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Meta-analysis of Icelandic and UK data sets identifies missense variants in SMO, IL11, COL11A1 and 13 more new loci associated with osteoarthritis

Nature Genetics volume 50, pages 1681–1687 (2018)Cite this article

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Abstract

Osteoarthritis has a highly negative impact on quality of life because of the associated pain and loss of joint function. Here we describe the largest meta-analysis so far of osteoarthritis of the hip and the knee in samples from Iceland and the UK Biobank (including 17,151 hip osteoarthritis patients, 23,877 knee osteoarthritis patients, and more than 562,000 controls). We found 23 independent associations at 22 loci in the additive meta-analyses, of which 16 of the loci were novel: 12 for hip and 4 for knee osteoarthritis. Two associations are between rare or low-frequency missense variants and hip osteoarthritis, affecting the genes SMO (rs143083812, frequency 0.11%, odds ratio (OR) = 2.8, P = 7.9 × 10−12, p.Arg173Cys) and IL11 (rs4252548, frequency 2.08%, OR = 1.30, P = 2.1 × 10−11, p.Arg112His). A common missense variant in the COL11A1 gene also associates with hip osteoarthritis (rs3753841, frequency 61%, P = 5.2 × 10–10, OR = 1.08, p.Pro1284Leu). In addition, using a recessive model, we confirm an association between hip osteoarthritis and a variant of CHADL1 (rs117018441, P = 1.8 × 10−25, OR = 5.9). Furthermore, we observe a complex relationship between height and risk of osteoarthritis.

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Fig. 1: Manhattan plots showing genome-wide association results from our meta-analysis of hip and knee osteoarthritis.
Fig. 2: Correlation between odds ratios of hip and knee osteoarthritis risk variants and effects on height and BMI.

Data availability

The Icelandic population whole-genome sequencing data have been deposited at the European Variant Archive under accession code PRJEB15197. The authors declare that the data supporting the findings of this study are available within the article, its supplementary files, and upon reasonable request.

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Acknowledgements

We thank the study subjects for their valuable participation. This research has been conducted using the UK Biobank Recourse under application number 23359.

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Authors and Affiliations

  1. deCODE genetics/Amgen, Inc., Reykjavik, Iceland

    Unnur Styrkarsdottir, Sigrun H. Lund, Gudmar Thorleifsson, Florian Zink, Olafur A. Stefansson, Jon K. Sigurdsson, Kristinn Juliusson, Kristbjörg Bjarnadottir, Stefan Jonsson, Kristjan Norland, Lilja Stefansdottir, Asgeir Sigurdsson, Gardar Sveinbjornsson, Asmundur Oddsson, Gyda Bjornsdottir, Reynir L. Gudmundsson, Gisli H. Halldorsson, Thorunn Rafnar, Ingileif Jonsdottir, Gudmundur L. Norddahl, Gisli Masson, Patrick Sulem, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir & Kari Stefansson

  2. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    Sigrun H. Lund, Ingileif Jonsdottir, Helgi Jonsson, Thorvaldur Ingvarsson, Unnur Thorsteinsdottir & Kari Stefansson

  3. Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    Sara Sigurbjornsdottir & Eirikur Steingrimsson

  4. Department of Immunology, Landspitali–The National University Hospital of Iceland, Reykjavik, Iceland

    Ingileif Jonsdottir

  5. Department of Medicine, Landspitali–The National University Hospital of Iceland, Reykjavik, Iceland

    Helgi Jonsson

  6. Department of Orthopedic Surgery, Akureyri Hospital, Akureyri, Iceland

    Thorvaldur Ingvarsson

  7. Institution of Health Science, University of Akureyri, Akureyri, Iceland

    Thorvaldur Ingvarsson

  8. School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland

    Daniel F. Gudbjartsson

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  1. Unnur Styrkarsdottir
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Contributions

U.S., U.T., G.T., and K.S. designed the study and interpreted the results. S.H.L., G.T., F.Z., J.K.S., K.J., K.N., G.S., A.O., A.S., L.S., G.M., D.F.G., and U.S. coordinated or performed statistical and bioinformatics analyses. R.L.G. and G.H. analysed the RNA expression data. O.A.S. performed analyses of regulatory regions. E.S., G.L.N., K.B., and S.S. coordinated and performed experiments. S.J. performed X-ray structure analysis. H.J., T.I., T.R., I.J., G.T., G.B., and U.S. managed phenotype data on the Icelandic subjects. U.S. and G.T. managed phenotype data for the UK Biobank dataset. F.Z., G.T., and G.M. coordinated association analyses of the UK Biobank dataset. U.S., U.T., P.S., D.F.G., and K.S. drafted the manuscript. All authors contributed to the final version of the manuscript.

Corresponding authors

Correspondence to Unnur Styrkarsdottir or Kari Stefansson.

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Competing interests

Authors U.S., S.H.L., G.T., F.Z., O.A.S., J.K.S., K.J., K.B., S.J., K.N., L.S., G.S., A.O., G.B., R.L.G., A.S., T.R., G.L.N., I.J., G.M., P.S., D.F.G., U.T., and K.S. are employed by deCODE genetics/Amgen, Inc.

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Styrkarsdottir, U., Lund, S.H., Thorleifsson, G. et al. Meta-analysis of Icelandic and UK data sets identifies missense variants in SMO, IL11, COL11A1 and 13 more new loci associated with osteoarthritis. Nat Genet 50, 1681–1687 (2018). https://doi.org/10.1038/s41588-018-0247-0

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