Article | Published:

An atlas of genetic influences on osteoporosis in humans and mice

Nature Genetics (2018) | Download Citation

Abstract

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10−75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.

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Data availability

Human genotype and phenotype data on which the results of this study were based are available upon application from the UK Biobank (http://www.ukbiobank.ac.uk). GWAS summary statistics for eBMD and fracture can be downloaded from the GEFOS website (http://www.gefos.org/). RNA-seq and ATAC-seq data generated for human osteoblast cell lines, including re-called DHS peaks from human primary osteoblasts, can be downloaded from the Gene Expression Omnibus (accession number GSE120755). Mouse phenotype data are available online from the IMPC (http://www.mousephenotype.org) and OBCD (http://www.boneandcartilage.com).

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Acknowledgements

This research has been conducted using the UK Biobank Resource (accession IDs: 24268, 12703 and 4580). J.B.R. was supported by the Canadian Institutes of Health Research, the Canadian Foundation for Innovation and the Fonds de Recherche Santé Québec (FRSQ), and a FRQS Clinical Research Scholarship. TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy’s and St Thomas’s NHS Foundation Trust in partnership with King’s College London. J.A.M. was funded by the Canadian Institutes of Health Research. D.M.E. was funded by a National Health and Medical Research Council Senior Research Fellowship (APP1137714) and funded by a Medical Research Council Programme Grant (MC_UU_12013/4). J.P.K. was funded by a University of Queensland Development Fellowship (UQFEL1718945). C.L.G. was funded by Arthritis Research UK (ref; 20000). G.R.W., J.H.D.B., and P.I.C. were funded by the Wellcome Trust (Strategic Award grant number 101123; project grant 094134), and P.I.C. was also funded by the Mrs. Janice Gibson and the Ernest Heine Family Foundation. D.K. was supported by Israel Science Foundation grant #1283/14. Y-H.H. was funded by US NIH NIAMS 1R01AR072199. F.R., C.M-G., and K.T. were funded by the Netherlands Organization for Health Research and Development (ZonMw VIDI 016.136.361 grant). C.L.A-B. was funded by NIH/NIAMS AR063702 AR060981. D.P.K. was funded by grants from the National Institute of Arthritis Musculoskeletal and Skin Diseases R01 AR041398, R01 AR072199. S.Y. was funded by the Australian Government Research Training Program Scholarship. J.R. and S.K. were funded by the Genetic Factors of Osteoporosis-GEFOS EU FP7 Integrated Project Grant Reference: 201865 2008-12 and 2007-12 UK NIHR Biomedical Research Centre Grant (Musculoskeletal theme) to Cambridge Clinical School. C.O. was supported by the Swedish Research Council, Swedish Foundation for Strategic Research, ALF/LUA research grant from the Sahlgrenska University Hospital, Lundberg Foundation, European Calcified Tissue Society, Torsten and Ragnar Söderberg’s Foundation, Novo Nordisk Foundation, and Knut and Alice Wallenberg Foundation. M.T.M. was supported by NIH grant R35 GM119703. We thank M. Schull for assistance with high-performance computing at the University of Queensland Diamantina Institute and T. Winkler for invaluable technical support for the EasyStrata Software used in this study. We thank the Sanger Institute’s Research Support Facility, Mouse Pipelines and Mouse Informatics Group who generated the mice and collected materials for this manuscript. We would like to thank the research participants and employees of 23andMe, Inc. for making this work possible.

Author information

Author notes

  1. These authors contributed equally: John A. Morris, John P. Kemp.

  2. These authors jointly supervised this work: David M. Evans, J. Brent Richards.

Affiliations

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

    • John A. Morris
    •  & J. Brent Richards
  2. Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada

    • John A. Morris
    • , Laetitia Laurent
    • , Vincenzo Forgetta
    •  & J. Brent Richards
  3. University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia

    • John P. Kemp
    • , Thomas A. D. Hassall
    •  & David M. Evans
  4. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK

    • John P. Kemp
    •  & David M. Evans
  5. Garvan Institute of Medical Research, Sydney, New South Wales, Australia

    • Scott E. Youlten
    • , Ryan C. Chai
    • , Sindhu T. Mohanty
    • , C. Marcelo Sergio
    • , Julian Quinn
    • , Paul Baldock
    •  & Peter I. Croucher
  6. Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK

    • John G. Logan
    • , Elena J. Ghirardello
    • , Natalie C. Butterfield
    • , Katharine F. Curry
    • , Victoria D. Leitch
    • , Penny C. Sparkes
    • , Anne-Tounsia Adoum
    • , Naila S. Mannan
    • , Davide S. K. Komla-Ebri
    • , Andrea S. Pollard
    • , Hannah F. Dewhurst
    • , Graham R. Williams
    •  & J. H. Duncan Bassett
  7. Institute for Systems Genetics, New York University Langone Medical Center, New York, NY, USA

    • Nicholas A. Vulpescu
    •  & Matthew T. Maurano
  8. Department of Research, 23andMe, Inc., Mountain View, CA, USA

