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

Paget’s disease of bone (PDB) is a common disorder with a strong genetic component characterised by focal increases in bone turnover which in some cases is caused by SQSTM1 mutations. To identify additional susceptibility genes we performed a genome wide association study in 750 PDB cases without SQSTM1 mutations and 1002 controls and identified three candidate loci for the disease which were replicated in an independent set of 500 cases and 535 controls. The strongest signal was with rs484959 on 1p13 close to the CSF1 gene (P = 5.38 × 10(−24)) and significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 × 10(−13)) and with rs3018362 on 18q21 close to 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 novel candidate genes for disease susceptibility.