Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies

Nature Genetics

Volumn 41, Issue 11, 2009, Pages 1199-1206

  Rivadeneira, Fernando ^a,p   Styrkársdottir, Unnur ^b   Estrada, Karol ^a,p   Halldórsson, Bjarni V ^b,c   Hsu, Yi Hsiang ^d   Richards, J Brent ^e,f,g   Zillikens, M Carola ^a,p   Kavvoura, Fotini K ^h   Amin, Najaf ^a   Aulchenko, Yurii S ^a,p   Cupples, L Adrienne ⁱ   Deloukas, Panagiotis ^j   Demissie, Serkalem ⁱ   Grundberg, Elin ^f   Hofman, Albert ^a,p   Kong, Augustine ^b   Karasik, David ^d   Van Meurs, Joyce B ^a,p   Oostra, Ben ^a   Pastinen, Tomi ^f   Pols, Huibert A P ^a   Sigurdsson, Gunnar ^k,l   Soranzo, Nicole ^e,j   Thorleifsson, Gudmar ^b   Thorsteinsdottir, Unnur ^b,k   Williams, Frances M K ^g   Wilson, Scott G ^g,m   Zhou, Yanhua ⁱ   Ralston, Stuart H ⁿ   Van Duijn, Cornelia M ^a,p   Spector, Timothy ^g   Kiel, Douglas P ^d   Stefansson, Kari ^b,k   Ioannidis, John P A ^h,o   Uitterlinden, André G ^a,p   more..

^a ERASMUS MEDICAL CENTER   (Netherlands)

^b DECODE GENETICS   (Iceland)

^c REYKJAVIK UNIVERSITY   (Iceland)

^d HARVARD MEDICAL SCHOOL   (United States)

^e Harvard Medical School ^*

^f MCGILL UNIVERSITY   (Canada)

^g KING'S COLLEGE LONDON   (United Kingdom)

^h UNIVERSITY OF IOANNINA   (Greece)

ⁱ BOSTON UNIVERSITY   (United States)

^j WELLCOME TRUST SANGER INSTITUTE   (United Kingdom)

^k UNIVERSITY OF ICELAND   (Iceland)

^l LANDSPITALI UNIVERSITY HOSPITAL   (Iceland)

^m UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

ⁿ WESTERN GENERAL HOSPITAL   (United Kingdom)

^o TUFTS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^p Netherlands Genomics Initiative   (Netherlands)

more..

Author keywords

[No Author keywords available]

Indexed keywords

GENOMIC DNA;

ARTICLE; BONE DENSITY; CLINICAL TRIAL; GENE EXPRESSION; GENE IDENTIFICATION; GENE LOCUS; GENETIC TRAIT; GENETIC VARIABILITY; HUMAN; META ANALYSIS; OSTEOPOROSIS; PRIORITY JOURNAL; SINGLE NUCLEOTIDE POLYMORPHISM; SYSTEMATIC REVIEW;

BONE DENSITY; EUROPEAN CONTINENTAL ANCESTRY GROUP; FEMUR; FRACTURES, BONE; GENE EXPRESSION REGULATION; GENOME-WIDE ASSOCIATION STUDY; GENOTYPE; HUMANS; LUMBAR VERTEBRAE; POLYMORPHISM, SINGLE NUCLEOTIDE; QUANTITATIVE TRAIT LOCI; RISK FACTORS;

EID: 70350646912     PISSN: 10614036     EISSN: 15461718     Source Type: Journal    
DOI: 10.1038/ng.446     Document Type: Article

References (73)

