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Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone

Nature Genetics volume 42, pages 520–524 (2010)Cite this article

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Abstract

Paget's disease of bone (PDB) is a common disorder with a strong genetic component characterized by focal increases in bone turnover, which in some cases is caused by mutations in SQSTM1. To identify additional susceptibility genes, we performed a genome-wide association study in 750 individuals with PDB (cases) without SQSTM1 mutations and 1,002 controls and identified three candidate disease loci, which were then replicated in an independent set of 500 cases and 535 controls. The strongest signal was with rs484959 on 1p13 near the CSF1 gene (P = 5.38 × 10−24). Significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 × 10−13) and with rs3018362 on 18q21 near the TNFRSF11A gene (P = 5.27 × 10−13). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as candidate genes for disease susceptibility.

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Figure 1: Detection of loci conferring susceptibility to PDB by genome-wide association.
Figure 2: Details of loci associated with PDB.

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  • 16 May 2010

    In the version of this paper originally published online, the name of the 12th author was misspelled (the correct spelling is Javier del Pino Montes), affiliation 10 was incorrect (the correct affiliation is “Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca and Hospital Universitario de Salamanca, RETICEF, Salamanca, Spain”) and the following sentence was missing from the Acknowledgments ( “The work was also supported by grants from Cancer Research UK (C348/A3758, C348/A8896), and the Medical Research Council (G0000657-53203) to M.G.D. and A.T.”). These errors have been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We acknowledge the contribution of the many participants who provided samples for the analysis. We thank L. Murphy and A. Fawkes of the Wellcome Trust Clinical Research Facility for technical support with the Illumina genotyping. We also thank A. Khatib for assistance with data management. The study was supported in part by grants to S.H.R. from the Arthritis Research Campaign (grants 13724, 17646 and 15389) and a grant to O.M.E.A. and S.H.R. from the National Association for Relief of Paget's Disease. The work was also supported by grants from Cancer Research UK (C348/A3758, C348/A8896), and the Medical Research Council (G0000657-53203) to M.G.D. and A.T.

Author information

Authors and Affiliations

  1. Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK

    Omar M E Albagha, Micaela R Visconti, Nerea Alonso, Anne L Langston & Stuart H Ralston

  2. Edinburgh Clinical Trials Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK

    Anne L Langston & Stuart H Ralston

  3. Department of Medicine, University of Auckland, Auckland, New Zealand

    Tim Cundy

  4. University Department of Medicine, Glasgow Royal Infirmary, Glasgow, UK

    Rosemary Dargie

  5. Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK

    Malcolm G Dunlop & Albert Tenesa

  6. Department of Clinical Chemistry, Royal Liverpool University Hospital, Liverpool, UK

    William D Fraser

  7. Department of Medicine, The University of Sydney and Central Sydney Area Health Service, Sydney, Australia

    Michael J Hooper

  8. Medical and Surgical Department, Geriatric Section, University of Torino, Torino, Italy

    Gianluca Isaia & Marco di Stefano

  9. Department of Clinical and Biomedical Sciences, Barwon Health, Geelong Hospital, University of Melbourne, Melbourne, Australia

    Geoff C Nicholson

  10. Departamento de Medicina, Unidad de Medicina Molecular, Universidad de Salamanca and Hospital Universitario de Salamanca, RETICEF, Salamanca, Spain

    Javier del Pino Montes & Rogelio Gonzalez-Sarmiento

  11. Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Australia

    John P Walsh

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Contributions

O.M.E.A. contributed to study design, oversaw the genotyping, performed data management, quality control, statistical and bioinformatic analyses and wrote the first draft of the manuscript. S.H.R. designed the study, obtained funding, coordinated the sample collection and phenotyping and revised the manuscript. A.L.L., T.C., R.D., W.D.F., M.J.H., G.I., G.C.N., J.d.P.M., R.G.-S., M.d.S. and J.P.W. contributed toward clinical sample collection and phenotyping. M.G.D. and A.T. provided genotype data for the stage 1 control samples. M.R.V. and N.A. assisted in sample preparation and performed DNA sequencing to identify samples with SQSTM1 mutations. All authors critically reviewed the article for important intellectual content and approved the final manuscript.

Corresponding author

Correspondence to Stuart H Ralston.

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Competing interests

S.H.R. and O.M.E.A. have submitted patents on the use of various genetic markers as diagnostic tests in PDB, including those described in this paper.

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Albagha, O., Visconti, M., Alonso, N. et al. Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone. Nat Genet 42, 520–524 (2010). https://doi.org/10.1038/ng.562

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