Identification of a major locus for Paget's disease on chromosome 10p13 in families of British descent

Lucas, Gavin J. A., Riches, Phillip L., Hocking, Lynne J., Cundy, Tim, Nicholson, Geoffrey C., Walsh, John P. and Ralston, Stuart H. (2008) Identification of a major locus for Paget's disease on chromosome 10p13 in families of British descent. Journal of Bone And Mineral Research, 23 1: 58-63. doi:10.1359/JBMR.071004

Author Lucas, Gavin J. A.
Riches, Phillip L.
Hocking, Lynne J.
Cundy, Tim
Nicholson, Geoffrey C.
Walsh, John P.
Ralston, Stuart H.
Title Identification of a major locus for Paget's disease on chromosome 10p13 in families of British descent
Journal name Journal of Bone And Mineral Research   Check publisher's open access policy
ISSN 0884-0431
Publication date 2008-01
Sub-type Article (original research)
DOI 10.1359/JBMR.071004
Volume 23
Issue 1
Start page 58
End page 63
Total pages 6
Place of publication Malden, MA, United States
Publisher Wiley-Blackwell
Language eng
Abstract Mutations of SQSTM1 are an important cause of PDB, but other genes remain to be discovered. A major susceptibility locus for PDB was identified on chromosome 10p13 by a genome-wide linkage scan in families of British descent, which accounted for the vast majority of cases not caused by SQSTM1 mutations. Introduction: Paget's disease of bone (PDB) has a strong genetic component, and several susceptibility loci have been identified by genome-wide linkage scans. We previously identified three susceptibility loci for PDB using this approach on chromosomes 5q35, 2q36, and 10p13 in 62 families of mainly British descent, but subsequently, mutations in the SQSTM1 gene were found to be the cause of PDB in 23 families from this cohort. Here we reanalyzed the results of our genome-wide search in families from this cohort who did not have SQSTM1 mutations. Materials and Methods: The study population consisted of 210 individuals from 39 families of predominantly British descent with autosomal dominant inheritance of PDB in whom SQSTM1 mutations had been excluded by mutation screening. The average family size was 5.44 ± 3.98 (SD) individuals (range, 2-24 individuals). Genotyping was performed using standard techniques with 382 microsatellite markers spaced at an average distance of 9.06 cM throughout the autosomes. Multipoint linkage analysis was performed using the GENEHUNTER program under models of homogeneity and heterogeneity. Results: Multipoint parametric linkage analysis under a model of homogeneity and nonparametric linkage analysis under a model of heterogeneity both showed strong evidence of linkage to a single locus on chromosome 10p13 (LOD score, +4.08) close to the marker D10S1653 at 41.43cM. No evidence of linkage was detected at the chromosome 2q36 locus previously identified in this population, and linkage to other candidate loci previously implicated in the pathogenesis of PDB was excluded. Conclusions: We conclude that there is an important susceptibility gene for PDB on chromosome 10p13 in families of British descent and find no evidence to support the existence of a susceptibility locus on chromosome 2q36 or other previously identified candidate loci for PDB in this population. The gene that lies within the 10p13 locus seems to account for the development of PDB in the vast majority of families of British descent who do not carry SQSTM1 mutations.
Keyword Paget's disease of bone
linkage analysis
genome-wide scan
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
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