title: Identification of rare genetic variants in novel loci associated with Paget's disease of bone.
abstract: In genome-wide association studies, single nucleotide polymorphisms located in five novel loci were associated with PDB. We aimed at identifying rare genetic variants of candidate genes located in these loci and search for genetic association with PDB in the French-Canadian population. Exons, promoter and exon-intron junctions from patients with familial PDB and healthy individuals were sequenced in candidate genes, located within novel loci associated with PDB in our population. Rare variant was defined by a minor allele frequency <0.05 or absent from dbSNP (NCBI). We sequenced seven genes in 1p13 locus, three genes in 7q33, three genes in 8q22, and five genes in 15q24 locus. We identified 126 rare variants in at least one patient with PDB of whom 55 were located in 1p13 locus, 32 in 7q33, 10 in 8q22 and 29 in 15q24 locus. We located 71 of these 126 rare variants in an intron, 30 in an exon and 9 in an untranslated region. 60 % of these variants were located in functionally relevant gene regions. Among the 12 missense rare variants in PDB, two (rs62620995 in TM7SF4; rs62641691 in CD276) were predicted to be damaging by in silico analysis tools. Rs62620995, which altered a conserved amino acid (p.Leu397Phe) in the TM7SF4 gene, encoding the DC-STAMP protein involved in osteoclastogenesis through RANK signaling pathway, was found to have a marginal association with PDB (p = 0.09). Rs35500845, located in the CTHRC1 gene, which encodes a regulator of collagen matrix deposition, was also associated with PDB in the French-Canadian population (p = 0.046).
authors.affiliation: CHU de Québec Research Centre, Quebec, QC, Canada.
authors.forename: Mariejka
authors.initials: M
authors.lastname: Beauregard
authors.forename: Edith
authors.initials: E
authors.lastname: Gagnon
authors.forename: Sabrina
authors.initials: S
authors.lastname: Guay-Bélanger
authors.forename: Jean
authors.initials: J
authors.lastname: Morissette
authors.forename: Jacques P
authors.initials: JP
authors.lastname: Brown
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Michou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D002170:Canada / Q000453:epidemiology; D003198:Computer Simulation; D005091:Exons; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D005602:France / Q000208:ethnology; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007438:Introns; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D010001:Osteitis Deformans / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502426:CTHRC1 protein, human; C501589:DCSTAMP protein, human; D016326:Extracellular Matrix Proteins; D008565:Membrane Proteins