J. Brent Richards, MD, MSc; Fotini K. Kavvoura, MD, PhD; Fernando Rivadeneira, MD, PhD; Unnur Styrkársdóttir, PhD; Karol Estrada, MSc; Bjarni V. Halldórsson, PhD; Yi-Hsiang Hsu, MD, ScD; M. Carola Zillikens, MD; Scott G. Wilson, PhD; Benjamin H. Mullin, BSc; Najaf Amin, MSc; Yurii S. Aulchenko, PhD; L. Adrienne Cupples, PhD; Panagiotis Deloukas, PhD; Serkalem Demissie, PhD; Albert Hofman, MD, PhD; Augustine Kong, PhD; David Karasik, PhD; Joyce B. van Meurs, PhD; Ben A. Oostra, PhD; Huibert A.P. Pols, MD, PhD; Gunnar Sigurdsson, MD, PhD; Unnur Thorsteinsdottir, PhD; Nicole Soranzo, PhD; Frances M.K. Williams, MD, PhD; Yanhua Zhou, MSc; Stuart H. Ralston, MD; Gudmar Thorleifsson, PhD; Cornelia M. van Duijn, PhD; Douglas P. Kiel, MD, MPH; Kari Stefansson, MD, PhD; André G. Uitterlinden, PhD; John P.A. Ioannidis, MD, PhD; Tim D. Spector, MD, MSc; for the GEFOS (Genetic Factors for Osteoporosis) Consortium
Acknowledgment: The authors thank Pascal Arp, Mila Jhamai, Dr. Michael Moorhouse, Marijn Verkerk, and Sander Bervoets for their help in creating the Genome-Wide Association Studies (GWAS) database. They also thank the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. For genotyping of TwinsUK samples, the authors thank the staff from the Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation, quality control, and genotyping; Centre National de Génotypage; Duke University; and Institute for Molecular Medicine Finland, Finnish Genome Center, University of Helsinki.
Grant Support: By the European Union (grant FP7-Health-F2-2008-201865-GEFOS), and in part by the European Union FP5 (grant HEALTH-LRP4-2008-201865), the Wellcome Trust, the National Institutes of Health, the Canadian Institutes of Health Research, deCODE Genetics, Netherlands Organisation for Scientific Research (NWO), Research Institute for Diseases in the Elderly, and Netherlands Genomics Initiative (NGI). For more details of the GEFOS Consortium, see www.gefos.org. The TwinsUK study was funded by the Wellcome Trust, European Commission Framework (FP7/2007-2013), ENGAGE project HEALTH-F4-2007-201413, and the FP5 GenomEUtwin Project (QLG2-CT-2002-01254). It also receives support from the Arthritis Research Campaign, Chronic Disease Research Foundation, the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London, and a Biotechnology and Biological Sciences Research Council project grant (G20234). Dr. Spector is an NIHR senior investigator. The Framingham Osteoporosis Study was funded by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute on Aging (R01 AR/AG 41398 [Dr. Kiel] and R01 AR 050066 [Dr. Karasik]). The Framingham Heart Study was supported by the National Heart, Lung, and Blood Institute (contract N01-HC-25195) and by Affymetrix (contracted for genotyping services; contract N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource project. A portion of this research was conducted by using the Linux Cluster for Genetic Analysis, funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The generation and management of GWAS genotype data for the Rotterdam Study are supported by the NWO Investments (175.010.2005.011, 911-03-012). The Rotterdam Study is funded by the Research Institute for Diseases in the Elderly (014-93-015); NGI/NWO (project 050-060-810); NGI/Netherlands Consortium on Healthy Ageing; Erasmus Medical Center and Erasmus University; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam.
Potential Conflicts of Interest:Employment: U. Styrkársdóttir (deCODE Genetics), B.V. Halldórsson (deCODE Genetics), A. Kong (deCODE Genetics), U. Thorsteinsdottir (deCODE Genetics), G. Thorleifsson (deCODE Genetics), K. Stefansson (deCODE Genetics). Consultancies: S.H. Ralston (Novartis, Procter & Gamble, Merck). Stock ownership or options (other than mutual funds): U. Styrkársdóttir (deCODE Genetics), B.V. Halldórsson (deCODE Genetics), A. Kong (deCODE Genetics), U. Thorsteinsdottir (deCODE Genetics), G. Thorleifsson (deCODE Genetics), K. Stefansson (deCODE Genetics). Grants received: U. Styrkársdóttir (GEFOS Consortium), B.V. Halldórsson (GEFOS Consortium), U. Thorsteinsdottir (GEFOS Consortium), S.H. Ralston (Wyeth, Novartis), K. Stefansson (GEFOS Consortium). Patents received: S.H. Ralston (COL1A1 as a diagnostic marker).
Reproducible Research Statement:Study protocol: Not available. Statistical code: Available from Dr. Ioannidis (firstname.lastname@example.org). Data set: Certain portions are available to approved individuals through written agreements with the GEFOS Consortium through Dr. Uitterlinden (email@example.com).
Requests for Single Reprints: John Ioannidis, MD, PhD, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, PO Box 1186, 45110 Ioannina, Greece; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Richards: Department of Medicine, McGill University, 3755 Côte-Ste-Catherine Road, Montreal, Quebec, H3T-1E2, Canada.
Drs. Kavvoura and Ioannidis: Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, PO Box 1186, 45110, Ioannina, Greece.
