Influences Bone Mineral Density, Cortical Bone Thickness, Bone Strength, and Osteoporotic Fracture Risk
We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of −0.11 standard deviations [SD] per C allele, P = 6.2×10−9). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (−0.14 SD per C allele, P = 2.3×10−12, and −0.16 SD per G allele, P = 1.2×10−15, respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10−9), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10−6 and rs2707466: OR = 1.22, P = 7.2×10−6). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16−/− mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%–61% (6.5×10−13<P<5.9×10−4) at both femur and tibia, compared with their wild-type littermates. Natural variation in humans and targeted disruption in mice demonstrate that WNT16 is an important determinant of CBT, BMD, bone strength, and risk of fracture.
Vyšlo v časopise:
Influences Bone Mineral Density, Cortical Bone Thickness, Bone Strength, and Osteoporotic Fracture Risk. PLoS Genet 8(7): e32767. doi:10.1371/journal.pgen.1002745
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002745
Souhrn
We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of −0.11 standard deviations [SD] per C allele, P = 6.2×10−9). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (−0.14 SD per C allele, P = 2.3×10−12, and −0.16 SD per G allele, P = 1.2×10−15, respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10−9), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10−6 and rs2707466: OR = 1.22, P = 7.2×10−6). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16−/− mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%–61% (6.5×10−13<P<5.9×10−4) at both femur and tibia, compared with their wild-type littermates. Natural variation in humans and targeted disruption in mice demonstrate that WNT16 is an important determinant of CBT, BMD, bone strength, and risk of fracture.
Zdroje
1. 1993 Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. The American journal of medicine 94 646 650
2. KanisJAJohnellOOdenASemboIRedlund-JohnellI 2000 Long-term risk of osteoporotic fracture in Malmo. Osteoporos Int 11 669 674
3. OrganizationWH WHO scientific group on the assessment of osteoporosis at primary health care level; 2007 May 5; Brussels, Belgium
4. BurgeRDawson-HughesBSolomonDHWongJBKingA 2007 Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. Journal of bone and mineral research 22 465 475
5. GueguenRJouannyPGuilleminFKuntzCPourelJ 1995 Segregation analysis and variance components analysis of bone mineral density in healthy families. J Bone Miner Res 10 2017 2022
6. SmithDMNanceWEKangKWChristianJCJohnstonCCJr 1973 Genetic factors in determining bone mass. J Clin Invest 52 2800 2808
7. KielDPDemissieSDupuisJLunettaKLMurabitoJM 2007 Genome-wide association with bone mass and geometry in the Framingham Heart Study. BMC medical genetics 8 Suppl 1 S14
8. RichardsJBRivadeneiraFInouyeMPastinenTMSoranzoN 2008 Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371 1505 1512
9. StyrkarsdottirUHalldorssonBVGretarsdottirSGudbjartssonDFWaltersGB 2008 Multiple genetic loci for bone mineral density and fractures. N Engl J Med 358 2355 2365
10. RivadeneiraFStyrkarsdottirUEstradaKHalldorssonBVHsuYH 2009 Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41 1199 1206
11. DuncanELDanoyPKempJPLeoPJMcCloskeyE 2011 Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS Genet 7 e1001372 doi:10.1371/journal.pgen.1001372
12. GuoYTanLJLeiSFYangTLChenXD 2010 Genome-wide association study identifies ALDH7A1 as a novel susceptibility gene for osteoporosis. PLoS Genet 6 e1000806 doi:10.1371/journal.pgen.1000806
13. ChoYSGoMJKimYJHeoJYOhJH 2009 A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet 41 527 534
14. PaternosterLLorentzonMVandenputLKarlssonMKLjunggrenO 2010 Genome-wide association meta-analysis of cortical bone mineral density unravels allelic heterogeneity at the RANKL locus and potential pleiotropic effects on bone. PLoS Genet 6 e1001217 doi:10.1371/journal.pgen.1001217
