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Genome-wide association identifies three new susceptibility loci for Paget's disease of bone

Nature Genetics volume 43, pages 685–689 (2011)Cite this article

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Abstract

Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of bone remodeling. We previously identified variants at the CSF1, OPTN and TNFRSF11A loci as risk factors for PDB by genome-wide association study1. Here we extended this study, identified three new loci and confirmed their association with PDB in 2,215 affected individuals (cases) and 4,370 controls from seven independent populations. The new associations were with rs5742915 within PML on 15q24 (odds ratio (OR) = 1.34, P = 1.6 × 10−14), rs10498635 within RIN3 on 14q32 (OR = 1.44, P = 2.55 × 10−11) and rs4294134 within NUP205 on 7q33 (OR = 1.45, P = 8.45 × 10−10). Our data also confirmed the association of TM7SF4 (rs2458413, OR = 1.40, P = 7.38 × 10−17) with PDB. These seven loci explained ∼13% of the familial risk of PDB. These studies provide new insights into the genetic architecture and pathophysiology of PDB.

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Figure 1: Loci for susceptibility to PDB detected by GWAS.
Figure 2: Regional association plots of loci showing genome-wide significant association with PDB.
Figure 3: Forest plots showing association in the different datasets for SNPs at 7q33, 8q22.3, 14q32.12 and 15q24.1.
Figure 4: Cumulative contribution of genome-wide significant loci to the risk of PDB.

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Acknowledgements

The authors would like to 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 and A. Khatib for her assistance in data management. The study was supported in part by grants to S.H.R. (13724, 17646 and 15389) and to S.H.R. and O.M.E.A. (19520) from the Arthritis Research UK and a grant to O.M.E.A. and S.H.R. from the Paget's Association. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/, and funding for the project was provided by the Wellcome Trust under awards 076113 and 085475. J.d.P.M. is funded by Redes Temáticas de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF). We thank other members of the GDPD consortium for sample collection and clinical phenotyping of the following groups: Italian cohorts: S. Adami and M. Rossini, University of Verona, Vellegio Hospital, Verona, Italy; M. Benucci, Rheumatology Unit, Nuovo Ospedale, Florence, Italy; S. Bergui and G. Isaia, Department of Internal Medicine, University of Torino, Torino, Italy; D. Merlotti, Department of Internal Medicine, University of Siena, Siena, Italy; O. Di Munno, Rheumatology Unit, University of Pisa, Pisa, Italy; S. Ortolani, Centre for Metabolic Bone Disease, Instituto Auxologico Italiano, Milan, Italy; M. Fabio Uliviera, Ospedale Maggiore, Milan, Italy; F. Torricelli, Unit of Genetic Diagnosis, Carregi Hospital, Florence, Italy; and G. Mossetti and A. Del Puento, Federico II, University of Naples, Naples, Italy. For the Belgian and Dutch cohorts: S. Boonen, Department of Experimental Medicine, Leuven University, Leuven, Belgium; S. Goemaere and H.-G. Zmierczak, Unit for Osteoporosis and Metabolic Bone Diseases, Ghent University Hospital, Ghent, Belgium; P. Geusens, Biomedical Research Unit, University of Hasselt, Diepenbeek, Belgium, and Maastricht University, Maastricht, The Netherlands; M. Karperien, Department of Tissue Regeneration, University of Twente, Enschede, The Netherlands; J.Van Offel and F. Vanhoenacker, University Hospital of Antwerp, Edegem, Belgium; L. Verbruggen, Department of Rheumatology, UZ Brussels, Brussels, Belgium; R. Westhovens, Department of Rheumatology, University Hospital Gasthuisberg KU Leuven, Leuven, Belgium; and E. Marelise Eekhoff, Department of Endocrinology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands. This work was supported by grants from the 'Fonds voor Wetenschappelijk onderzoek' (FWO, G.0065.10N) and a network of excellence grant (EuroBoNeT) from the European Union (FP6) to W.V.H. For the Australian cohort: B.G.A. Stuckey, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia and School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia; and B.K. Ward, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.