Drs. Styrkársdóttir, Halldórsson, Kong, Thorsteinsdottir, Thorleifsson, and Stefansson: deCODE Genetics, Sturlugata 8, IS-101, Reykjavík, Iceland.
Mr. Estrada and Drs. Zillikens, van Meurs, and Uitterlinden: Department of Internal Medicine, Erasmus Medical Center, PO Box 2400, 3000 CA, Rotterdam, the Netherlands.
Drs. Hsu, Karasik, and Kiel: Hebrew SeniorLife, 1200 Centre Street, Boston, MA 02131.
Dr. Wilson and Mr. Mullin: Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Perth 6009, Western Australia.
Ms. Amin and Drs. Aulchenko, Oostra, and van Duijn: Department of Clinical Genetics, Erasmus Medical Center, PO Box 2400, 3000 CA, Rotterdam, the Netherlands.
Drs. Cupples and Demissie and Mr. Zhou: Department of Biostatistics, Boston University School of Public Health, 801 Massachusetts Avenue, Boston, MA 02118.
Drs. Deloukas and Soranzo: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom.
Drs. Hofman and Pols: Department of Epidemiology, Erasmus Medical Center, PO Box 2400, 3000 CA, Rotterdam, the Netherlands.
Dr. Sigurdsson: Division of Endocrinology and Metabolism, Landspítali University Hospital, Fossvogur, 108, Reykjavík, Iceland.
Drs. Williams and Spector: Department of Twin Research & Genetic Epidemiology, King's College London, Strand, London, WC2R 2LS, United Kingdom.
Dr. Ralston: Molecular Medicine Centre, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom.
Author Contributions: Conception and design: J.B. Richards, L.A. Cupples, A. Hofman, H.A.P. Pols, Y. Zhou, S.H. Ralston, D.P. Kiel, J.P.A. Ioannidis, T.D. Spector.
Analysis and interpretation of the data: J.B. Richards, F.K. Kavvoura, U. Styrkársdóttir, K. Estrada, B.V. Halldórsson, Y.-H. Hsu, N. Amin, L.A. Cupples, P. Deloukas, S. Demissie, U. Thorsteinsdottir, N. Soranzo, Y. Zhou, S.H. Ralston, C.M. van Duijn, D.P. Kiel, J.P.A. Ioannidis, T.D. Spector.
Drafting of the article: J.B. Richards, J.P.A. Ioannidis.
Critical revision of the article for important intellectual content: J.B. Richards, F.K. Kavvoura, K. Estrada, B.V. Halldórsson, Y.-H. Hsu, M.C. Zillikens, S.G. Wilson, B.H. Mullin, N. Amin, Y.S. Aulchenko, P. Deloukas, A. Hofman, J.B. van Meurs, H.A.P. Pols, G. Sigurdsson, F.M.K. Williams, S.H. Ralston, C.M. van Duijn, D.P. Kiel, J.P.A. Ioannidis, T.D. Spector.
Final approval of the article: J.B. Richards, F.K. Kavvoura, U. Styrkársdóttir, B.V. Halldórsson, Y.-H. Hsu, M.C. Zillikens, S.G. Wilson, B.H. Mullin, N. Amin, Y.S. Aulchenko, L.A. Cupples, P. Deloukas, S. Demissie, A. Hofman, A. Kong, J.B. van Meurs, H.A.P. Pols, G. Sigurdsson, U. Thorsteinsdottir, F.M.K. Williams, S.H. Ralston, G. Thorleifsson, C.M. van Duijn, D.P. Kiel, J.P.A. Ioannidis.
Provision of study materials or patients: A. Hofman, B.A. Oostra, H.A.P. Pols, G. Sigurdsson, N. Soranzo, D.P. Kiel, T.D. Spector.
Statistical expertise: J.B. Richards, K. Estrada, B.V. Halldórsson, Y.-H. Hsu, N. Amin, Y.S. Aulchenko, L.A. Cupples, S. Demissie, A. Kong, J.B. van Meurs, N. Soranzo, G. Thorleifsson, C.M. van Duijn, J.P.A. Ioannidis.
Obtaining of funding: A. Hofman, H.A.P. Pols, N. Soranzo, S.H. Ralston, D.P. Kiel, K. Stefansson, J.P.A. Ioannidis, T.D. Spector.
Administrative, technical, or logistic support: J.B. Richards, U. Styrkársdóttir, S.G. Wilson, B.H. Mullin, A. Hofman, H.A.P. Pols, U. Thorsteinsdottir, D.P. Kiel, K. Stefansson, J.P.A. Ioannidis.
Collection and assembly of data: U. Styrkársdóttir, M.C. Zillikens, A. Hofman, D. Karasik, H.A.P. Pols, G. Sigurdsson, N. Soranzo, F.M.K. Williams, D.P. Kiel.
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.
To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes.
Large-scale meta-analysis of genome-wide association data.
5 international, multicenter, population-based studies.
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.
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.
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.
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.
In this large-scale collaborative genome-wide meta-analysis, 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.
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.
Richards JB, Kavvoura FK, Rivadeneira F, Styrkársdóttir U, Estrada K, Halldórsson BV, et al. Collaborative Meta-analysis: Associations of 150 Candidate Genes With Osteoporosis and Osteoporotic Fracture. Ann Intern Med. 2009;151:528–537. doi: 10.7326/0003-4819-151-8-200910200-00006
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Published: Ann Intern Med. 2009;151(8):528-537.
Endocrine and Metabolism, Metabolic Bone Disorders.
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