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Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22
  1. Evangelos Evangelou1,
  2. Ana M Valdes2,
  3. Hanneke J M Kerkhof3,4,
  4. Unnur Styrkarsdottir5,
  5. YanYan Zhu6,
  6. Ingrid Meulenbelt4,7,
  7. Rik J Lories8,
  8. Fotini B Karassa1,
  9. Przemko Tylzanowski8,
  10. Steffan D Bos4,7,
  11. arcOGEN Consortium,
  12. Toru Akune9,
  13. Nigel K Arden10,11,
  14. Andrew Carr12,
  15. Kay Chapman12,13,
  16. L Adrienne Cupples6,
  17. Jin Dai14,
  18. Panos Deloukas15,
  19. Michael Doherty16,
  20. Sally Doherty16,
  21. Gunnar Engstrom17,
  22. Antonio Gonzalez18,
  23. Bjarni V Halldorsson5,19,
  24. Christina L Hammond20,
  25. Deborah J Hart2,
  26. Hafdis Helgadottir5,
  27. Albert Hofman21,
  28. Shiro Ikegawa22,
  29. Thorvaldur Ingvarsson23,
  30. Qing Jiang14,
  31. Helgi Jonsson24,25,
  32. Jaakko Kaprio26,27,28,
  33. Hiroshi Kawaguchi29,
  34. Kalle Kisand30,
  35. Margreet Kloppenburg31,32,
  36. Urho M Kujala33,34,
  37. L Stefan Lohmander35,
  38. John Loughlin36,
  39. Frank P Luyten8,
  40. Akihiko Mabuchi37,
  41. Andrew McCaskie36,38,
  42. Masahiro Nakajima22,
  43. Peter M Nilsson17,
  44. Nao Nishida37,
  45. William E R Ollier39,
  46. Kalliope Panoutsopoulou40,
  47. Tom van de Putte41,
  48. Stuart H Ralston42,
  49. Fernado Rivadeneira3,21,
  50. Janna Saarela26,
  51. Stefan Schulte-Merker20,
  52. Dongquan Shi14,
  53. P Eline Slagboom4,7,
  54. Akihiro Sudo43,
  55. Agu Tamm44,
  56. Ann Tamm45,
  57. Gudmar Thorleifsson5,
  58. Unnur Thorsteinsdottir5,25,
  59. Aspasia Tsezou46,
  60. Gillian A Wallis47,
  61. J Mark Wilkinson48,49,
  62. Noriko Yoshimura50,
  63. Eleftheria Zeggini40,51,
  64. Guangju Zhai2,
  65. Feng Zhang2,
  66. Ingileif Jonsdottir5,25,
  67. Andre G Uitterlinden3,4,21,
  68. David T Felson52,
  69. Joyce B van Meurs3,4,
  70. Kari Stefansson5,25,
  71. John P A Ioannidis1,53,54,55,
  72. Timothy D Spector2,
  73. Translation Research in Europe Applied Technologies for Osteoarthritis (TreatOA)
  1. 1Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
  2. 2Department of Twin Research and Genetic Epidemiology, St. Thomas' Hospital, King's College London, London, UK
  3. 3Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
  4. 4The Netherlands Genomics Initiative-Sponsored Netherlands Consortium for Healthy Aging, Rotterdam, The Netherlands
  5. 5deCODE Genetics, Reykjavik, Iceland
  6. 6Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA
  7. 7Department of Molecular Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands
  8. 8Laboratory for Skeletal Development and Joint Disorders, Department of Musculoskeletal Sciences, Division of Rheumatology, Katholieke Universiteit Leuven, Leuven, Belgium
  9. 9Department of Clinical Motor System Medicine, 22nd Century Medical and Research Center, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  10. 10MRC Epidemiology Resource Centre, Southampton, UK
  11. 11Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK
  12. 12Botnar Research Centre, University of Oxford, Nuffield Orthopaedic Centre, Oxford, UK
  13. 13Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  14. 14The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
  15. 15Wellcome Trust Sanger Institute, UK
  16. 16University of Nottingham, Academic Rheumatology, City Hospital, Nottingham, UK
  17. 17Department of Clinical Sciences Malmo, Lund University, Sweden
  18. 18Laboratorio Investigacion 10 and Rheumatology Service, Instituto Investigacion Sanitaria-Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain
  19. 19Reykjavik University, Reykjavic, Iceland
  20. 20Hubrecht Institute – KNAW and UMC, Utrecht, The Netherlands
  21. 21Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
  22. 22Laboratory for Bone and Joint Diseases, Center for Genomic Medicine, RIKEN, Tokyo, Japan
  23. 23FSA University Hospital, Institution of Health Science, University of Akureyri, Akureyri, Iceland
  24. 24Department of Medicine, Landspitali University Hospital, Reykjavik, Iceland
  25. 25Faculty of Medicine, University of Iceland, Reykjavik, Iceland
  26. 26Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
