Osteoarthritis is the most common form of arthritis and is a major cause of pain and disability in the elderly. To search for sequence variants that confer risk of osteoarthritis of the hand, we carried out a genome-wide association study (GWAS) in subjects with severe hand osteoarthritis, using variants identified through the whole-genome sequencing of 2,230 Icelanders. We found two significantly associated loci in the Icelandic discovery set: at 15q22 (frequency of 50.7%, odds ratio (OR) = 1.51, P = 3.99 × 10−10) in the ALDH1A2 gene and at 1p31 (frequency of 0.02%, OR = 50.6, P = 9.8 × 10−10). Among the carriers of the variant at 1p31 is a family with several members in whom the risk allele segregates with osteoarthritis. The variants within the ALDH1A2 gene were confirmed in replication sets from The Netherlands and the UK, yielding an overall association of OR = 1.46 and P = 1.1 × 10−11 (rs3204689).

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We thank the subjects of the deCODE study, the Rotterdam study, the GARP, LLS, RAAK and PAPRIKA studies, the TwinsUK and Chingford studies, and the MDC study for their valuable participation. This work was supported by European Union Framework Programme 7 grant 200800 TREAT-OA. Full acknowledgments are given in the Supplementary Note.

Author information


  1. deCODE Genetics/Amgen, Reykjavik, Iceland.

    • Unnur Styrkarsdottir
    • , Gudmar Thorleifsson
    • , Hafdis T Helgadottir
    • , Aslaug Jonasdottir
    • , Asgeir Sigurdsson
    • , Michael L Frigge
    • , Augustine Kong
    • , Sigurjon A Gudjonsson
    • , Olafur T Magnusson
    • , Gisli Masson
    • , Unnur Thorsteinsdottir
    • , Ingileif Jonsdottir
    •  & Kari Stefansson
  2. Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

    • Nils Bomer
    • , Annelieke M Strijbosch
    • , Marian Beekman
    • , P Eline Slagboom
    •  & Ingrid Meulenbelt
  3. Department of Twin Research, King's College London, St. Thomas' Hospital, London, UK.

    • Sarah Metrustry
    • , Deborah Hart
    • , Tim Spector
    •  & Ana M Valdes
  4. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

    • S Bierma-Zeinstra
    • , Fernando Rivadeneira
    • , Andre Uitterlinden
    •  & Joyce van Meurs
  5. Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.

    • Evangelos Evangelou
  6. Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

    • Evangelos Evangelou
  7. Integrated Research on Developmental Determinants of Ageing and Longevity (IDEAL), Leiden, The Netherlands.

    • Marian Beekman
    •  & P Eline Slagboom
  8. Genomics Initiative, sponsored by the Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.

    • Marian Beekman
    • , P Eline Slagboom
    •  & Ingrid Meulenbelt
  9. Arctic Mass, Reykjavik, Iceland.

    • Finnur F Eiriksson
    •  & Margret Thorsteinsdottir
  10. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Margret Thorsteinsdottir
    • , Unnur Thorsteinsdottir
    • , Ingileif Jonsdottir
    • , Helgi Jonsson
    •  & Kari Stefansson
  11. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Albert Hofman
    • , Fernando Rivadeneira
    •  & Andre Uitterlinden
  12. National Institute for Health Research (NIHR) Biomedical Research Unit, University of Oxford, Oxford, UK.

    • Nigel K Arden
  13. Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland.

    • Thorvaldur Ingvarsson
  14. Institution of Health Science, University of Akureyri, Akureyri, Iceland.

    • Thorvaldur Ingvarsson
  15. Department of Orthopedics, Clinical Sciences Lund, Lund University, Lund, Sweden.

    • Stefan Lohmander
  16. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

    • Margreet Kloppenburg
  17. Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.

    • Margreet Kloppenburg
  18. Deptartment of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands.

    • Rob G H H Nelissen
  19. Academic Rheumatology, University of Nottingham, Nottingham City Hospital, Nottingham, UK.

    • Ana M Valdes
  20. Department of Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.

    • Helgi Jonsson


  1. The TREAT-OA Consortium

    Full list of members and affiliations appears in the Supplementary Note.

  2. arcOGEN Consortium

    Full list of members and affiliations appears in the Supplementary Note.


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The study was designed and results were interpreted by U.S., G.T., I.M., U.T., I.J., H.J. and K.S. Phenotype data and Icelandic subject recruitment were coordinated and managed by T.I. and H.J. D.H., S.M., N.K.A., T.S. and A.M.V. coordinated, managed, genotyped and analyzed the TwinsUK and Chingford cohort samples. M.B., M.K., P.E.S. and I.M. coordinated, managed, genotyped and analyzed the samples from the GARP, LLS, PAPRIKA and RAAK studies. A.H., F.R., A.U., S.B.-Z. and J.v.M. coordinated, managed, genotyped and analyzed the samples from the Rotterdam cohorts. S.L. coordinated and managed the samples from the MDC study. E.E. undertook the meta-analysis for the TreatOA consortium. G.M., U.T., G.T. and U.S. coordinated sequence data analysis, imputation and association analysis in the Icelandic data set. O.T.M. and S.A.G. performed exome sequencing and analysis. S.A.G., A.J. and A.S. carried out bioinformatics analysis for 1p31. Shared haplotype analysis was performed by M.L.F. and A.K. Sanger sequencing of Icelandic samples and Centaurus genotyping of Icelandic and Swedish samples were carried out and analyzed by H.T.H. and U.S. Expression experiments were carried out and analyzed by N.B., A.M.S., R.G.H.H.N., A.J., A.S., F.F.E. and M.T. The manuscript was drafted by U.S., G.T. and K.S. All authors contributed to the final version of the manuscript.

Competing interests

U.S., G.T., H.T.H., A.J., A.S., S.A.G., M.L.F., A.K., O.T.M., G.M., U.T., I.J. and K.S. are employed by deCODE Genetics/Amgen.

Corresponding authors

Correspondence to Unnur Styrkarsdottir or Kari Stefansson.

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