P and Dennison, EM and Eastell, R and Eisman, JA and Gudnason, V and Hofman, A and Jackson, RD and Jones, G and Jukema, JW and Khaw, K-T and Lehtimaki, T and Liu, Y and Lorentzon, M and McCloskey, E and Mitchell, BD and Nandakumar, K and Nicholson, GC and Oostra, BA and Peacock, M and Pols, HAP and Prince, RL and Raitakari, O and Reid, IR and Robbins, J and Sambrook, PN and Sham, PC and Shuldiner, AR and Tylavsky, FA and van Duijn, CM and Wareham, NJ and Cupples, LA and Econs, MJ and Evans, DM and Harris, TB and Kung, AWC and Psaty, BM and Reeve, J and Spector, TD and Streeten, EA and Zillikens, MC and Thorsteinsdottir, U and Ohlsson, C and Karasik, D and Richards, JB and Brown, MA and Stefansson, K and Uitterlinden, AG and Ralston, SH and Ioannidis, JPA and Kiel, DP and Rivadeneira, F, Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture, Nature Genetics, 44, (5) pp. 491-501. ISSN 1061-4036 (2012) [Refereed Article]

Copyright Statement

Copyright 2012 Nature America, Inc.

DOI: doi:10.1038/ng.2249

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.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Clinical Sciences
Research Field:Rheumatology and Arthritis
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Skeletal System and Disorders (incl. Arthritis)
Author:Jones, G (Professor Graeme Jones)
ID Code:82264
Year Published:2012
Web of Science® Times Cited:436
Deposited By:Menzies Institute for Medical Research
Deposited On:2013-01-23
Last Modified:2017-10-23
Downloads:0

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