  27. 27Department of Public Health, University of Helsinki, Helsinki, Finland
  28. 28National Institute for Health and Welfare, Helsinki, Finland
  29. 29Department of Orthopaedic Surgery, Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  30. 30Immunology Group, Institute of General and Molecular Pathology, University of Tartu, Tartu, Estonia
  31. 31Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands
  32. 32Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands
  33. 33Department of Health Sciences, University of Jyvaskyla, Jyvaskyla, Finland
  34. 34ORTON Orthopaedic Hospital, ORTON Foundation, Helsinki, Finland
  35. 35Department of Clinical Sciences Lund, Orthopedics, Lund University, Lund, Sweden
  36. 36Institute of Cellular Medicine, Musculoskeletal Research Group, The Medical School, Newcastle University, Newcastle Upon Tyne, UK
  37. 37Department of Human Genetics, International Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  38. 38The Newcastle upon Tyne Hospitals NHS Trust, The Freeman Hospital, Newcastle, UK
  39. 39Centre for Integrated Genomic Medical Research, The University of Manchester, Manchester, UK
  40. 40Wellcome Trust Sanger Institute, Hinxton, UK
  41. 41Tigenix, Leuven, Belgium
  42. 42Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, UK
  43. 43Department of Orthopaedic Surgery, Faculty of Medicine, Mie University, Mie, Japan
  44. 44Department of Internal Medicine, University of Tartu, Tartu, Estonia
  45. 45Department of Sports Medicine and Rehabilitation, University of Tartu, Tartu, Estonia
  46. 46Department of Biology, University of Thessaly Medical School, Larissa, Greece
  47. 47Wellcome Trust Centre for Cell-Matrix Research, School of Translational Medicine, University of Manchester, Manchester, UK
  48. 48Academic Unit of Bone Metabolism, Northern General Hospital, University of Sheffield, Sheffield, UK
  49. 49NIHR Bone Biomedical Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
  50. 50Department of Joint Disease Research, 22nd Century Medical and Research Center, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  51. 51Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
  52. 52Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Massachusetts, USA
  53. 53Center for Genetic Epidemiology and Modelling, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA
  54. 54Biomedical Research Institute, Foundation for Research and Development-Hellas, Ioannina, Greece
  55. 55Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
  1. Correspondence to Tim Spector, Department of Twin Research and Genetic Epidemiology, St Thomas' Hospital, King's College London, London SE1 7EH, UK; tim.spector{at}kcl.ac.uk or John P A Ioannidis; jioannid{at}cc.uoi.gr

Abstract

Objectives Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in older people. It is characterised by changes in joint structure, including degeneration of the articular cartilage, and its aetiology is multifactorial with a strong postulated genetic component.

Methods A meta-analysis was performed of four genome-wide association (GWA) studies of 2371 cases of knee OA and 35 909 controls in Caucasian populations. Replication of the top hits was attempted with data from 10 additional replication datasets.

Results With a cumulative sample size of 6709 cases and 44 439 controls, one genome-wide significant locus was identified on chromosome 7q22 for knee OA (rs4730250, p=9.2×10−9), thereby confirming its role as a susceptibility locus for OA.

Conclusion The associated signal is located within a large (500 kb) linkage disequilibrium block that contains six genes: PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, β), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like) and BCAP29 (B cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.

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Footnotes

  • Funding European Commission framework 7 programme grant 200800 TREAT-OA, NWO Investments (175.010.2005.011).

  • Ethics approval Each study participating in this meta-analysis has obtained approval from respective ethics committe.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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