Letter | Published:

Whole‐genome sequencing identifies EN1 as a determinant of bone density and fracture

Nature volume 526, pages 112117 (01 October 2015) | Download Citation

Abstract

The extent to which low‐frequency (minor allele frequency (MAF) between 1–5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants1,2,3,4,5,6,7,8, as well as rare, population‐specific, coding variants9. Here we identify novel non‐coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole‐genome sequencing (n = 2,882 from UK10K (ref. 10); a population‐based genome sequencing consortium), whole‐exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low‐frequency non‐coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10−14), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10−11; ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low‐frequency non‐coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10−11). In general, there was an excess of association signals arising from deleterious coding and conserved non‐coding variants. These findings provide evidence that low‐frequency non‐coding variants have large effects on BMD and fracture, thereby providing rationale for whole‐genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

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Acknowledgements

Full acknowledgements are listed in the Supplementary Information.

Author information

Author notes

    • Hou‐Feng Zheng
    • , Vincenzo Forgetta
    • , Yi‐Hsiang Hsu
    • , Karol Estrada
    • , Alberto Rosello‐Diez
    • , Paul J. Leo
    • , Chitra L. Dahia
    • , Kyung Hyun Park‐Min
    • , Jonathan H. Tobias
    •  & Charles Kooperberg

    These authors contributed equally to this work.

    • Rebecca D. Jackson
    • , David W. Rowe
    • , Cynthia A. Loomis
    • , David M. Evans
    • , Cheryl L. Ackert‐Bicknell
    • , Alexandra L. Joyner
    • , Emma L. Duncan
    • , Douglas P. Kiel
    • , Fernando Rivadeneira
    •  & J. Brent Richards

    These authors jointly supervised this work.

Affiliations

  1. Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montréal H3A 1A2, Canada.

    • Hou‐Feng Zheng
    • , Vincenzo Forgetta
    • , Rui Li
    •  & J. Brent Richards
  2. Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montréal H3T 1E2, Canada.

    • Hou‐Feng Zheng
    • , Vincenzo Forgetta
    • , Rui Li
    • , Lauren E. Mokry
    • , Celia M. T. Greenwood
    •  & J. Brent Richards
  3. Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts 02131, USA.

    • Yi‐Hsiang Hsu
    • , Wen‐Chi Chou
    • , Melina Claussnitzer
    • , Chia‐Ho Cheng
    • , David Karasik
    •  & Douglas P. Kiel
  4. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Yi‐Hsiang Hsu
    • , Karol Estrada
    • , Wen‐Chi Chou
    • , Melina Claussnitzer
    • , Daniel I. Chasman
    • , Paul M. Ridker
    •  & Douglas P. Kiel
  5. Broad Institute of MIT and Harvard, Boston, Massachusetts 02115, USA.

    • Yi‐Hsiang Hsu
    • , Karol Estrada
    • , Melina Claussnitzer
    •  & Douglas P. Kiel
  6. Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.

    • Karol Estrada
    • , Mila Jhamai
    • , Katerina Trajanoska
    • , Carolina Medina‐Gómez
    • , Ling Oei
    • , Robert Kraaij
    • , Anke W. Enneman
    • , Nathalie van der Velde
    • , Jeroen van Rooij
    • , Andre G. Uitterlinden
    • , Pascal P. Arp
    • , Fjorda Koromani
    • , M. Carola Zillikens
    • , Joyce B. J. van Meurs
    •  & Fernando Rivadeneira
  7. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Karol Estrada
  8. Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065, USA.

    • Alberto Rosello‐Diez
    •  & Alexandra L. Joyner
  9. The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia.

    • Paul J. Leo
    • , Mhairi Marshall
    • , Brooke B. Gardiner
    • , Katie Cremin
    • , John P. Kemp
    • , Matthew A. Brown
    • , David M. Evans
    •  & Emma L. Duncan
  10. Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA.

    • Chitra L. Dahia
  11. Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York 10021, USA.

    • Chitra L. Dahia
  12. Rheumatology Divison, Hospital for Special Surgery New York, New York 10021, USA.

    • Kyung Hyun Park‐Min
  13. School of Clinical Science, University of Bristol, Bristol BS10 5NB, UK.

    • Jonathan H. Tobias
  14. MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.

