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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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.
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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