title: 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.
abstract: Paget's disease of bone (PDB) is one of the most frequent metabolic bone disorders (1-5%), next to osteoporosis, affecting individuals above age 55. Sequestosome1 mutations explain a part of the PDB patients, but still the disease pathogenesis in the remaining PDB patients is largely unknown. Therefore, association studies investigating the relationship between genetic polymorphisms and sporadic PDB have been performed to find the genetic risk variants. Previously such studies indicated a role of the OPG and RANK gene. The latter was recently confirmed in a genome-wide association study (GWAS) which also indicated the involvement of chromosomal regions harbouring the CSF1 and OPTN gene. In this study, we sought to replicate these findings in a Belgian and a Dutch population. Similar significant results were obtained for the single nucleotide polymorphisms and the haplotypes. The most significant results are found in the CSF1 gene region, followed by the OPTN and TNFRSF11A gene region (p values ranging from 1.3 × 10(-4) to 3.8 × 10(-8), OR = 1.523-1.858). We next obtained significant association with a polymorphism from the chromosomal region around the TM7SF4 gene (p = 2.7 × 10(-3), OR = 1.427), encoding DC-STAMP which did not reach genome-wide significance in the GWAS, but based on its function in osteoclasts it can be considered a strong candidate gene. After meta-analysis with the GWAS data, p values ranged between 2.6 × 10(-4) and 8.8 × 10(-32). The calculated cumulative population attributable risk of these four loci turned out to be about 67% in our two populations, indicating that most of the genetic risk for PDB is coming from genetic variants close to these four genes.
authors.affiliation: Department of Medical Genetics, University and University Hospital of Antwerp, 2610, Antwerp, Belgium.
authors.forename: Pui Yan Jenny
authors.initials: PY
authors.lastname: Chung
authors.forename: Greet
authors.initials: G
authors.lastname: Beyens
authors.forename: Steven
authors.initials: S
authors.lastname: Boonen
authors.forename: Socrates
authors.initials: S
authors.lastname: Papapoulos
authors.forename: Piet
authors.initials: P
authors.lastname: Geusens
authors.forename: Marcel
authors.initials: M
authors.lastname: Karperien
authors.forename: Filip
authors.initials: F
authors.lastname: Vanhoenacker
authors.forename: Leon
authors.initials: L
authors.lastname: Verbruggen
authors.forename: Erik
authors.initials: E
authors.lastname: Fransen
authors.forename: Jan
authors.initials: J
authors.lastname: Van Offel
authors.forename: Stefan
authors.initials: S
authors.lastname: Goemaere
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Zmierczak
authors.forename: René
authors.initials: R
authors.lastname: Westhovens
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Devogelaer
authors.forename: Wim
authors.initials: W
authors.lastname: Van Hul
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018797:Cell Cycle Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics*; D026901:Membrane Transport Proteins; D008875:Middle Aged; D010001:Osteitis Deformans / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics*; D035582:Transcription Factor TFIIIA / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C501589:DCSTAMP protein, human; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C409460:OPTN protein, human; D053246:Receptor Activator of Nuclear Factor-kappa B; D035582:Transcription Factor TFIIIA; D016173:Macrophage Colony-Stimulating Factor