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


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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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, 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.

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Authors and Affiliations



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.

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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).

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