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Publisher: Nature Publishing Group
Languages: English
Types: Article
Subjects:
Classified by OpenAIRE into
mesheuropmc: musculoskeletal diseases
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.
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- 1. Burge R, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005- 2025. J Bone Miner Res. 2007; 22:465- 75. [PubMed: 17144789]
- 2. Johnell O, et al. Predictive value of BMD for hip and other fractures. J Bone Miner Res. 2005; 20:1185- 94. [PubMed: 15940371]
- 3. Kanis JA, et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int. 2007; 18:1033- 46. [PubMed: 17323110]
- 4. Peacock M, Turner CH, Econs MJ, Foroud T. Genetics of osteoporosis. Endocr Rev. 2002; 23:303- 26. [PubMed: 12050122]
- 5. Ralston SH, Uitterlinden AG. Genetics of osteoporosis. Endocr Rev. 2010; 31:629- 62. [PubMed: 20431112]
- 6. Hardy J, Singleton A. Genomewide association studies and human disease. N Engl J Med. 2009; 360:1759- 68. [PubMed: 19369657]
- 7. Manolio TA. Genomewide association studies and assessment of the risk of disease. N Engl J Med. 2010; 363:166- 76. [PubMed: 20647212]
- 8. Richards JB, et al. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet. 2008; 371:1505- 12. [PubMed: 18455228]
- 9. Styrkarsdottir U, et al. Multiple genetic loci for bone mineral density and fractures. N Engl J Med. 2008; 358:2355- 65. [PubMed: 18445777]
- 10. Rivadeneira F, et al. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet. 2009; 41:1199- 206. [PubMed: 19801982]
- 11. Styrkarsdottir U, et al. New sequence variants associated with bone mineral density. Nat Genet. 2009; 41:15- 7. [PubMed: 19079262]
- 12. Hsu YH, et al. An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits. PLoS Genet. 2010; 6:e1000977. [PubMed: 20548944]
- 13. Kung AW, et al. Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies. Am J Hum Genet. 2010; 86:229- 39. [PubMed: 20096396]
- 14. Duncan EL, et al. Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS Genet. 2011; 7:e1001372. [PubMed: 21533022]
- 15. Richards JB, et al. Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med. 2009; 151:528- 37. [PubMed: 19841454]
- 16. van Meurs JB, et al. Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. Jama. 2008; 299:1277- 90. [PubMed: 18349089]
- 17. Bagger YZ, et al. Links between cardiovascular disease and osteoporosis in postmenopausal women: serum lipids or atherosclerosis per se? Osteoporos Int. 2007; 18:505- 12. [PubMed: 17109061]
- 18. Kiel DP, et al. Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men. Bone. 2007; 40:587- 96. [PubMed: 17137849]
- 19. Raychaudhuri S, et al. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet. 2009; 5:e1000534. [PubMed: 19557189]
- 20. Lango Allen H, et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature. 2010; 467:832- 8. [PubMed: 20881960]
- 21. Brunkow ME, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet. 2001; 68:577- 89. [PubMed: 11179006]
- 22. Guo YF, et al. Polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with obesity phenotypes in a large family-based association study. J Med Genet. 2006; 43:798- 803. [PubMed: 16723389]
- 23. Kornak U, et al. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell. 2001; 104:205- 15. [PubMed: 11207362]
- 24. Panagiotou OA, Evangelou E, Ioannidis JP. Genome-wide significant associations for variants with minor allele frequency of 5% or less--an overview: A HuGE review. Am J Epidemiol. 2010; 172:869- 89. [PubMed: 20876667]
- 25. Jin W, et al. Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice. J Clin Invest. 2008; 118:1858- 66. [PubMed: 18382763]
- 26. Sundaram K, Shanmugarajan S, Rao DS, Reddy SV. Mutant p62P392L stimulation of osteoclast differentiation in Paget' s disease of bone. Endocrinology. 2011; 152:4180- 9. [PubMed: 21878516]
- 27. Grundberg E, et al. Population genomics in a disease targeted primary cell model. Genome Res. 2009; 19:1942- 52. [PubMed: 19654370]
- 28. Duan Y, Beck TJ, Wang XF, Seeman E. Structural and biomechanical basis of sexual dimorphism in femoral neck fragility has its origins in growth and aging. J Bone Miner Res. 2003; 18:1766- 74. [PubMed: 14584886]
