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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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References

  1. Albagha, O.M. 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).

    Article  CAS  Google Scholar 

  2. Cooper, C. et al. The epidemiology of Paget's disease in Britain: is the prevalence decreasing? J. Bone Miner. Res. 14, 192–197 (1999).

    Article  CAS  Google Scholar 

  3. Morales-Piga, A.A., Rey-Rey, J.S., Corres-Gonzalez, J., Garcia-Sagredo, J.M. & Lopez-Abente, G. Frequency and characteristics of familial aggregation of Paget's disease of bone. J. Bone Miner. Res. 10, 663–670 (1995).

    Article  CAS  Google Scholar 

  4. Visconti, M.R. et al. Mutations of SQSTM1 are associated with severity and clinical outcome in Paget disease of bone. J. Bone Miner. Res. 25, 2368–2373 (2010).

    Article  CAS  Google Scholar 

  5. Laurin, N., Brown, J.P., Morissette, J. & Raymond, V. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am. J. Hum. Genet. 70, 1582–1588 (2002).

    Article  CAS  Google Scholar 

  6. Hocking, L.J. et al. Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. Hum. Mol. Genet. 11, 2735–2739 (2002).

    Article  CAS  Google Scholar 

  7. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  8. Chung, P.Y. et al. The majority of the genetic risk for Paget's disease of bone is explained by genetic variants close to the CSF1, OPTN, TM7SF4, and TNFRSF11A genes. Hum. Genet. 128, 615–626 (2010).

    Article  Google Scholar 

  9. Hartgers, F.C. et al. DC-STAMP, a novel multimembrane-spanning molecule preferentially expressed by dendritic cells. Eur. J. Immunol. 30, 3585–3590 (2000).

    Article  CAS  Google Scholar 

  10. Yagi, M. et al. DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. J. Exp. Med. 202, 345–351 (2005).

    Article  CAS  Google Scholar 

  11. Kukita, T. et al. RANKL-induced DC-STAMP is essential for osteoclastogenesis. J. Exp. Med. 200, 941–946 (2004).

    Article  CAS  Google Scholar 

  12. Nishida, T., Emura, K., Kubota, S., Lyons, K.M. & Takigawa, M. CCN family 2/connective tissue growth factor (CCN2/CTGF) promotes osteoclastogenesis via induction of and interaction with dendritic cell-specific transmembrane protein (DC-STAMP). J. Bone Miner. Res. 26, 351–363 (2010).

    Article  Google Scholar 

  13. Grandi, P. et al. Nup93, a vertebrate homologue of yeast Nic96p, forms a complex with a novel 205-kDa protein and is required for correct nuclear pore assembly. Mol. Biol. Cell 8, 2017–2038 (1997).

    Article  CAS  Google Scholar 

  14. Saito, K. et al. A novel binding protein composed of homophilic tetramer exhibits unique properties for the small GTPase Rab5. J. Biol. Chem. 277, 3412–3418 (2002).

    Article  CAS  Google Scholar 

  15. Kajiho, H. et al. RIN3: a novel Rab5 GEF interacting with amphiphysin II involved in the early endocytic pathway. J. Cell Sci. 116, 4159–4168 (2003).

    Article  CAS  Google Scholar 

  16. Coxon, F.P. & Rogers, M.J. The role of prenylated small GTP-binding proteins in the regulation of osteoclast function. Calcif. Tissue Int. 72, 80–84 (2003).

    Article  CAS  Google Scholar 

  17. Van Wesenbeeck, L. et al. Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans. J. Clin. Invest. 117, 919–930 (2007).

    Article  CAS  Google Scholar 

  18. Watts, G.D. et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat. Genet. 36, 377–381 (2004).

    Article  CAS  Google Scholar 

  19. Lin, H.K., Bergmann, S. & Pandolfi, P.P. Cytoplasmic PML function in TGF-β signalling. Nature 431, 205–211 (2004).

    Article  CAS  Google Scholar 

  20. Smits, P. et al. Lethal skeletal dysplasia in mice and humans lacking the golgin GMAP-210. N. Engl. J. Med. 362, 206–216 (2010).

    Article  CAS  Google Scholar 

  21. Hennies, H.C. et al. Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin. Nat. Genet. 40, 1410–1412 (2008).

    Article  CAS  Google Scholar 

  22. Siris, E.S., Ottman, R., Flaster, E. & Kelsey, J.L. Familial aggregation of Paget's disease of bone. J. Bone Miner. Res. 6, 495–500 (1991).

    Article  CAS  Google Scholar 

  23. Rivadeneira, F. et al. Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat. Genet. 41, 1199–1206 (2009).

    Article  CAS  Google Scholar 

  24. Zeller, T. et al. Genetics and beyond—the transcriptome of human monocytes and disease susceptibility. PLoS ONE 5, e10693 (2010).

    Article  Google Scholar 

  25. Langston, A.L. et al. Randomized trial of intensive bisphosphonate treatment versus symptomatic management in Paget's disease of bone. J. Bone Miner. Res. 25, 20–31 (2010).

    Article  CAS  Google Scholar 

  26. Falchetti, A. et al. Genetic epidemiology of Paget's disease of bone in Italy: sequestosome1/p62 gene mutational test and haplotype analysis at 5q35 in a large representative series of sporadic and familial Italian cases of Paget's disease of bone. Calcif. Tissue Int. 84, 20–37 (2009).

    Article  CAS  Google Scholar 

  27. Gennari, L. et al. SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone. J. Bone Miner. Res. 25, 1375–1384 (2010).

    Article  CAS  Google Scholar 

  28. Eekhoff, M.E. et al. Paget's disease of bone in The Netherlands: a population-based radiological and biochemical survey—the Rotterdam Study. J. Bone Miner. Res. 19, 566–570 (2004).

    Article  Google Scholar 

  29. Li, Y. & Abecasis, G.R. Mach 1.0: rapid haplotype reconstruction and missing genotype inference. Am. J. Hum. Genet. S79, 2290 (2006).

    Google Scholar 

  30. Aulchenko, Y.S., Struchalin, M.V. & van Duijn, C.M. ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics 11, 134 (2010).

    Article  Google Scholar 

  31. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  32. Clayton, D.G. et al. Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat. Genet. 37, 1243–1246 (2005).

    Article  CAS  Google Scholar 

  33. Pe'er, I., Yelensky, R., Altshuler, D. & Daly, M.J. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet. Epidemiol. 32, 381–385 (2008).

    Article  Google Scholar 

  34. DerSimonian, R. & Laird, N. Meta-analysis in clinical trials. Control. Clin. Trials 7, 177–188 (1986).

    Article  CAS  Google Scholar 

  35. Voight, B.F. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat. Genet. 42, 579–589 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. Schadt, E.E. et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008).

    Article  Google Scholar 

  38. Stranger, B.E. et al. Population genomics of human gene expression. Nat. Genet. 39, 1217–1224 (2007).

    Article  CAS  Google Scholar 

  39. Veyrieras, J.B. et al. High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet. 4, e1000214 (2008).

    Article  Google Scholar 

  40. Montgomery, S.B. et al. Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464, 773–777 (2010).

    Article  CAS  Google Scholar 

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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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