15. JohnellOKanisJ 2005 Epidemiology of osteoporotic fractures. Osteoporos Int 16 Suppl 2 S3 7
16. ZebazeRMGhasem-ZadehABohteAIuliano-BurnsSMiramsM 2010 Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study. Lancet 375 1729 1736
17. HolzerGvon SkrbenskyGHolzerLAPichlW 2009 Hip fractures and the contribution of cortical versus trabecular bone to femoral neck strength. J Bone Miner Res 24 468 474
18. JohannesdottirFPooleKEReeveJSiggeirsdottirKAspelundT 2011 Distribution of cortical bone in the femoral neck and hip fracture: a prospective case-control analysis of 143 incident hip fractures; the AGES-REYKJAVIK Study. Bone 48 1268 1276
19. HavillLMMahaneyMCTLBSpeckerBL 2007 Effects of genes, sex, age, and activity on BMC, bone size, and areal and volumetric BMD. J Bone Miner Res 22 737 746
20. PearsonTAManolioTA 2008 How to interpret a genome-wide association study. JAMA 299 1335 1344
21. MichaelssonKMelhusHFermHAhlbomAPedersenNL 2005 Genetic liability to fractures in the elderly. Archives of internal medicine 165 1825 1830
22. AndrewTAntioniadesLScurrahKJMacgregorAJSpectorTD 2005 Risk of wrist fracture in women is heritable and is influenced by genes that are largely independent of those influencing BMD. Journal of bone and mineral research 20 67 74
23. ZhengHFSpectorTDRichardsJB 2011 Insights into the genetics of osteoporosis from recent genome-wide association studies. Expert reviews in molecular medicine 13 e28
24. DuncanELBrownMA 2010 Genetic determinants of bone density and fracture risk–state of the art and future directions. The Journal of clinical endocrinology and metabolism 95 2576 2587
25. QiuCPapasianCJDengHWShenH 2011 Genetics of osteoporotic fracture. Orthop Res Rev 3 11 21
26. GongYSleeRBFukaiNRawadiGRoman-RomanS 2001 LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107 513 523
27. BoydenLMMaoJBelskyJMitznerLFarhiA 2002 High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346 1513 1521
28. ClementsWKKimADOngKGMooreJCLawsonND 2011 A somitic Wnt16/Notch pathway specifies haematopoietic stem cells. Nature 474 220 224
29. GuoXDayTFJiangXGarrett-BealLTopolL 2004 Wnt/beta-catenin signaling is sufficient and necessary for synovial joint formation. Genes Dev 18 2404 2417
30. StyrkarsdottirUHalldorssonBVGretarsdottirSGudbjartssonDFWaltersGB 2009 New sequence variants associated with bone mineral density. Nature genetics 41 15 17
31. HudelmaierMKuhnVLochmullerEMWellHPriemelM 2004 Can geometry-based parameters from pQCT and material parameters from quantitative ultrasound (QUS) improve the prediction of radial bone strength over that by bone mass (DXA)? Osteoporos Int 15 375 381
32. MeltonLJ3rdRiggsBLvan LentheGHAchenbachSJMullerR 2007 Contribution of in vivo structural measurements and load/strength ratios to the determination of forearm fracture risk in postmenopausal women. J Bone Miner Res 22 1442 1448
33. KatahiraTNakagiriSTeradaKFurukawaT 2010 Secreted factor FAM3C (ILEI) is involved in retinal laminar formation. Biochemical and biophysical research communications 392 301 306
34. RalstonSHUitterlindenAGBrandiMLBalcellsSLangdahlBL 2006 Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study. PLoS Med 3 e90 doi:10.1371/journal.pmed.0030090
35. IoannidisJPRalstonSHBennettSTBrandiMLGrinbergD 2004 Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. JAMA 292 2105 2114
36. RichardsJBKavvouraFKRivadeneiraFStyrkarsdottirUEstradaK 2009 Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Annals of internal medicine 151 528 537
37. ZhangLSHuHGLiuYJLiJYuP 2011 A follow-up association study of two genetic variants for bone mineral density variation in Caucasians. Osteoporos Int
38. TayoBOLukeAZhuXAdeyemoACooperRS 2009 Association of regions on chromosomes 6 and 7 with blood pressure in Nigerian families. Circulation Cardiovascular genetics 2 38 45
