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The DOT1L rs12982744 polymorphism is associated with osteoarthritis of the hip with genome-wide statistical significance in males
  1. Evangelos Evangelou1,2,
  2. Ana M Valdes2,3,
  3. Martha C Castano-Betancourt4,5,
  4. M Doherty3,
  5. Sally Doherty3,
  6. Tonu Esko6,
  7. Thorvaldur Ingvarsson7,8,9,
  8. John P A Ioannidis1,10,
  9. Margreet Kloppenburg11,
  10. Andres Metspalu6,
  11. Evangelia E Ntzani1,
  12. Kalliope Panoutsopoulou12,
  13. P Eline Slagboom5,13,
  14. Lorraine Southam12,
  15. Tim D Spector2,
  16. Unnur Styrkarsdottir14,
  17. Kari Stefanson9,13,
  18. André G Uitterlinden4,5,
  19. Margaret Wheeler3,
  20. Eleftheria Zeggini12,
  21. Ingrid Meulenbelt5,13,
  22. Joyce B van Meurs4,5,
  23. arcOGEN consortium, the TREAT-OA consortium
  1. 1Department of Hygiene and Epidemiology, University of Ioannina Medical School, University Campus, Ioannina, Greece
  2. 2Department of Twin Research and Genetic Epidemiology, St. Thomas’ Hospital, King's College, Lambeth Palace Road, London, UK
  3. 3Academic Rheumatology, University of Nottingham, City Hospital Nottingham, Nottingham, UK
  4. 4Department of Internal Medicine, ErasmusMC, Rotterdam, The Netherlands
  5. 5The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Rotterdam/Leiden, The Netherlands
  6. 6Estonian Genome Center, University of Tartu, Tartu, Estonia
  7. 7Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland
  8. 8Institution of Health Science, University of Akureyri, Akureyri, Iceland
  9. 9Faculty of Medicine, University of Iceland, Reykjavik, Iceland
  10. 10Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, USA
  11. 11Department of Rheumatology and Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
  12. 12Wellcome Trust Sanger Institute, Hinxton, UK
  13. 13Department of Molecular Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands
  14. 14deCODE Genetics, Reykjavik, Iceland
  1. Correspondence to Dr Ana M Valdes, Academic Rheumatology, University of Nottingham, Clinical Sciences Bld, Nottingham City Hospital, Nottingham NG5 1PE, UK; ana.valdes{at}

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Osteoarthritis (OA) of the hip is a major cause of pain, disability and use of healthcare resources.1 Although OA is multifactorial, it is known to have significant genetic contribution and a number of studies have attempted to dissect such contribution (see2 for review).

The DOT1L gene encodes the DOT1-like histone H3 methyltransferaseis, a potentially dedicated enzyme for Wnt target gene activation in leukaemia recently shown to be associated with endochondral bone formation.3

A polymorphism (rs12982744) in DOT1L has been found to be strongly associated with minimum joint space width (minJSW) at the hip. This exact same single nucleotide polymorphism (SNP) was previously identified to be associated with increased height.4 ,5 The C allele associated with lower minJSW and lower height was associated with hip OA, although this association did not reach genome-wide significance (GWS) (OR 1.14, CI 1.06 to 1.22; p=1.5 × 10−4).3

The GWS level of p<5×10−8 is the threshold at which genetic associations are considered credible.6 The aim of our study was to prove that common genetic variation in the DOT1L gene is important …

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