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

Nature Genetics volume 41, pages 1199–1206 (2009)Cite this article

This article has been updated

Abstract

Bone mineral density (BMD) is a heritable complex trait used in the clinical diagnosis of osteoporosis and the assessment of fracture risk. We performed meta-analysis of five genome-wide association studies of femoral neck and lumbar spine BMD in 19,195 subjects of Northern European descent. We identified 20 BMD loci that reached genome-wide significance (GWS; P < 5 × 10−8), of which 13 map to regions not previously associated with this trait: 1p31.3 (GPR177), 2p21 (SPTBN1), 3p22 (CTNNB1), 4q21.1 (MEPE), 5q14 (MEF2C), 7p14 (STARD3NL), 7q21.3 (FLJ42280), 11p11.2 (LRP4, ARHGAP1, F2), 11p14.1 (DCDC5), 11p15 (SOX6), 16q24 (FOXL1), 17q21 (HDAC5) and 17q12 (CRHR1). The meta-analysis also confirmed at GWS level seven known BMD loci on 1p36 (ZBTB40), 6q25 (ESR1), 8q24 (TNFRSF11B), 11q13.4 (LRP5), 12q13 (SP7), 13q14 (TNFSF11) and 18q21 (TNFRSF11A). The many SNPs associated with BMD map to genes in signaling pathways with relevance to bone metabolism and highlight the complex genetic architecture that underlies osteoporosis and variation in BMD.

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Figure 1: Quantile-quantile (Q-Q) plots.
Figure 2: Manhattan plots.
Figure 3: Forest plots for the top SNPs for each of the nine newly discovered loci.
Figure 4: Forest plots for the top SNPs for each of the four loci attaining GWS for the first time in this study.
Figure 5: Histogram and line plot modeling in the Rotterdam Study of the combined allelic effect across all genome-wide significant associated loci.

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Change history

  • 11 October 2009

    NOTE: In the version of this article initially published online, the seventh and eighth sentences under the heading “Combined effect of the 20 GWS BMD loci and fracture risk” were incorrect. The correct wording is as follows: “The compound FN-BMD allelic score was significantly associated with the risk of incident nonvertebral fracture in the Rotterdam Study dataset (HR = 1.042, 95% CI [1.003, 1.084]; P = 0.04), whereas it was borderline significant for association with the risk of vertebral fracture (OR = 1.061, 95% CI [0.997, 1.129]; P = 0.06). In contrast, the compound LS-BMD allelic score was significantly associated with the risk of vertebral fracture (OR = 1.061, 95% CI [1.009, 1.116]; P = 0.02), whereas it was not significant for association with the risk of incident nonvertebral fracture (HR = 1.025, 95% CI [0.993, 1.058]; P = 0.13).” The error has been corrected for all versions of the article.

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Acknowledgements

We thank all study participants for making this work possible. This research and the Genetic Factors for Osteoporosis (GEFOS) consortium (http://www.gefos.org) have been funded by the European Commission (HEALTH-F2-2008-201865-GEFOS). Rotterdam Study (RS): This study was funded by the Netherlands Organization of Scientific Research NWO Investments (175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2) and the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) project 050-060-810. We thank P. Arp, M. Jhamai, M. Moorhouse, M. Verkerk and S. Bervoets for their help in creating the GWAS database. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. We thank the staff from the Rotterdam Study, particularly L. Buist and J.H. van den Boogert and also the participating general practitioners and pharmacists. Erasmus Rucphen Family (ERF): The study was supported by grants from The Netherlands Organization for Scientific Research (NWO), Erasmus MC and the Centre for Medical Systems Biology (CMSB). We thank all general practitioners for their contributions, P. Veraart for help in genealogy, J. Vergeer for supervision of the laboratory work and P. Snijders for help in data collection. Twins UK (TUK): The study was funded by the Wellcome Trust, the Arthritis Research Campaign, the Chronic Disease Research Foundation, the Canadian Institutes of Health Research (J.B.R.), the European Society for Clinical and Economic Aspects of Osteoporosis (J.B.R.) and the European Union FP-5 GenomEUtwin Project (QLG2-CT-2002-01254). The study also receives support from a National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London. We thank the staff of the Twins UK study; the DNA Collections and Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation; Quality Control of the Twins UK cohort for genotyping (in particular A. Chaney, R. Ravindrarajah, D. Simpkin, C. Hinds and T. Dibling); P. Martin and S. Potter of the DNA and Genotyping Informatics teams for data handling; Le Centre National de Génotypage, France, led by M. Lathrop, for genotyping; Duke University, North Carolina, USA, led by D. Goldstein, for genotyping; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki, led by A. Palotie. Icelandic deCODE Study (dCG): We thank the staff of the deCODE core facilities and recruitment centre for their important contributions to this work. Framingham Osteoporosis Study (FOS): The study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR/AG 41398; DPK and R01 AR 050066; DK). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. eQTL HOb Study: The study was supported by Genome Quebec, Genome Canada and the Canadian Institutes of Health Research (CIHR). T.P. holds a Canada Research Chair. We thank O. Nilsson, H. Mallmin and Ö. Ljunggren at the Departments of Surgical and Medical Sciences, Uppsala University Hospital, Sweden, for large-scale collection of primary bone samples.