    • Aaron Kleinman
    • , Michelle Agee
    • , Babak Alipanahi
    • , Adam Auton
    • , Robert K. Bell
    • , Katarzyna Bryc
    • , Sarah L. Elson
    • , Pierre Fontanillas
    • , Nicholas A. Furlotte
    • , Jennifer C. McCreight
    • , Karen E. Huber
    • , Nadia K. Litterman
    • , Matthew H. McIntyre
    • , Joanna L. Mountain
    • , Elizabeth S. Noblin
    • , Carrie A. M. Northover
    • , Steven J. Pitts
    • , J. Fah Sathirapongsasuti
    • , Olga V. Sazonova
    • , Janie F. Shelton
    • , Suyash Shringarpure
    • , Chao Tian
    • , Joyce Y. Tung
    • , Vladimir Vacic
    • , Catherine H. Wilson
    •  & David A. Hinds
  9. Research Institute of the McGill University Health Centre, Montréal, Québec, Canada

    • Loan Nguyen-Yamamoto
    • , Aimee-Lee Luco
    •  & David Goltzman
  10. McGill University and Genome Quebec Innovation Centre, Montréal, Québec, Canada

    • Jinchu Vijay
    • , Marie-Michelle Simon
    • , Albena Pramatarova
    •  & Elin Grundberg
  11. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

    • Carolina Medina-Gomez
    • , Katerina Trajanoska
    •  & Fernando Rivadeneira
  12. Department of Biomedical Genetics, University of Rochester, Rochester, NY, USA

    • Michael-John G. Beltejar
  13. Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    • Douglas J. Adams
  14. Department of Medicine, McGill University, Montréal, Québec, Canada

    • Suzanne M. Vaillancourt
    •  & J. Brent Richards
  15. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    • Stephen Kaptoge
  16. MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK

    • Cyrus Cooper
    •  & Nicholas C. Harvey
  17. NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK

    • Cyrus Cooper
    •  & Nicholas C. Harvey
  18. NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK

    • Cyrus Cooper
    •  & Jonathan Reeve
  19. Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece

    • Evangelia E. Ntzani
    •  & Evangelos Evangelou
  20. Center for Evidence Synthesis in Health, Department of Health Services, Policy and Practice, School of Public Health, Brown University, Providence, RI, USA

    • Evangelia E. Ntzani
  21. Department of Epidemiology and Biostatistics, Imperial College London, London, UK

    • Evangelos Evangelou
  22. Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Gothenburg, Sweden

    • Claes Ohlsson
  23. Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA

    • David Karasik
    • , Douglas P. Kiel
    •  & Yi-Hsiang Hsu
  24. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

    • Douglas P. Kiel
    •  & Yi-Hsiang Hsu
  25. Department of Medicine, Harvard Medical School, Boston, MA, USA

    • Douglas P. Kiel
    •  & Yi-Hsiang Hsu
  26. Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, USA

    • Douglas P. Kiel
    •  & Yi-Hsiang Hsu
  27. Musculoskeletal Research Unit, Department of Translational Health Sciences, University of Bristol, Bristol, UK

    • Jonathan H. Tobias
    •  & Celia L. Gregson
  28. Children’s Mercy Hospitals and Clinics, Kansas City, MO, USA

    • Elin Grundberg
  29. Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK

    • David J. Adams
    •  & Christopher J. Lelliott
  30. Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester, Rochester, NY, USA

    • Cheryl L. Ackert-Bicknell
  31. Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montréal, Québec, Canada

    • J. Brent Richards
  32. Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK

    • J. Brent Richards

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Consortia

  1. 23andMe Research Team

Contributions

J.A.M., J.P.K., A.P., C.L.A-B., C.L.G., C.O., D.K., D.P.K., E.E., E.G., F.R., G.R.W., J.H.D.B., J.H.T., M.T.M., N.C.H., P.I.C., V.F., Y-H.H., D.M.E. and J.B.R. conceived of and designed experiments. J.A.M., J.P.K., A.K., A.S.P., A.-T.A., C.C., D.A.H., D.G., D.S.K.K.-E., E.E.N., E.J.G., H.F.D., J.G.L., J.R., K.F.C., K.T., M.-J.G.B., N.A.V., N.C.B., N.S.M., P.C.S., R.C.C., S.E.Y., S.M.V., S.K., T.A.D.H., V.D.L., A.P., C.L.A.-B., C.L.G., D.M.E., E.G., G.R.W., J.H.D.B., M.T.M., N.C.H., V.F., Y.-H.H. and J.B.R. performed data analysis. J.A.M., J.P.K, A-L.L., A-T.A., C.J.L., C.M-G., C.M.S., D.G., David J. Adams, Douglas J. Adams, E.J.G., H.F.D., J.G.L., J.Q., J.V., K.F.C., L.L., L.N-Y., M.-J.G.B., M-M.S., N.S.M., P.B., P.C.S., R.C.C., S.E.Y., S.T.M., A.P., C.L.A.-B., and Y.-H.H. conducted experiments. J.A.M., J.P.K., G.R.W., J.H.D.B., D.M.E. and J.B.R. wrote the manuscript. J.A.M. and J.P.K. were the lead analysts. All authors revised and reviewed the paper.

Competing interests

A.K. and D.A.H. are employees of 23andMe, Inc.

Corresponding authors

Correspondence to David M. Evans or J. Brent Richards.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–23 and Supplementary Note

  2. Reporting Summary

  3. Supplementary Tables

    Supplementary Tables 1–22

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DOI

https://doi.org/10.1038/s41588-018-0302-x

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