    • Jonathan H. Tobias
    • , Josine Min
    • , John P. Kemp
    • , George Davey‐Smith
    • , Nicholas J. Timpson
    •  & David M. Evans
  15. Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.

    • Charles Kooperberg
    • , Li Hsu
    • , Chris Carlson
    • , Ulrike Peters
    •  & Jeff Haessler
  16. Department of Research, 23andMe, Mountain View, California 94041, USA.

    • Aaron Kleinman
    • , Joyce Y. Tung
    •  & David A. Hinds
  17. Department of Population Genomics, deCODE Genetics, Reykjavik IS‐101, Iceland.

    • Unnur Styrkarsdottir
    •  & Unnur Thorsteinsdottir
  18. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.

    • Ching‐Ti Liu
    • , Yanhua Zhou
    •  & L. Adrienne Cupples
  19. Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S‐413 45, Sweden.

    • Charlotta Uggla
    • , Joel Eriksson
    • , Dan Mellström
    • , Liesbeth Vandenput
    •  & Claes Ohlsson
  20. California Pacific Medical Center Research Institute, San Francisco, California 94158, USA.

    • Daniel S. Evans
  21. Department of Public Health and Preventive Medicine, Oregon Health & Science University, Portland, Oregon 97239, USA.

    • Carrie M. Nielson
    •  & Gregory J. Tranah
  22. Bone & Mineral Unit, Oregon Health & Science University, Portland, Oregon 97239, USA.

    • Carrie M. Nielson
    • , Gregory J. Tranah
    •  & Eric S. Orwoll
  23. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK.

    • Klaudia Walter
    • , Shane McCarthy
    • , Yasin Memari
    • , Jie Huang
    • , Petr Danecek
    • , Nicole Soranzo
    •  & Richard Durbin
  24. Departments of Pharmacology and Clinical Neurosciences, Umeå University, Umeå S‐901 87, Sweden.

    • Ulrika Pettersson‐Kymmer
  25. Department of Public Health and Clinical Medicine, Umeå University, Umeå SE‐901 87, Sweden.

    • Ulrika Pettersson‐Kymmer
    •  & Göran Hallmans
  26. Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S‐413 45, Sweden.

    • Joel Eriksson
  27. McGill University and Genome Quebec Innovation Centre, Montréal H3A 0G1, Canada.

    • Tony Kwan
    • , Warren Cheung
    • , Bing Ge
    • , Shu‐Huang Chen
    • , Tomi Pastinen
    •  & Elin Grundberg
  28. Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.

    • Katerina Trajanoska
    • , Carolina Medina‐Gómez
    • , Ling Oei
    • , Robert Kraaij
    • , Albert Hofman
    • , Andre G. Uitterlinden
    • , Fjorda Koromani
    • , Joyce B. J. van Meurs
    •  & Fernando Rivadeneira
  29. Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon 97239, USA.

    • Beth Wilmot
  30. Department of Medical and Clinical Informatics, Oregon Health & Science University, Portland, Oregon 97239, USA.

    • Beth Wilmot
  31. Farr Institute of Health Informatics Research, University College London, London NW1 2DA, UK.

    • Alireza Moayyeri
    •  & Stephen Kaptoge
  32. Department of Twin Research and Genetic Epidemiology, King’s College London, London SE1 7EH, UK.

    • Alireza Moayyeri
    • , Scott G. Wilson
    • , Tim Spector
    •  & J. Brent Richards
  33. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.

    • Melina Claussnitzer
    •  & Douglas P. Kiel
  34. Department of Human Genetics, McGill University, Montréal H3A 1B1, Canada.

    • Warren Cheung
    • , Tomi Pastinen
    • , Elin Grundberg
    •  & Celia M. T. Greenwood
  35. Netherlands Genomics Initiative (NGI)‐sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands.

    • Carolina Medina‐Gómez
    • , Ling Oei
    • , Robert Kraaij
    • , Albert Hofman
    • , Jeroen van Rooij
    • , Andre G. Uitterlinden
    •  & Fernando Rivadeneira
  36. Center for Musculoskeletal Research, University of Rochester, Rochester, New York 14642, USA.

    • Kwangbom Choi
    • , Matthew A. Hibbs
    •  & Cheryl L. Ackert‐Bicknell
  37. Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montréal H3G 1Y6, Canada.

