title: Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone.
abstract: 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 x 10(-24)). Significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 x 10(-13)) and with rs3018362 on 18q21 near the TNFRSF11A gene (P = 5.27 x 10(-13)). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as candidate genes for disease susceptibility.
authors.affiliation: Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors.forename: Omar M E
authors.initials: OM
authors.lastname: Albagha
authors.forename: Micaela R
authors.initials: MR
authors.lastname: Visconti
authors.forename: Nerea
authors.initials: N
authors.lastname: Alonso
authors.forename: Anne L
authors.initials: AL
authors.lastname: Langston
authors.forename: Tim
authors.initials: T
authors.lastname: Cundy
authors.forename: Rosemary
authors.initials: R
authors.lastname: Dargie
authors.forename: Malcolm G
authors.initials: MG
authors.lastname: Dunlop
authors.forename: William D
authors.initials: WD
authors.lastname: Fraser
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hooper
authors.forename: Gianluca
authors.initials: G
authors.lastname: Isaia
authors.forename: Geoff C
authors.initials: GC
authors.lastname: Nicholson
authors.forename: Javier
authors.initials: J
authors.lastname: del Pino Montes
authors.forename: Rogelio
authors.initials: R
authors.lastname: Gonzalez-Sarmiento
authors.forename: Marco
authors.initials: M
authors.lastname: di Stefano
authors.forename: Albert
authors.initials: A
authors.lastname: Tenesa
authors.forename: John P
authors.initials: JP
authors.lastname: Walsh
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
mesh_terms: D018797:Cell Cycle Proteins; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics*; D026901:Membrane Transport Proteins; D010001:Osteitis Deformans / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics*; D012307:Risk Factors; D035582:Transcription Factor TFIIIA / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D026901:Membrane Transport Proteins; C409460:OPTN protein, human; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; D035582:Transcription Factor TFIIIA; D016173:Macrophage Colony-Stimulating Factor