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Original article
A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus
  1. Ling Oei1,2,3,
  2. Yi-Hsiang Hsu4,5,6,
  3. Unnur Styrkarsdottir7,
  4. Bert H Eussen8,
  5. Annelies de Klein8,
  6. Marjolein J Peters1,3,
  7. Bjarni Halldorsson7,9,
  8. Ching-Ti Liu10,
  9. Nerea Alonso11,
  10. Stephen K Kaptoge12,
  11. Gudmar Thorleifsson7,
  12. Göran Hallmans13,
  13. Lynne J Hocking14,
  14. Lise Bjerre Husted15,
  15. Karen A Jameson16,
  16. Marcin Kruk17,
  17. Joshua R Lewis18,19,
  18. Millan S Patel20,
  19. Serena Scollen21,
  20. Olle Svensson22,
  21. Stella Trompet23,24,
  22. Natasja M van Schoor25,
  23. Kun Zhu18,19,
  24. Brendan M Buckley26,
  25. Cyrus Cooper16,
  26. Ian Ford27,
  27. David Goltzman28,
  28. Jesús González-Macías29,30,
  29. Bente Lomholt Langdahl15,
  30. William D Leslie31,
  31. Paul Lips32,33,
  32. Roman S Lorenc17,
  33. José M Olmos29,30,
  34. Ulrika Pettersson-Kymmer13,34,
  35. David M Reid14,
  36. José A Riancho29,30,
  37. P Eline Slagboom3,35,
  38. Carmen Garcia-Ibarbia30,
  39. Thorvaldur Ingvarsson36,37,38,
  40. Hrefna Johannsdottir7,
  41. Robert Luben12,
  42. Carolina Medina-Gómez1,2,3,
  43. Pascal Arp1,
  44. Kannabiran Nandakumar4,6,
  45. Stefan Th Palsson7,
  46. Gunnar Sigurdsson38,
  47. Joyce B J van Meurs1,2,3,
  48. Yanhua Zhou10,
  49. Albert Hofman2,3,
  50. J Wouter Jukema23,39,40,
  51. Huibert A P Pols1,2,
  52. Richard L Prince18,19,
  53. L Adrienne Cupples10,41,
  54. Christian R Marshall42,43,
  55. Dalila Pinto42,
  56. Daisuke Sato42,
  57. Stephen W Scherer42,43,44,
  58. Jonathan Reeve45,
  59. Unnur Thorsteinsdottir7,38,
  60. David Karasik4,
  61. J Brent Richards28,46,47,48,
  62. Kari Stefansson7,38,
  63. André G Uitterlinden1,2,3,
  64. Stuart H Ralston11,
  65. John P A Ioannidis49,
  66. Douglas P Kiel4,6,41,
  67. Fernando Rivadeneira1,2,3,
  68. Karol Estrada1,50,51
  1. 1Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
  2. 2Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
  3. 3Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands
  4. 4Institute for Aging Research, Hebrew SeniorLife, Boston, USA
  5. 5Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, USA
  6. 6Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA
  7. 7deCODE Genetics, Reykjavik, Iceland
  8. 8Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
  9. 9School of Science and Engineering, Reykjavik University, Reykjavik, Iceland
  10. 10Department of Biostatistics, Boston University School of Public Health, Boston, USA
  11. 11Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
  12. 12Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  13. 13Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
  14. 14Musculoskeletal Research Programme, Division of Applied Medicine, University of Aberdeen, Aberdeen, UK
  15. 15Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C, Denmark
  16. 16MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK
  17. 17Department of Biochemistry, Radioimmunology & Experimental Medicine, The Children's Memorial Health Institute, Warsaw, Poland
  18. 18School of Medicine and Pharmacology, University of Western Australia, Perth, Australia
  19. 19Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Australia
  20. 20Department of Medical Genetics, University of British Columbia, Vancouver, Canada
  21. 21Department of Medicine, University of Cambridge, Cambridge, UK
  22. 22Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden
  23. 23Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
  24. 24Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
  25. 25Department of Epidemiology and Biostatistics, EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands
  26. 26Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
  27. 27Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK
  28. 28Department of Medicine, McGill University, Montreal, Canada
  29. 29Department of Medicine, University of Cantabria, RETICEF, Santander, Spain
  30. 30Department of Internal Medicine, Hospital Universitario Marqués de Valdecilla and Instituto de Formación e Investigación Marqués de Valdecilla (IFIMAV), Santander, Spain
  31. 31Department of Internal Medicine, University of Manitoba, Winnipeg, Canada
  32. 32Department of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands
  33. 33EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands
  34. 34Department of Pharmacology and Neuroscience, Umeå University, Umeå, Sweden
  35. 35Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
  36. 36Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland
  37. 37Institution of Health Science, University Of Akureyri, Akureyri, Iceland
  38. 38Faculty of Medicine, University of Iceland, Reykjavik, Iceland
  39. 39Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands
  40. 40Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
  41. 41Framingham Heart Study, Framingham, USA
  42. 42The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
  43. 43McLaughlin Centre, University of Toronto, Toronto, Canada
  44. 44Department of Molecular Genetics, University of Toronto, Toronto, Canada
  45. 45Medicine box 157, University of Cambridge, Cambridge, UK
  46. 46Department of Human Genetics, Lady Davis Institute, McGill University, Montréal, Canada
  47. 47Department of Epidemiology and Biostatistics, Lady Davis Institute, McGill University, Montréal, Canada
  48. 48Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
  49. 49Stanford Prevention Research Center, Stanford University, Stanford, USA
  50. 50Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA
  51. 51Program in Medical and Population Genetics, Broad Institute, Cambridge, USA
  1. Correspondence to Dr Karol Estrada, Department of Internal Medicine, Erasmus Medical Center, PO Box 2040 Ee5-79, Rotterdam 3000CA, The Netherlands; j.estradagil{at}


Background Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk.

Aim To identify CNVs associated with osteoporotic bone fracture risk.

Method We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies.

Results A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10−5). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk.

Conclusions These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

  • Osteoporosis
  • Copy-Number
  • Calcium and Bone
  • Genetic Epidemiology
  • Genome-Wide

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