    • James Fraser
    • , Denis Paquette
    • , Soizik Berlivet
    •  & Josée Dostie
  38. Department of Computer Science, Trinity University, San Antonio, Texas 78212, USA.

    • Matthew A. Hibbs
  39. Musculoskeletal Research Unit, University of Bristol, Bristol BS10 5NB, UK.

    • Celia L. Gregson
    •  & Adrian Sayers
  40. Department of Radiation Sciences, Umeå University, Umeå S‐901 87, Sweden.

    • Carl Wibom
    •  & Beatrice Melin
  41. School of Public Health, University of Wisconsin, Milwaukee, Wisconsin 53726, USA.

    • Paul Auer
  42. School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.

    • Sue Ring
  43. Department of Statistics, deCODE Genetics, Reykjavik IS‐101, Iceland.

    • Gudmar Thorleifsson
  44. Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam 1007 MB, The Netherlands.

    • Natasja M. van Schoor
  45. Department of Human Nutrition, Wageningen University, Wageningen 6700 EV, The Netherlands.

    • Lisette C. P. G. M. de Groot
  46. Department of Internal Medicine, Section Geriatrics, Academic Medical Center, Amsterdam 1105, The Netherlands.

    • Nathalie van der Velde
  47. Nordic Bioscience, Herlev 2730, Denmark.

    • Claus Christiansen
  48. Cordeliers Research Centre, INSERM UMRS 1138, Paris 75006, France.

    • Sophie Calderari
    •  & Dominique Gauguier
  49. Institute of Cardiometabolism and Nutrition, University Pierre & Marie Curie, Paris 75013, France.

    • Sophie Calderari
    •  & Dominique Gauguier
  50. Departments of Medicine (Cardiovascular Medicine), Centre for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.

    • Stephen R. Williams
    •  & Charles Farber
  51. Department of Genetics, University of Barcelona, Barcelona 08028, Spain.

    • Daniel Grinberg
  52. U‐720, Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona 28029, Spain.

    • Daniel Grinberg
  53. Department of Human Molecular Genetics, The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain.

    • Daniel Grinberg
  54. Women’s Health Center of Excellence Family Medicine and Public Health, University of California – San Diego, San Diego, California 92093, USA.

    • Andrea Z. LaCroix
  55. Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02215, USA.

    • Daniel I. Chasman
    • , Franco Giulianini
    • , Lynda M. Rose
    •  & Paul M. Ridker
  56. Osteoporosis & Bone Biology Program, Garvan Institute of Medical Research, Sydney 2010, Australia.

    • John A. Eisman
    • , Tuan V. Nguyen
    •  & Jacqueline R. Center
  57. School of Medicine Sydney, University of Notre Dame Australia, Sydney 6959, Australia.

    • John A. Eisman
  58. St. Vincent’s Hospital & Clinical School, NSW University, Sydney 2010, Australia.

    • John A. Eisman
    • , Tuan V. Nguyen
    •  & Jacqueline R. Center
  59. Musculoskeletal Research Group, Institut Hospital del Mar d’Investigacions Mèdiques, Barcelona 08003, Spain.

    • Xavier Nogues
    •  & Natalia Garcia‐Giralt
  60. Cooperative Research Network on Aging and Fragility (RETICEF), Institute of Health Carlos III, 28029, Spain.

    • Xavier Nogues
    •  & Natalia Garcia‐Giralt
  61. Department of Internal Medicine, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona 08193, Spain.

    • Xavier Nogues
  62. Neuroepidemiology Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • Lenore L. Launer
  63. Icelandic Heart Association, Kopavogur IS‐201, Iceland.

    • Vilmunder Gudnason
    • , Albert V. Smith
    •  & Kristin Siggeirsdottir
  64. Faculty of Medicine, University of Iceland, Reykjavik IS‐101, Iceland.

    • Vilmunder Gudnason
    • , Albert V. Smith
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  65. Genetic epidemiology unit, Department of Epidemiology, Erasmus MC, Rotterdam 3000CA, The Netherlands.

    • Najaf Amin
    •  & Cornelia M. van Duijn
  66. Department of Orthopaedics, Skåne University Hospital Malmö 205 02, Sweden.