Author information

Author notes

  1. Fernando Rivadeneira, Unnur Styrkársdottir, Karol Estrada, Bjarni V Halldórsson, Yi-Hsiang Hsu, J Brent Richards, M Carola Zillikens, Fotini K Kavvoura, Cornelia M van Duijn, Timothy Spector, Douglas P Kiel, Kari Stefansson, John P A Ioannidis and André G Uitterlinden: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Internal Medicine, Rotterdam, The Netherlands

    Fernando Rivadeneira, Karol Estrada, M Carola Zillikens, Joyce B van Meurs, Huibert A P Pols & André G Uitterlinden

  2. Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands

    Fernando Rivadeneira, Najaf Amin, Yurii S Aulchenko, Albert Hofman, Joyce B van Meurs, Huibert A P Pols, Cornelia M van Duijn & André G Uitterlinden

  3. deCODE Genetics, Reykjavík, Iceland

    Unnur Styrkársdottir, Bjarni V Halldórsson, Augustine Kong, Gudmar Thorleifsson, Unnur Thorsteinsdottir & Kari Stefansson

  4. Reykjavik University, Reykjavik, Iceland

    Bjarni V Halldórsson

  5. Hebrew SeniorLife, Harvard Medical School, Boston, Massachusetts, USA

    Yi-Hsiang Hsu, David Karasik & Douglas P Kiel

  6. Department of Medicine, Montréal, Québec, Canada

    J Brent Richards & Nicole Soranzo

  7. Department of Human Genetics, McGill University, Montréal, Québec, Canada

    Elin Grundberg & Tomi Pastinen

  8. Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK

    J Brent Richards, Frances M K Williams, Scott G Wilson & Timothy Spector

  9. Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece

    Fotini K Kavvoura & John P A Ioannidis

  10. Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts, USA

    L Adrienne Cupples, Serkalem Demissie & Yanhua Zhou

  11. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

    Panagiotis Deloukas & Nicole Soranzo

  12. McGill University and Genome Quebec Innovation Centre, Montréal, Québec, Canada

    Elin Grundberg & Tomi Pastinen

  13. Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands

    Ben Oostra

  14. Faculty of Medicine, University of Iceland, Reykjavík, Iceland

    Gunnar Sigurdsson, Unnur Thorsteinsdottir & Kari Stefansson

  15. Department of Endocrinology and Metabolism, University Hospital, Reykjavik, Iceland

    Gunnar Sigurdsson

  16. The University of Western Australia and Department of Endocrinology & Diabetes, School of Medicine & Pharmacology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia

    Scott G Wilson

  17. Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, UK

    Stuart H Ralston

  18. Center for Genetic Epidemiology and Modeling, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA

    John P A Ioannidis

  19. Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA).,

    Fernando Rivadeneira, Karol Estrada, M Carola Zillikens, Yurii S Aulchenko, Albert Hofman, Joyce B van Meurs, Cornelia M van Duijn & André G Uitterlinden

Consortia

the Genetic Factors for Osteoporosis (GEFOS) Consortium

  • Fernando Rivadeneira
  • , Unnur Styrkársdottir
  • , Karol Estrada
  • , Bjarni V Halldórsson
  • , Yi-Hsiang Hsu
  • , J Brent Richards
  • , M Carola Zillikens
  • , Fotini K Kavvoura
  • , Najaf Amin
  • , Yurii S Aulchenko
  • , L Adrienne Cupples
  • , Panagiotis Deloukas
  • , Serkalem Demissie
  • , Elin Grundberg
  • , Albert Hofman
  • , Augustine Kong
  • , David Karasik
  • , Joyce B van Meurs
  • , Ben Oostra
  • , Tomi Pastinen
  • , Huibert A P Pols
  • , Gunnar Sigurdsson
  • , Nicole Soranzo
  • , Gudmar Thorleifsson
  • , Unnur Thorsteinsdottir
  • , Frances M K Williams
  • , Scott G Wilson
  • , Yanhua Zhou
  • , Stuart H Ralston
  • , Cornelia M van Duijn
  • , Timothy Spector
  • , Douglas P Kiel
  • , Kari Stefansson
  • , John P A Ioannidis
  •  & André G Uitterlinden

Contributions

F.R., K.E., B.V.H., F.K.K. and J.P.A.I. ran meta-analysis; F.R., K.E., B.V.H., Y.-H.H., J.B.R., M.C.Z., N.A., Y.S.A., L.A.C., S.D., N.S., G.T. and Y.Z. ran statistical analysis in studies; F.R., U.S., P.D., J.B.v.M., U.T. and A.G.U. coordinated GWA genotyping of studies; E.G. and T.P. did expression studies; F.R., U.S., M.C.Z., A.H., B.O., H.A.P.P., G.S., G.T., F.M.K.W., S.G.W., C.M.v.D., T.S., D.P.K. and A.G.U. coordinated/collected phenotypic information; U.S., L.A.C., A.H., A.K., D.K., B.O., H.A.P.P., U.T., C.M.v.D., T.S., D.P.K., K.S. and A.G.U. designed studies; F.R., U.S., J.B.v.M., T.S., U.T., S.H.R., J.P.A.I. and A.G.U. established the consortium and U.T., S.H.R., J.P.A.I. and A.G.U. obtained funding; all authors interpreted results; all authors critically read the manuscript; and F.R. wrote the manuscript draft.

Corresponding authors

Correspondence to John P A Ioannidis or André G Uitterlinden.

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Competing interests

The coauthors affiliated with deCODE Genetics in Reykjavík Iceland withhold stock options in that company.

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Supplementary Tables 1–10 and Supplementary Figures 1–3. (PDF 1495 kb)

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the Genetic Factors for Osteoporosis (GEFOS) Consortium. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41, 1199–1206 (2009). https://doi.org/10.1038/ng.446

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