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Identification of rare genetic variants in novel loci associated with Paget’s disease of bone

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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).

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Acknowledgments

Mariejka Beauregard was supported by a summer program for medicine student award from the Canadian Institute of Health Research, followed by a scholarship of the Fonds de Recherche du Québec-Santé (FRQ-S) for the Master. Dr. Michou is supported by a career award from the FRQ-S. This study was funded by the Canadian Institute of Health Research (Catalyst Grant: Bone Health), the Fondation du CHUQ, the Canadian Foundation for Innovation, the FRQ-S, the Laval University and the CHU de Québec Research Centre.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. CHU de Québec Research Centre, Quebec, QC, Canada

    Mariejka Beauregard, Edith Gagnon, Sabrina Guay-Bélanger, Jean Morissette, Jacques P. Brown & Laëtitia Michou

  2. Division of Rheumatology, Department of Medicine, Laval University, Quebec, QC, Canada

    Mariejka Beauregard, Sabrina Guay-Bélanger, Jacques P. Brown & Laëtitia Michou

  3. Department of Rhumatologie-S763, CHU de Québec, 2705 boulevard Laurier, Quebec, QC, G1V 4G2, Canada

    Jacques P. Brown & Laëtitia Michou

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Correspondence to Laëtitia Michou.

Additional information

Accession numbers Nucleotide sequence data for novel reported rare variants (Table 2) are permanently available from the ENA browser at http://www.ebi.ac.uk/ena/data/view/HG005313-HG005349 once they are released into the public domain, in the ‘European Nucleotide Archive’ database.

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Beauregard, M., Gagnon, E., Guay-Bélanger, S. et al. Identification of rare genetic variants in novel loci associated with Paget’s disease of bone. Hum Genet 133, 755–768 (2014). https://doi.org/10.1007/s00439-013-1409-x

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