Collaborative meta-analysis : associations of 150 candidate genes with osteoporosis and osteoporotic fracture

J.B. Richards, F.K. Kavvoura, F. Rivadeneira, U. Styrkarsdottir, K. Estrada, B.V. Halldorsson, Y.H. Hsu, M.C. Zillikens, Scott Wilson, Benjamin Mullin, N. Amin, Y.S. Aulchenko, L.A. Cupples, P. Deloukas, S. Demissie, A. Hofman, A. Kong, D. Karasik, J.B. Van Meurs, B.A. Oostra & 14 others H.A.P. Pols, G. Sigurdsson, U. Thorsteinsdottir, N. Soranzo, F.M.K. Williams, Y. Zhou, S.H. Ralston, G. Thorleifsson, C.M. Van Duijn, D.P. Kiel, K. Stefansson, A.G. Uitterlinden, J.P.A. Ioannidis, T.D. Spector

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Abstract

Background: Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies. Objective: To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes. Design: Large-scale meta-analysis of genome-wide association data. Setting: 5 international, multicenter, population-based studies. Participants: Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands. Measurements: Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures. Results: 150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST. Limitation: Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded. Conclusion: In this large-scale collaborative genome-wide metaanalysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD. Primary Funding Source: European Union, Netherlands Organisation for Scientific Research, Research Institute for Diseases in the Elderly, Netherlands Genomics Initiative, Wellcome Trust, National Institutes of Health, deCODE Genetics, and Canadian Institutes of Health Research.
Original languageEnglish
Pages (from-to)528-537
JournalAnnals of Internal Medicine
Volume151
Issue number8
Publication statusPublished - 2009

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Osteoporotic Fractures
Osteoporosis
Meta-Analysis
Single Nucleotide Polymorphism
Bone Density
Genes
Netherlands
HapMap Project
Human Genome
Alleles
Genome
Femur Neck
Bone Fractures
Linkage Disequilibrium
National Institutes of Health (U.S.)
European Union
Genomics
Haplotypes
Population
Epidemiology

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Richards, J. B., Kavvoura, F. K., Rivadeneira, F., Styrkarsdottir, U., Estrada, K., Halldorsson, B. V., ... Spector, T. D. (2009). Collaborative meta-analysis : associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Annals of Internal Medicine, 151(8), 528-537.
Richards, J.B. ; Kavvoura, F.K. ; Rivadeneira, F. ; Styrkarsdottir, U. ; Estrada, K. ; Halldorsson, B.V. ; Hsu, Y.H. ; Zillikens, M.C. ; Wilson, Scott ; Mullin, Benjamin ; Amin, N. ; Aulchenko, Y.S. ; Cupples, L.A. ; Deloukas, P. ; Demissie, S. ; Hofman, A. ; Kong, A. ; Karasik, D. ; Van Meurs, J.B. ; Oostra, B.A. ; Pols, H.A.P. ; Sigurdsson, G. ; Thorsteinsdottir, U. ; Soranzo, N. ; Williams, F.M.K. ; Zhou, Y. ; Ralston, S.H. ; Thorleifsson, G. ; Van Duijn, C.M. ; Kiel, D.P. ; Stefansson, K. ; Uitterlinden, A.G. ; Ioannidis, J.P.A. ; Spector, T.D. / Collaborative meta-analysis : associations of 150 candidate genes with osteoporosis and osteoporotic fracture. In: Annals of Internal Medicine. 2009 ; Vol. 151, No. 8. pp. 528-537.
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abstract = "Background: Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies. Objective: To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes. Design: Large-scale meta-analysis of genome-wide association data. Setting: 5 international, multicenter, population-based studies. Participants: Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands. Measurements: Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures. Results: 150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST. Limitation: Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded. Conclusion: In this large-scale collaborative genome-wide metaanalysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD. Primary Funding Source: European Union, Netherlands Organisation for Scientific Research, Research Institute for Diseases in the Elderly, Netherlands Genomics Initiative, Wellcome Trust, National Institutes of Health, deCODE Genetics, and Canadian Institutes of Health Research.",
author = "J.B. Richards and F.K. Kavvoura and F. Rivadeneira and U. Styrkarsdottir and K. Estrada and B.V. Halldorsson and Y.H. Hsu and M.C. Zillikens and Scott Wilson and Benjamin Mullin and N. Amin and Y.S. Aulchenko and L.A. Cupples and P. Deloukas and S. Demissie and A. Hofman and A. Kong and D. Karasik and {Van Meurs}, J.B. and B.A. Oostra and H.A.P. Pols and G. Sigurdsson and U. Thorsteinsdottir and N. Soranzo and F.M.K. Williams and Y. Zhou and S.H. Ralston and G. Thorleifsson and {Van Duijn}, C.M. and D.P. Kiel and K. Stefansson and A.G. Uitterlinden and J.P.A. Ioannidis and T.D. Spector",
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Richards, JB, Kavvoura, FK, Rivadeneira, F, Styrkarsdottir, U, Estrada, K, Halldorsson, BV, Hsu, YH, Zillikens, MC, Wilson, S, Mullin, B, Amin, N, Aulchenko, YS, Cupples, LA, Deloukas, P, Demissie, S, Hofman, A, Kong, A, Karasik, D, Van Meurs, JB, Oostra, BA, Pols, HAP, Sigurdsson, G, Thorsteinsdottir, U, Soranzo, N, Williams, FMK, Zhou, Y, Ralston, SH, Thorleifsson, G, Van Duijn, CM, Kiel, DP, Stefansson, K, Uitterlinden, AG, Ioannidis, JPA & Spector, TD 2009, 'Collaborative meta-analysis : associations of 150 candidate genes with osteoporosis and osteoporotic fracture' Annals of Internal Medicine, vol. 151, no. 8, pp. 528-537.