1. Ellies, D.L. et al. Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. J. Bone Miner. Res. 21, 1738-1749 (2006).
2. Theoleyre, S. et al. The molecular triad Opg/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev. 15, 457-475 (2004).
3. Ioannidis, J.P. et al. Meta-analysis of genome-wide scans provides evidence for sex-and site-specifc regulation of bone mass. J. Bone Miner. Res. 22, 173-183 (2007).
4. Ioannidis, J.P. Why most published research fndings are false. PLoS Med. 2, e124 (2005).
5. Ioannidis, J.P. Genetic associations: false or true? Trends Mol. Med. 9, 135-138 (2003).
6. Ioannidis, J.P. et al. Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. J. Am. Med. Assoc. 292, 2105-2114 (2004).
7. Langdahl, B.L. et al. Large-scale analysis of association between polymorphisms in the transforming growth factor beta 1 gene (TGFB1) and osteoporosis: the GENOMOS study. Bone 42, 969-981 (2008).
8. Ralston, S.H. et al. Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study. PLoS Med. 3, e90 (2006).
9. Uitterlinden, A.G. et al. The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis. Ann. Intern. Med. 145, 255-264 (2006).
10. van Meurs, J.B. et al. Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. J. Am. Med. Assoc. 299, 1277-1290 (2008).
11. McCarthy, M.I. et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat. Rev. Genet. 9, 356-369 (2008).
12. Styrkarsdottir, U. et al. New sequence variants associated with bone mineral density. Nat. Genet. 41, 15-17 (2009).
13. Styrkarsdottir, U. et al. Multiple genetic loci for bone mineral density and fractures. N. Engl. J. Med. 358, 2355-2365 (2008).
14. Kanis, J.A., Delmas, P., Burckhardt, P., Cooper, C. & Torgerson, D. Guidelines for diagnosis and management of osteoporosis. The European Foundation for Osteoporosis and Bone Disease. Osteoporos. Int. 7, 390-406 (1997).
15. Blake, G.M., Knapp, K.M., Spector, T.D. & Fogelman, I. Predicting the risk of fracture at any site in the skeleton: are all bone mineral density measurement sites equally effective? Calcif. Tissue Int. 78, 9-17 (2006).
16. Peacock, M., Turner, C.H., Econs, M.J. & Foroud, T. Genetics of osteoporosis. Endocr. Rev. 23, 303-326 (2002).
17. Weedon, M.N. et al. Genome-wide association analysis identifes 20 loci that infuence adult height. Nat. Genet. 40, 575-583 (2008).
18. Gudbjartsson, D.F. et al. Many sequence variants affecting diversity of adult human height. Nat. Genet. 40, 609-615 (2008).
19. Visscher, P.M. Sizing up human height variation. Nat. Genet. 40, 489-490 (2008).
20. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997-1004 (1999).
21. Willer, C.J. et al. Six new loci associated with body mass index highlight a neuronal infuence on body weight regulation. Nat. Genet. 41, 25-34 (2009).
22. Pe'er, I., Yelensky, R., Altshuler, D. & Daly, M.J. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet. Epidemiol. 32, 381-385 (2008).
23. Frazer, K.A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851-861 (2007).
24. Richards, J.B. et al. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371, 1505-1512 (2008).
25. Bänziger, C. et al. Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell 125, 509-522 (2006).
26. Matsuda, A. et al. Large-scale identifcation and characterization of human genes that activate NF-κB and MAPK signaling pathways. Oncogene 22, 3307-3318 (2003).
27. Glass, D.A. II et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev. Cell 8, 751-764 (2005).
28. Potthoff, M.J. et al. Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofbers. J. Clin. Invest. 117, 2459-2467 (2007).
29. Cho, Y.S. et al. A large-scale genome-wide association study of Asian populations uncovers genetic factors infuencing eight quantitative traits. Nat. Genet. 41, 527-534 (2009).
30. Smits, P. et al. The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. Dev. Cell 1, 277-290 (2001).
31. Zhou, G. et al. Dominance of SOX9 function over RUNX2 during skeletogenesis. Proc. Natl. Acad. Sci. USA 103, 19004-19009 (2006).
32. Reiner, O. et al. The evolving doublecortin (DCX) superfamily. BMC Genomics 7, 188 (2006).
33. Kim, S.H. et al. The forkhead transcription factor Foxc2 stimulates osteoblast differentiation. Biochem. Biophys. Res. Commun. 386, 532-536 (2009).
34. Nifuji, A., Miura, N., Kato, N., Kellermann, O. & Noda, M. Bone morphogenetic protein regulation of forkhead/winged helix transcription factor Foxc2 (Mfh1) in a murine mesodermal cell line C1 and in skeletal precursor cells. J. Bone Miner. Res. 16, 1765-1771 (2001).
35. Winnier, G.E., Hargett, L. & Hogan, B.L. The winged helix transcription factor MFH1 is required for proliferation and patterning of paraxial mesoderm in the mouse embryo. Genes Dev. 11, 926-940 (1997).
36. Stankiewicz, P. et al. Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am. J. Hum. Genet. 84, 780-791 (2009).
37. Tang, Y. et al. Disruption of transforming growth factor-β signaling in ELF β-spectrin-defcient mice. Science 299, 574-577 (2003).
38. Alford, A.I. & Hankenson, K.D. Matricellular proteins: extracellular modulators of bone development, remodeling, and regeneration. Bone 38, 749-757 (2006).
39. Gowen, L.C. et al. Targeted disruption of the osteoblast/osteocyte factor 45 gene (OF45) results in increased bone formation and bone mass. J. Biol. Chem. 278, 1998-2007 (2003).