- 29. Karasik D, Ferrari SL. Contribution of gender-specific genetic factors to osteoporosis risk. Ann Hum Genet. 2008; 72:696- 714. [PubMed: 18485052]
- 30. Ohlsson C, et al. Genetic determinants of serum testosterone concentrations in men. PLoS Genet. 2011; 7:e1002313. [PubMed: 21998597]
- 31. Styrkarsdottir U, et al. European bone mineral density loci are also associated with BMD in EastAsian populations. PLoS One. 2010; 5:e13217. [PubMed: 20949110]
- 32. Wood AR, et al. Allelic heterogeneity and more detailed analyses of known loci explain additional phenotypic variation and reveal complex patterns of association. Human molecular genetics. 2011; 20:4082- 92. [PubMed: 21798870]
- 33. Mosekilde L, Torring O, Rejnmark L. Emerging anabolic treatments in osteoporosis. Curr Drug Saf. 2011; 6:62- 74. [PubMed: 21524248]
- 34. Hasselblad V, Hedges LV. Meta-analysis of screening and diagnostic tests. Psychol Bull. 1995; 117:167- 78. [PubMed: 7870860]
- 35. Harris ST, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999; 282:1344- 52. [PubMed: 10527181]
- 36. Jackson RD, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006; 354:669- 83. [PubMed: 16481635]
- 37. Frazer KA, et al. A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007; 449:851- 61. [PubMed: 17943122]
- 38. Servin B, Stephens M. Imputation-based analysis of association studies: candidate regions and quantitative traits. PLoS Genet. 2007; 3:e114. [PubMed: 17676998]
- 39. Marchini J, Howie B, Myers S, McVean G, Donnelly P. A new multipoint method for genomewide association studies by imputation of genotypes. Nat Genet. 2007; 39:906- 13. [PubMed: 17572673]
- 40. Li Y, Willer C, Sanna S, Abecasis G. Genotype imputation. Annu Rev Genomics Hum Genet. 2009; 10:387- 406. [PubMed: 19715440]
- 41. Estrada K, et al. GRIMP: a web-and grid-based tool for high-speed analysis of large-scale genomewide association using imputed data. Bioinformatics. 2009; 25:2750- 2. [PubMed: 19700477]
- 42. Abecasis GR, Cherny SS, Cookson WO, Cardon LR. Merlin--rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet. 2002; 30:97- 101. [PubMed: 11731797]
- 43. Aulchenko YS, Struchalin MV, van Duijn CM. ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics. 2010; 11:134. [PubMed: 20233392]
- 44. Devlin B, Roeder K, Wasserman L. Genomic control, a new approach togenetic-based association studies. Theor Popul Biol. 2001; 60:155- 66. [PubMed: 11855950]
- 45. Ioannidis JP, Thomas G, Daly MJ. Validating, augmenting and refining genome-wide association signals. Nature reviews. Genetics. 2009; 10:318- 29.
- 46. Pereira TV, Patsopoulos NA, Salanti G, Ioannidis JP. Discovery properties of genome-wide association signals from cumulatively combined data sets. Am J Epidemiol. 2009; 170:1197- 206. [PubMed: 19808636]
- 47. Yang J, et al. Genomic inflation factors under polygenic inheritance. Eur J Hum Genet. 2011; 19:807- 12. [PubMed: 21407268]
- 48. Pe' er I, Yelensky R, Altshuler D, Daly MJ. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet Epidemiol. 2008; 32:381- 5. [PubMed: 18348202]
- 49. Reppe S, et al. Eight genes are highly associated with BMD variation in postmenopausal Caucasian women. Bone. 2010; 46:604- 12. [PubMed: 19922823]
- 50. Ge B, et al. Global patterns of cis variation in human cells revealed by high-density allelic expression analysis. Nat Genet. 2009; 41:1216- 22. [PubMed: 19838192]
- 51. Montgomery SB, et al. Transcriptome genetics using second generation sequencing in a Caucasian population. Nature. 2010; 464:773- 7. [PubMed: 20220756]
- 52. Stranger BE, et al. Population genomics of human gene expression. Nat Genet. 2007; 39:1217- 24. [PubMed: 17873874]
- 53. Grundberg E, et al. Global analysis of the impact of environmental perturbation on cis-regulation of gene expression. PLoS Genet. 2011; 7:e1001279. [PubMed: 21283786]
- 54. Emilsson V, et al. Genetics of gene expression and its effect on disease. Nature. 2008; 452:423- 8. [PubMed: 18344981]
- 55. Zeller T, et al. Genetics and beyond--the transcriptome of human monocytes and disease susceptibility. PLoS One. 2010; 5:e10693. [PubMed: 20502693]
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