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, Sachin E Wani, Micaela R Visconti, Nerea Alonso & Stuart H Ralston

  2. Edinburgh Clinical Trials Unit, University of Edinburgh, Western General Hospital, Edinburgh, UK

    Kirsteen Goodman & Stuart H Ralston

  3. Department of Internal Medicine, University of Florence, Florence, Italy

    Maria Luisa Brandi & Alberto Falchetti

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

    Tim Cundy

  5. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium

    Pui Yan Jenny Chung & Wim Van Hul

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

    Rosemary Dargie

  7. Department of Rheumatology, Saint-Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium

    Jean-Pierre Devogelaer

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

    William D Fraser

  9. Department of Internal Medicine, Endocrine Metabolic Sciences and Biochemistry, University of Siena, Siena, Italy

    Luigi Gennari & Ranuccio Nuti

  10. Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso', Italian National Research Council, Naples, Italy

    Fernando Gianfrancesco

  11. Department of Medicine, University of Sydney, Sydney, Australia

    Michael J Hooper

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

    Gianluca Isaia & Marco Di Stefano

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

    Geoff C Nicholson

  14. Department of Endocrinology & Metabolic Diseases, Leiden University Medical Centre, Leiden, The Netherlands

    Socrates Papapoulos

  15. Departamento de Medicina, Universidad de Salamanca, Servicio de Reumatología, Hospital Universitario de Salamanca, Salamanca, Spain

    Javier del Pino Montes

  16. Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia

    Thomas Ratajczak, Sarah L Rea, Lynley C Ward & John P Walsh

  17. Western Australian Institute for Medical Research, Centre for Medical Research, University of Western Australia, Crawley, Western Australia, Australia

    Thomas Ratajczak & Sarah L Rea

  18. Department of Clinical and Experimental Medicine Federico II University of Naples, Naples, Italy

    Domenico Rendina

  19. Departamento de Medicina, Unidad de Medicina Molecular, Instituto de Biología Molecular y Celular del Cáncer, Universidad de Salamanca-CSIC, Salamanca, Spain

    Rogelio Gonzalez-Sarmiento

  20. School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia

    John P Walsh

Consortia

the Genetic Determinants of Paget's Disease (GDPD) Consortium

  • Omar M E Albagha
  • , Sachin E Wani
  • , Micaela R Visconti
  • , Nerea Alonso
  • , Kirsteen Goodman
  • , Maria Luisa Brandi
  • , Tim Cundy
  • , Pui Yan Jenny Chung
  • , Rosemary Dargie
  • , Jean-Pierre Devogelaer
  • , Alberto Falchetti
  • , William D Fraser
  • , Luigi Gennari
  • , Fernando Gianfrancesco
  • , Michael J Hooper
  • , Wim Van Hul
  • , Gianluca Isaia
  • , Geoff C Nicholson
  • , Ranuccio Nuti
  • , Socrates Papapoulos
  • , Javier del Pino Montes
  • , Thomas Ratajczak
  • , Sarah L Rea
  • , Domenico Rendina
  • , Rogelio Gonzalez-Sarmiento
  • , Marco Di Stefano
  • , Lynley C Ward
  • , John P Walsh
  •  & Stuart H Ralston

Contributions

O.M.E.A. contributed to the study design and funding, oversaw the genotyping, performed data management, quality control, statistical and bioinformatics 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. K.G., M.L.B., T.C., P.Y.J.C., R.D., J.-P. D., A.F., W.D.F., L.G., F.G., M.J.H., W.V.H, G.I., G.C.N., R.N., S.P., J.d.P.M., T.R., S.L.R, D.R., R.G.-S., M.d.S., L.C.W. and J.P.W. contributed toward clinical sample collection and phenotyping. M.R.V., N.A., S.E.W., R.G.-S., P.Y.J.C. and F.G. contributed to sample preparation and carried out DNA sequencing to identify samples with SQSTM1 mutations. All authors critically reviewed the article for important intellectual content and approved the final manuscript.

Corresponding authors

Correspondence to Omar M E Albagha or Stuart H Ralston.

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Competing interests

O.M.E.A. and S.H.R. have applied for an International PCT (Patent Co-operation Treaty) patent filing (European Office) on the use of genetic profiling to identify patients at risk of Paget's disease, which contains subject matter drawn from the work also published here.

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the Genetic Determinants of Paget's Disease (GDPD) Consortium. Genome-wide association identifies three new susceptibility loci for Paget's disease of bone. Nat Genet 43, 685–689 (2011). https://doi.org/10.1038/ng.845

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