39. LorentzonMSwansonCAnderssonNMellstromDOhlssonC 2005 Free testosterone is a positive, whereas free estradiol is a negative, predictor of cortical bone size in young Swedish men: the GOOD study. J Bone Miner Res 20 1334 1341
40. LorentzonMMellstromDOhlssonC 2005 Age of attainment of peak bone mass is site specific in Swedish men―The GOOD Study. J Bone Miner Res 20 1223 1227
41. LiYAbecasisGR 2006 Mach 1.0: Rapid Haplotype Reconstruction and Missing Genotype Inference. Am J Hum Genet S79 2290
42. RaitakariOTJuonalaMRonnemaaTKeltikangas-JarvinenLRasanenL 2008 Cohort profile: the cardiovascular risk in Young Finns Study. Int J Epidemiol 37 1220 1226
43. LaaksonenMSievanenHTolonenSMikkilaVRasanenL 2010 Determinants of bone strength and fracture incidence in adult Finns: Cardiovascular Risk in Young Finns Study (the GENDI pQCT study). Arch Osteoporosis 5 119 130
44. GoldingJPembreyMJonesR 2001 ALSPAC–the Avon Longitudinal Study of Parents and Children. I. Study methodology. Paediatr Perinat Epidemiol 15 74 87
45. JonesRWRingSTyfieldLHamvasRSimmonsH 2000 A new human genetic resource: a DNA bank established as part of the Avon longitudinal study of pregnancy and childhood (ALSPAC). Eur J Hum Genet 8 653 660
46. MellstromDJohnellOLjunggrenOErikssonALLorentzonM 2006 Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden. J Bone Miner Res 21 529 535
47. AndrewTHartDJSniederHde LangeMSpectorTD 2001 Are twins and singletons comparable? A study of disease-related and lifestyle characteristics in adult women. Twin research 4 464 477
48. HowieBNDonnellyPMarchiniJ 2009 A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 5 e1000529 doi:10.1371/journal.pgen.1000529
49. StreetenEAMcBrideDJPollinTIRyanKShapiroJ 2006 Quantitative trait loci for BMD identified by autosome-wide linkage scan to chromosomes 7q and 21q in men from the Amish Family Osteoporosis Study. Journal of bone and mineral research 21 1433 1442
50. StreetenEAMcBrideDJLodgeALPollinTIStinchcombDG 2004 Reduced incidence of hip fracture in the Old Order Amish. Journal of bone and mineral research 19 308 313
51. OhlssonCDarelidANilssonMMelinJMellstromD 2011 Cortical consolidation due to increased mineralization and endosteal contraction in young adult men: a five-year longitudinal study. J Clin Endocrinol Metab 96 2262 2269
52. SimsAMShephardNCarterKDoanTDowlingA 2008 Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes. Journal of bone and mineral research 23 499 506
53. EnglundUNordstromPNilssonJBuchtGBjornstigU 2011 Physical activity in middle-aged women and hip fracture risk: the UFO study. Osteoporosis international 22 499 505
54. HallmansGAgrenAJohanssonGJohanssonAStegmayrB 2003 Cardiovascular disease and diabetes in the Northern Sweden Health and Disease Study Cohort - evaluation of risk factors and their interactions. Scandinavian journal of public health Supplement 61 18 24
55. RichardsJBPapaioannouAAdachiJDJosephLWhitsonHE 2007 Effect of selective serotonin reuptake inhibitors on the risk of fracture. Archives of internal medicine 167 188 194
56. LadouceurMLeslieWDDastaniZGoltzmanDRichardsJB 2010 An efficient paradigm for genetic epidemiology cohort creation. PLoS ONE 5 e14045 doi:10.1371/journal.pone.0014045
57. AulchenkoYSStruchalinMVvan DuijnCM 2010 ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics 11 134
58. EstradaKAbuseirisAGrosveldFGUitterlindenAGKnochTA 2009 GRIMP: a web- and grid-based tool for high-speed analysis of large-scale genome-wide association using imputed data. Bioinformatics 25 2750 2752
59. MagiRMorrisAP 2010 GWAMA: software for genome-wide association meta-analysis. BMC bioinformatics 11 288
60. PereiraTVPatsopoulosNASalantiGIoannidisJP 2009 Discovery properties of genome-wide association signals from cumulatively combined data sets. American journal of epidemiology 170 1197 1206
61. DevlinBRoederKWassermanL 2001 Genomic control, a new approach to genetic-based association studies. Theoretical population biology 60 155 166
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 7
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