Abstract

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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References

  1. 1.

    , , & Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 64, 1697–1707 (2012).

  2. 2.

    et al. The inheritance of hand osteoarthritis in Iceland. Arthritis Rheum. 48, 391–395 (2003).

  3. 3.

    & Risk factors for osteoarthritis: genetics. Osteoarthritis Cartilage 12 (suppl. A), S39–S44 (2004).

  4. 4.

    et al. The Genetics of Generalized Osteoarthritis (GOGO) study: study design and evaluation of osteoarthritis phenotypes. Osteoarthritis Cartilage 15, 120–127 (2007).

  5. 5.

    et al. Prevalence, incidence and progression of hand osteoarthritis in the general population: the Framingham Osteoarthritis Study. Ann. Rheum. Dis. 70, 1581–1586 (2011).

  6. 6.

    et al. A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22. Arthritis Rheum. 62, 499–510 (2010).

  7. 7.

    et al. Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22. Ann. Rheum. Dis. 70, 349–355 (2011).

  8. 8.

    et al. A variant in MCF2L is associated with osteoarthritis. Am. J. Hum. Genet. 89, 446–450 (2011).

  9. 9.

    et al. Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis. Proc. Natl. Acad. Sci. USA 109, 8218–8223 (2012).

  10. 10.

    arcOGEN Consortium. Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study. Lancet 380, 815–823 (2012).

  11. 11.

    et al. Common variants in DVWA on chromosome 3p24.3 are associated with susceptibility to knee osteoarthritis. Nat. Genet. 40, 994–998 (2008).

  12. 12.

    et al. New sequence variants in HLA class II/III region associated with susceptibility to knee osteoarthritis identified by genome-wide association study. PLoS ONE 5, e9723 (2010).

  13. 13.

    et al. A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip. Ann. Rheum. Dis. 10.1136/annrheumdis-2012-203114 (4 September 2013).

  14. 14.

    et al. Evidence for familial aggregation of hand, hip, and spine but not knee osteoarthritis in siblings with multiple joint involvement: the GARP study. Ann. Rheum. Dis. 64, 438–443 (2005).

  15. 15.

    et al. Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden Longevity Study. Eur. J. Hum. Genet. 14, 79–84 (2006).

  16. 16.

    et al. The Rotterdam Study: 2012 objectives and design update. Eur. J. Epidemiol. 26, 657–686 (2011).

  17. 17.

    & The UK Adult Twin Registry (TwinsUK). Twin Res. Hum. Genet. 9, 899–906 (2006).

  18. 18.

    & Cigarette smoking and risk of osteoarthritis in women in the general population: the Chingford study. Ann. Rheum. Dis. 52, 93–96 (1993).

  19. 19.

    et al. Does hand osteoarthritis predict future hip or knee osteoarthritis? Arthritis Rheum. 52, 3520–3527 (2005).

  20. 20.

    et al. Hand osteoarthritis severity is associated with total knee joint replacements independently of BMI. The Ages-Reykjavik Study. Open Rheumatol. J. 5, 7–12 (2011).

  21. 21.

    et al. Involvement of different risk factors in clinically severe large joint osteoarthritis according to the presence of hand interphalangeal nodes. Arthritis Rheum. 62, 2688–2695 (2010).

  22. 22.

    & Retinoic acid signalling during development. Development 139, 843–858 (2012).

  23. 23.

    Emerging roles for retinoids in regeneration and differentiation in normal and disease states. Biochim. Biophys. Acta 1821, 213–221 (2012).

  24. 24.

    & Retinoids and their receptors in skeletal development. Microsc. Res. Tech. 43, 137–155 (1998).

  25. 25.

    , & Revisiting the role of retinoid signaling in skeletal development. Birth Defects Res. C Embryo Today 69, 156–173 (2003).

  26. 26.

    et al. Craniosynostosis and multiple skeletal anomalies in humans and zebrafish result from a defect in the localized degradation of retinoic acid. Am. J. Hum. Genet. 89, 595–606 (2011).

  27. 27.

    , & From carrot to clinic: an overview of the retinoic acid signaling pathway. Cell. Mol. Life Sci. 67, 1423–1445 (2010).

  28. 28.

    , & Vitamin A and retinoid signaling: genomic and non-genomic effects. J. Lipid Res. 54, 1761–1775 (2013).

  29. 29.

    & New sources of retinoic acid synthesis revealed by live imaging of an Aldh1a2-GFP reporter fusion protein throughout zebrafish development. Dev. Dyn. 241, 1205–1216 (2012).

  30. 30.

    Retinoic acid synthesis and signaling during early organogenesis. Cell 134, 921–931 (2008).

  31. 31.

    , , & Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat. Genet. 21, 444–448 (1999).

  32. 32.

    et al. Retinoic acid promotes limb induction through effects on body axis extension but is unnecessary for limb patterning. Curr. Biol. 19, 1050–1057 (2009).

  33. 33.

    et al. ESPERR: learning strong and weak signals in genomic sequence alignments to identify functional elements. Genome Res. 16, 1596–1604 (2006).

  34. 34.

    ENCODE Project Consortium. A users guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol. 9, e1001046 (2011).

  35. 35.

    et al. Fine-scale recombination rate differences between sexes, populations and individuals. Nature 467, 1099–1103 (2010).

  36. 36.

    et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).

  37. 37.

    & Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst. 22, 719–748 (1959).

  38. 38.

    et al. Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. Nature 497, 517–520 (2013).

  39. 39.

    et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nat. Genet. 40, 1068–1075 (2008).

  40. 40.

    et al. Parental origin of sequence variants associated with complex diseases. Nature 462, 868–874 (2009).

  41. 41.

    & Genomic control for association studies. Biometrics 55, 997–1004 (1999).

  42. 42.

    et al. Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: the TREAT-OA consortium. Osteoarthritis Cartilage 19, 254–264 (2011).

  43. 43.

    et al. Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study. Ann. Rheum. Dis. 70, 864–867 (2011).

  44. 44.

    , , & Allelic expression analysis of the osteoarthritis susceptibility gene COL11A1 in human joint tissues. BMC Musculoskelet. Disord. 14, 85 (2013).

  45. 45.

    et al. Increased type II deiodinase protein in OA-affected cartilage and allelic imbalance of OA risk polymorphism rs225014 at DIO2 in human OA joint tissues. Ann. Rheum. Dis. 71, 1254–1258 (2012).

  46. 46.

    et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).

  47. 47.

    et al. A common inversion under selection in Europeans. Nat. Genet. 37, 129–137 (2005).

  48. 48.

    et al. The UCSC Genome Browser database: extensions and updates 2013. Nucleic Acids Res. 41, D64–D69 (2013).

  49. 49.

    et al. ENCODE data in the UCSC Genome Browser: year 5 update. Nucleic Acids Res. 41, D56–D63 (2013).

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Acknowledgements

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

Affiliations

  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

Consortia

  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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Contributions

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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https://doi.org/10.1038/ng.2957

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