40. Malaval, L. et al. Bone sialoprotein plays a functional role in bone formation and osteoclastogenesis. J. Exp. Med. 205, 1145-1153 (2008).
41. Yoshitake, H., Rittling, S.R., Denhardt, D.T. & Noda, M. Osteopontin-defcient mice are resistant to ovariectomy-induced bone resorption. Proc. Natl. Acad. Sci. USA 96, 8156-8160 (1999).
42. Meyers, V.E., Zayzafoon, M., Douglas, J.T. & McDonald, J.M. RhoA and cytoskeletal disruption mediate reduced osteoblastogenesis and enhanced adipogenesis of human mesenchymal stem cells in modeled microgravity. J. Bone Miner. Res. 20, 1858-1866 (2005).
43. Wang, L., Yang, L., Debidda, M., Witte, D. & Zheng, Y. Cdc42 GTPase-activating protein defciency promotes genomic instability and premature aging-like phenotypes. Proc. Natl. Acad. Sci. USA 104, 1248-1253 (2007).
44. McKinsey, T.A., Zhang, C.L., Lu, J. & Olson, E.N. Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature 408, 106-111 (2000).
45. Schroeder, T.M. & Westendorf, J.J. Histone deacetylase inhibitors promote osteoblast maturation. J. Bone Miner. Res. 20, 2254-2263 (2005).
46. Kang, J.S., Alliston, T., Delston, R. & Derynck, R. Repression of Runx2 function by TGF-β through recruitment of class II histone deacetylases by Smad3. EMBO J. 24, 2543-2555 (2005).
47. Ioannidis, J.P., Thomas, G. & Daly, M.J. Validating, augmenting and refning genome-wide association signals. Nat. Rev. Genet. 10, 318-329 (2009).
48. Online Mendelian Inheritance in Man (OMIM) database (McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, and National Center for Biotechnology Information, National Library of Medicine, Bethesda, Maryland, USA). http://www.ncbi.nlm.nih.gov/omim/.
49. McKusick, V.A. Mendelian Inheritance in Man. A Catalog of Human Genes and Genetic Disorders (Johns Hopkins University Press, Baltimore, Maryland, USA, 1998).
50. Hofman, A. et al. The Rotterdam Study: 2010 objectives and design update. Eur. J. Epidemiol. 24, 553-572 (2009).
51. Hofman, A., Grobbee, D.E., de Jong, P.T. & van den Ouweland, F.A. Determinants of disease and disability in the elderly: the Rotterdam Elderly Study. Eur. J. Epidemiol. 7, 403-422 (1991).
52. Aulchenko, Y.S. et al. Linkage disequilibrium in young genetically isolated Dutch population. Eur. J. Hum. Genet. 12, 527-534 (2004).
53. Arden, N.K., Baker, J., Hogg, C., Baan, K. & Spector, T.D. The heritability of bone mineral density, ultrasound of the calcaneus and hip axis length: a study of postmenopausal twins. J. Bone Miner. Res. 11, 530-534 (1996).
54. Dawber, T.R., Kannel, W.B. & Lyell, L.P. An approach to longitudinal studies in a community: the Framingham Study. Ann. NY Acad. Sci. 107, 539-556 (1963).
55. Kannel, W.B., Feinleib, M., McNamara, P.M., Garrison, R.J. & Castelli, W.P. An investigation of coronary heart disease in families. The Framingham offspring study. Am. J. Epidemiol. 110, 281-290 (1979).
56. Splansky, G.L. et al. The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination. Am. J. Epidemiol. 165, 1328-1335 (2007).
57. Price, A.L. et al. Principal components analysis corrects for stratifcation in genome-wide association studies. Nat. Genet. 38, 904-909 (2006).
58. International HapMap Consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851-861 (2007).
59. Li, Y. & Abecasis, G.R. Mach 1.0: rapid haplotype reconstruction and missing genotype inference. Am. J. Hum. Genet. s79, 2290 (2006).
60. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906-913 (2007).
61. Kutyavin, I.V. et al. A novel endonuclease IV post-PCR genotyping system. Nucleic Acids Res. 34, e128 (2006).
62. Little, J. et al. Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE statement. Eur. J. Epidemiol. 24, 37-55 (2009).
63. Abecasis, G.R., Cherny, S.S., Cookson, W.O. & Cardon, L.R. Merlin-rapid analysis of dense genetic maps using sparse gene fow trees. Nat. Genet. 30, 97-101 (2002).
64. Therneau, T. Kinship: mixed effects Cox models, sparse matrices, and modelling data from large pedigrees. R package version 1.1.0, edn. 19 (R Foundation for Statistical Computing, Vienna, Austria, 2008).
65. Aulchenko, Y.S., Ripke, S., Isaacs, A. & van Duijn, C.M. GenABEL: an R library for genome-wide association analysis. Bioinformatics 23, 1294-1296 (2007).
66. R Developmental Core Team. A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, Vienna, Austria, 2007).
67. de Bakker, P.I. et al. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum. Mol. Genet. 17, R122-R128 (2008).
68. Stata Statistical Software. Release 10 (StataCorp LP, College Station, Texas, USA, 2007).
69. Grundberg, E. et al. Systematic assessment of the human osteoblast transcriptome in resting and induced primary cells. Physiol. Genomics 33, 301-311 (2008).
70. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559-575 (2007).
71. Rivadeneira, F. et al. Estrogen receptor beta (ESR2) polymorphisms in interaction with estrogen receptor alpha (ESR1) and insulin-like growth factor I (IGF1) variants infuence the risk of fracture in postmenopausal women. J. Bone Miner. Res. 21, 1443-1456 (2006).
72. Schuit, S.C. et al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone 34, 195-202 (2004).
73. McCloskey, E.V. et al. The assessment of vertebral deformity: a method for use in population studies and clinical trials. Osteoporos. Int. 3, 138-147 (1993).