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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
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| Title | Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. |
| Publication Type | Journal Article |
| Year of Publication | 2012 |
| 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, García-Giralt, N, Giroux, S, Hallmans, G, Hocking, LJ, Husted, LBjerre, Jameson, KA, Khusainova, R, Kim, GSu, Kooperberg, C, Koromila, T, Kruk, M, Laaksonen, M, LaCroix, AZ, Lee, SHun, 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, MLuisa, 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, BLomholt, Leslie, WD, Lips, P, Ljunggren, O, Lorenc, RS, Marc, J, Mellström, D, Obermayer-Pietsch, B, Olmos, JM, Pettersson-Kymmer, U, Reid, DM, Riancho, JA, Ridker, PM, Rousseau, F, P Slagboom, E, 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, STh, 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, J Jukema, W, 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, PChung, Shuldiner, AR, Tylavsky, FA, van Duijn, CM, Wareham, NJ, Cupples, AL, Econs, MJ, Evans, DM, Harris, TB, Kung, AWai Chee, Psaty, BM, Reeve, J, Spector, TD, Streeten, EA, Zillikens, CM, Thorsteinsdottir, U, Ohlsson, C, Karasik, D, J Richards, B, Brown, MA, Stefansson, K, Uitterlinden, AG, Ralston, SH, Ioannidis, JPA, Kiel, DP, Rivadeneira, F |
| Journal | Nat Genet |
| Volume | 44 |
| Issue | 5 |
| Pagination | 491-501 |
| Date Published | 2012 Apr 15 |
| ISSN | 1546-1718 |
| Keywords | Bone Density, Computational Biology, European Continental Ancestry Group, Extracellular Matrix Proteins, Female, Femur Neck, Fractures, Bone, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, Low Density Lipoprotein Receptor-Related Protein-5, Lumbar Vertebrae, Male, Mitochondrial Membrane Transport Proteins, Osteoporosis, Phosphoproteins, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Spectrin |
| Abstract | <p>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.</p> |
| DOI | 10.1038/ng.2249 |
| Alternate Journal | Nat. Genet. |
| PubMed ID | 22504420 |
| PubMed Central ID | PMC3338864 |
| Grant List | M01-RR00425 / RR / NCRR NIH HHS / United States CZB/4/710 / / Chief Scientist Office / United Kingdom P01 AG018397-10 / AG / NIA NIH HHS / United States N01 HC-55222, / HC / NHLBI NIH HHS / United States T32 AG000262-12 / AG / NIA NIH HHS / United States P01 AG-18397 / AG / NIA NIH HHS / United States 254627 / / Medical Research Council / United Kingdom / / British Heart Foundation / United Kingdom R01 HL075366 / HL / NHLBI NIH HHS / United States R01 AR046838 / AR / NIAMS NIH HHS / United States N01AG12100 / AG / NIA NIH HHS / United States R01 AG015928-02 / AG / NIA NIH HHS / United States 15389 / / Arthritis Research UK / United Kingdom P30 DK072488-03 / DK / NIDDK NIH HHS / United States G0600705 / / Medical Research Council / United Kingdom R01 HL087652-03 / HL / NHLBI NIH HHS / United States 17539 / / Arthritis Research UK / United Kingdom R01 AG018728-05 / AG / NIA NIH HHS / United States R01 AG015928 / AG / NIA NIH HHS / United States N01 AG062101 / AG / NIA NIH HHS / United States G9800062 / / Medical Research Council / United Kingdom U01 HL080295 / HL / NHLBI NIH HHS / United States HL 043851 / HL / NHLBI NIH HHS / United States P30 CA015704 / CA / NCI NIH HHS / United States N01 HC075150 / HC / NHLBI NIH HHS / United States HL69757 / HL / NHLBI NIH HHS / United States R01 AG041517-02 / AG / NIA NIH HHS / United States R01 HL043851 / HL / NHLBI NIH HHS / United States 1R01AG032098 / AG / NIA NIH HHS / United States HL105756 / HL / NHLBI NIH HHS / United States N01 HC015103 / HC / NHLBI NIH HHS / United States RG/08/014/24067 / / British Heart Foundation / United Kingdom R01 AG027058-04 / AG / NIA NIH HHS / United States R01 AR046838-05 / AR / NIAMS NIH HHS / United States R56 AG020098 / AG / NIA NIH HHS / United States N01 HC025195 / HC / NHLBI NIH HHS / United States U01 HL084756-03 / HL / NHLBI NIH HHS / United States N01 AG062106 / AG / WHI NIH HHS / United States N01 HC085085 / HC / NHLBI NIH HHS / United States R01 HL080295-08 / HL / NHLBI NIH HHS / United States R01 AG18728 / AG / NIA NIH HHS / United States G1000143 / / Medical Research Council / United Kingdom T32 AG000262 / AG / NIA NIH HHS / United States 303169 / / Medical Research Council / United Kingdom M01 RR-00750 / RR / NCRR NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States R01 AR/AG 41398 / AG / NIA NIH HHS / United States AG-20098 / AG / NIA NIH HHS / United States R01 AG023629-06 / AG / NIA NIH HHS / United States N02 HL64278 / HL / WHI NIH HHS / United States HL087652 / HL / NHLBI NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States N01 AG062106 / AG / NIA NIH HHS / United States P30 DK063491-10 / DK / NIDDK NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States M01 RR000425-36 / RR / NCRR NIH HHS / United States N01-HC-85086 / HC / NHLBI NIH HHS / United States R01 AR041398 / AR / NIAMS NIH HHS / United States R01 HL075366-05 / HL / NHLBI NIH HHS / United States R01 AG041517 / AG / NIA NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States R01 CA047988-20 / CA / NCI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States P01 AG018397 / AG / NIA NIH HHS / United States M01 RR000750 / RR / NCRR NIH HHS / United States CA 047988 / CA / NCI NIH HHS / United States AG-027058 / AG / NIA NIH HHS / United States MC_UP_A620_1014 / / Medical Research Council / United Kingdom R01 AG032098 / AG / NIA NIH HHS / United States U01 HL084756 / HL / NHLBI NIH HHS / United States G9321536 / / Medical Research Council / United Kingdom P30 DK063491 / DK / NIDDK NIH HHS / United States HHSN268200782096C / HG / NHGRI NIH HHS / United States HL075366 / HL / NHLBI NIH HHS / United States / / Intramural NIH HHS / United States P30 DK072488 / DK / NIDDK NIH HHS / United States N01 AG062103 / AG / NIA NIH HHS / United States G0401527 / / Medical Research Council / United Kingdom N01 AG012100 / AG / WHI NIH HHS / United States G0800582 / / Medical Research Council / United Kingdom M01 RR000750-31 / RR / NCRR NIH HHS / United States R01AR046838 / AR / NIAMS NIH HHS / United States N01-HC-75150 / HC / NHLBI NIH HHS / United States R01 AR050066-04 / AR / NIAMS NIH HHS / United States R01 AG032098-05 / AG / NIA NIH HHS / United States R01 AG020098-09 / AG / NIA NIH HHS / United States MC_PC_U127561128 / / Medical Research Council / United Kingdom R01 HL080295 / HL / NHLBI NIH HHS / United States F32 AR059469-02 / AR / NIAMS NIH HHS / United States R01 CA047988 / CA / NCI NIH HHS / United States R01 HL043851-10 / HL / NHLBI NIH HHS / United States M01 RR000425 / RR / NCRR NIH HHS / United States R01 HL088119-04 / HL / NHLBI NIH HHS / United States N01 HC085084 / HC / NHLBI NIH HHS / United States R01 AG020098 / AG / NIA NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States N01HC75150 / HL / NHLBI NIH HHS / United States U19 HL069757 / HL / NHLBI NIH HHS / United States R01 HL105756-03 / HL / NHLBI NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States U19 HL069757-11 / HL / NHLBI NIH HHS / United States N01HC25195 / HL / NHLBI NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States N01-HC-85079 / HC / NHLBI NIH HHS / United States HHSN268200782096C / / PHS HHS / United States HL080295 / HL / NHLBI NIH HHS / United States K08 AR055688 / AR / NIAMS NIH HHS / United States N01-HC-85239 / HC / NHLBI NIH HHS / United States AG-023629 / AG / NIA NIH HHS / United States N01HC85079 / HL / NHLBI NIH HHS / United States F32 AR059469 / AR / NIAMS NIH HHS / United States R01 AR050066 / AR / NIAMS NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States R01 AG027058 / AG / NIA NIH HHS / United States N01 HC045133 / HC / NHLBI NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States / / Wellcome Trust / United Kingdom MC_U147585824 / / Medical Research Council / United Kingdom U01 HL069757 / HL / NHLBI NIH HHS / United States 86748 / / Canadian Institutes of Health Research / Canada R01 AG018728 / AG / NIA NIH HHS / United States N01 HC035129 / HC / NHLBI NIH HHS / United States R01 AR 050066 / AR / NIAMS NIH HHS / United States R56 AG023629 / AG / NIA NIH HHS / United States R01 AR041398-20 / AR / NIAMS NIH HHS / United States 572604 / / Medical Research Council / United Kingdom N01HC85081 / HL / NHLBI NIH HHS / United States R01 HL088119 / HL / NHLBI NIH HHS / United States |
ePub date:
12/04