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

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

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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 languageUndefined/Unknown
Pages (from-to)491-+
JournalNature Genetics
Volume44
Issue number5
DOIs
Publication statusPublished - 2012

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