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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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; González-Macías, J; Kähönen, M; Karlsson, M; Khusnutdinova, E; Koh, J-M; Kollia, P; Langdahl, BL; Leslie, WD; Lips, P; Ljunggren, Ö; Lorenc, RS; Marc, J; Mellström, 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-Gómez, 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; Lehtimäki, 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

Published Date

  • April 15, 2012

Published In

Volume / Issue

  • 44 / 5

Start / End Page

  • 491 - 501

PubMed ID

  • 22504420

Pubmed Central ID

  • PMC3338864

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

Digital Object Identifier (DOI)

  • 10.1038/ng.2249

Language

  • eng

Conference Location

  • United States