    • Magnus K. Karlsson
    •  & Kristina Åkesson
  67. Department of Medical Sciences, University of Uppsala, Uppsala 751 85, Sweden.

    • Östen Ljunggren
  68. Department of Surgical and Perioperative Sciences, Umeå Unviersity, Umeå 901 85, Sweden.

    • Olle Svensson
  69. Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec City G1V 0A6, Canada.

    • François Rousseau
  70. Axe Santé des Populations et Pratiques Optimales en Santé, Centre de recherche du CHU de Québec, Québec City G1V 4G2, Canada.

    • François Rousseau
    • , Sylvie Giroux
    •  & Johanne Bussière
  71. Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands 6009, Australia.

    • Richard L. Prince
    • , Joshua R. Lewis
    •  & Scott G. Wilson
  72. Department of Medicine, University of Western Australia, Perth 6009, Australia.

    • Richard L. Prince
    •  & Joshua R. Lewis
  73. Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C 8000, Denmark.

    • Bente L. Langdahl
  74. Department of Endocrinology, Odense University Hospital, Odense C 5000, Denmark.

    • A. Pernille Hermann
  75. Department of Endocrinology, Hvidovre University Hospital, Hvidovre 2650, Denmark.

    • Jens‐Erik B. Jensen
  76. Clinical Gerontology Unit, University of Cambridge, Cambridge CB2 2QQ, UK.

    • Kay‐Tee Khaw
  77. Medicine and Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.

    • Jonathan Reeve
  78. Institute of Musculoskeletal Sciences, The Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.

    • Jonathan Reeve
  79. Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida MSD 2080, Malta.

    • Melissa M. Formosa
    •  & Angela Xuereb‐Anastasi
  80. Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences Malmö, Lund University, 205 02, Sweden.

    • Kristina Åkesson
    • , Fiona E. McGuigan
    •  & Gaurav Garg
  81. Department of Medicine and Psychiatry, University of Cantabria, Santander 39011, Spain.

    • Jose M. Olmos
    •  & Jose A. Riancho
  82. Department of Internal Medicine, Hospital U.M. Valdecilla‐ IDIVAL, Santander 39008, Spain.

    • Jose M. Olmos
    •  & Jose A. Riancho
  83. Department of Legal Medicine, University of Cantabria, Santander 39011, Spain.

    • Maria T. Zarrabeitia
  84. Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK.

    • Stuart H. Ralston
    •  & Nerea Alonso
  85. Department of Reconstructive Sciences, College of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.

    • Xi Jiang
    •  & David W. Rowe
  86. Department of Medicine and Physiology, McGill University, Montréal H4A 3J1, Canada.

    • David Goltzman
  87. Department of Medicine, Oregon Health & Science University, Portland, Oregon 97239, USA.

    • Eric S. Orwoll
  88. Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13010, Israel.

    • David Karasik
  89. Laboratory of Epidemiology, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • Tamara B. Harris
  90. Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.

    • Matthew T. Maurano
  91. School of Medicine and Pharmacology, University of Western Australia, Crawley 6009, Australia.

    • Scott G. Wilson
  92. Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece.

    • Evangelia E. Ntzani
  93. Department of Health Services, Policy and Practice, Brown University School of Public Health, Providence, Rhode Island 02903, USA.

    • Evangelia E. Ntzani
  94. deCODE Genetics, Reykjavik IS‐101, Iceland.

    • Kari Stefansson
  95. Framingham Heart Study, Framingham, Massachusetts 01702, USA.

    • L. Adrienne Cupples
  96. Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal H3A 1A2, Canada.

    • Celia M. T. Greenwood
  97. Department of Oncology, Gerald Bronfman Centre, McGill University, Montréal H2W 1S6, Canada.

    • Celia M. T. Greenwood
  98. Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, Ohio 43210, USA.

    • Rebecca D. Jackson
  99. The Ronald O. Perelman Department of Dermatology and Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA.

    • Cynthia A. Loomis
  100. Department of Diabetes and Endocrinology, Royal Brisbane and Women’s Hospital, Brisbane 4029, Australia.

    • Emma L. Duncan

Consortia

  1. AOGC Consortium

    Lists of participants and their affiliations appear in the Supplementary Information.

  2. UK10K Consortium

    Lists of participants and their affiliations appear in the Supplementary Information.