Collaborative meta-analysis : associations of 150 candidate genes with osteoporosis and osteoporotic fracture. / Richards, J.B.; Kavvoura, F.K.; Rivadeneira, F.; Styrkarsdottir, U.; Estrada, K.; Halldorsson, B.V.; Hsu, Y.H.; Zillikens, M.C.; Wilson, Scott; Mullin, Benjamin; Amin, N.; Aulchenko, Y.S.; Cupples, L.A.; Deloukas, P.; Demissie, S.; Hofman, A.; Kong, A.; Karasik, D.; Van Meurs, J.B.; Oostra, B.A.; Pols, H.A.P.; Sigurdsson, G.; Thorsteinsdottir, U.; Soranzo, N.; Williams, F.M.K.; Zhou, Y.; Ralston, S.H.; Thorleifsson, G.; Van Duijn, C.M.; Kiel, D.P.; Stefansson, K.; Uitterlinden, A.G.; Ioannidis, J.P.A.; Spector, T.D.

In: Annals of Internal Medicine, Vol. 151, No. 8, 2009, p. 528-537.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Collaborative meta-analysis : associations of 150 candidate genes with osteoporosis and osteoporotic fracture

AU - Richards, J.B.

AU - Kavvoura, F.K.

AU - Rivadeneira, F.

AU - Styrkarsdottir, U.

AU - Estrada, K.

AU - Halldorsson, B.V.

AU - Hsu, Y.H.

AU - Zillikens, M.C.

AU - Wilson, Scott

AU - Mullin, Benjamin

AU - Amin, N.

AU - Aulchenko, Y.S.

AU - Cupples, L.A.

AU - Deloukas, P.

AU - Demissie, S.

AU - Hofman, A.

AU - Kong, A.

AU - Karasik, D.

AU - Van Meurs, J.B.

AU - Oostra, B.A.

AU - Pols, H.A.P.

AU - Sigurdsson, G.

AU - Thorsteinsdottir, U.

AU - Soranzo, N.

AU - Williams, F.M.K.

AU - Zhou, Y.

AU - Ralston, S.H.

AU - Thorleifsson, G.

AU - Van Duijn, C.M.

AU - Kiel, D.P.

AU - Stefansson, K.

AU - Uitterlinden, A.G.

AU - Ioannidis, J.P.A.

AU - Spector, T.D.

PY - 2009

Y1 - 2009

N2 - Background: Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies. Objective: To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes. Design: Large-scale meta-analysis of genome-wide association data. Setting: 5 international, multicenter, population-based studies. Participants: Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands. Measurements: Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures. Results: 150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST. Limitation: Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded. Conclusion: In this large-scale collaborative genome-wide metaanalysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD. Primary Funding Source: European Union, Netherlands Organisation for Scientific Research, Research Institute for Diseases in the Elderly, Netherlands Genomics Initiative, Wellcome Trust, National Institutes of Health, deCODE Genetics, and Canadian Institutes of Health Research.

AB - Background: Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies. Objective: To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes. Design: Large-scale meta-analysis of genome-wide association data. Setting: 5 international, multicenter, population-based studies. Participants: Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands. Measurements: Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures. Results: 150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST. Limitation: Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded. Conclusion: In this large-scale collaborative genome-wide metaanalysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD. Primary Funding Source: European Union, Netherlands Organisation for Scientific Research, Research Institute for Diseases in the Elderly, Netherlands Genomics Initiative, Wellcome Trust, National Institutes of Health, deCODE Genetics, and Canadian Institutes of Health Research.

M3 - Article

VL - 151

SP - 528

EP - 537

JO - Annals of Internal Medicine

JF - Annals of Internal Medicine

SN - 0003-4819

IS - 8

ER -

Richards JB, Kavvoura FK, Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson BV et al. Collaborative meta-analysis : associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Annals of Internal Medicine. 2009;151(8):528-537.