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