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Contributions

Principal Investigators: A.H., A.J., A.U., A.X.‐A., B.L., C.A.‐B., Ch.C., C.L., Cl.C., C.L.D., C.M.v.D., C.O., D.S.E., D.Ga., D.Go., D.Gr., D.H., D.Ki., D.M., E.D., E.O., F.Ri., F.Ro., G.D.S., J.B.R., J.D., J.Re., J.Ri., J.‐T.K., J.Tu., K.A., L.A.C., L.L., L.P.G.M.d.G., M.B., M.M.F., N.S., N.T., N.v.d.V., N.vS., P.R., R.D., R.D.J., R.L.P., S.G.W., S.H.R., T.H., T.P., T.S., U.P.‐K.,V.G., X.N.,Y.‐H.H. Genotyping: AOGC Consortium, A.U., B.M., B.W., C.L., C.M.v.D., C.N., C.O., C.W., D.C., D.Gr., E.D., E.O., F.Ri., G.G., G.Tr., J.Er., J.Jv.M., J.Re., J.Ri., J.‐T.K., J.v.R., M.B., M.C.F., M.J., M.Z., N.A., N.G.‐G., N.S., N.T., P.Ar., P.D., P.R., R.K., S.H.R., S.M., S.R., U.P.‐K., X.N. and Y.‐H.H. Phenotyping: A.E., A.H., A.L., AOGC Consortium, A.P.H., A.U., A.X.‐A., B.M., C.G., C.K., C.L., C.L.D., C.M.v.D., C.O., D.Go., D.Ka., D.Ki., D.M., E.D., E.N., E.O., F.E.M., F.K., F.Ri., F.Ro., G.H., J.B., J.C., J.Ei., J.O., J.Re., J.Ri., J.‐T.K., J.To., K.E., K.S., K.T., L.O., L.R., L.V., M.B., M.C.F., M.M.F., M.C.Z., M.K., M.Z., N.A., N.S., N.T., O.L., O.S., R.L.P., S.G.W., S.G., S.H.R., S.K., T.N., T.S. and U.P.‐K. Functional experiments: A.J., A.R.‐D., B.Ge, C.A.‐B., C.H., C.L., C.L.D., C.O., C.U., D.Ga., D.P., E.G., H.Y.P.‐M., J.D., J.F., K.Ch., Ma.M., M.H., N.S., O.S., S.B., S.C., S.‐H.C., St.W., T.K., T.P., U.P.‐K., W.C. and X.J. Data analysis: A.E., A.K., A.S., A.V.S., B.M., C.A.‐B., Ch.C., C.‐H.C., C.K., C.L., C.L.D., C.M.‐G., C.M.T.G., C.O., C.T.L., C.W., D.S.E., D.M.E., D.C., D.Ka., D.M., D.P., E.D., E.G., E.N., F.G., F.Ri., G.H., G.Th., H.‐F.Z., J.B.R., J.D., J.Er., J.F., J.Ha., J.Hu., J.K., J.v.R., K.Ch., K.E., K.W., L.A.C., L.H., L.M., L.O., L.R., L.V., M.B., M.C., M.H., M.K., N.A., N.S., N.T., O.L., P.Au., P.D., P.L., R.L., S.B., S.C., S.G.W., S.K., U.P., U.P.‐K., V.F., W.‐C.C., Y.‐H.H., Y.M. and Y.Z. Meta‐analysis: H.‐F.Z., V.F. and Y.‐H.H. Lead analysts: H.‐F.Z. and V.F. Wrote first draft: J.B.R.

Competing interests

Authors from deCODE Genetics are employees of deCODE Genetics. Authors from 23andMe are employees of 23andMe. Remaining authors declare no competing financial interests.

Corresponding author

Correspondence to J. Brent Richards.

Source code used in preparation of results is available at https://github.com/richardslab/gefos.seq/. BMD discovery meta‐analysis results are available from http://www.gefos.org. Information pertaining to UK10K can be obtained from http://www.uk10k.org.

Extended data

Supplementary information

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    Supplementary Information

    This file contains Supplementary Text and Supplementary References.

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  1. 1.

    Supplementary Tables

    This file contains Supplementary Tables 1-19.

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DOI

https://doi.org/10.1038/nature14878

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