Paget's Disease of Bone: Evidence for a Susceptibility Locus on Chromosome 18q and for Genetic Heterogeneity
Open Access
- 1 June 1998
- journal article
- research article
- Published by Oxford University Press (OUP) in Journal of Bone and Mineral Research
- Vol. 13 (6) , 911-917
- https://doi.org/10.1359/jbmr.1998.13.6.911
Abstract
Paget's disease of bone is a common condition characterized by bone pain, deformity, pathological fracture, and an increased incidence of osteosarcoma. Genetic factors play a role in the pathogenesis of Paget's disease but the molecular basis of the disease remains unclear. Previous genetic linkage studies have mapped the rare Paget's disease‐like bone dysplasia familial expansile osteolysis (FEO) to chromosome 18q21–22, and recent work has shown evidence of linkage between this locus and Paget's disease in one family. Here we studied the relationship between the 18q21–22 locus and Paget's disease in eight large multiplex families from diverse ethnic backgrounds with inherited Paget's disease. Paget's disease was inherited as an autosomal dominant trait in all families, with high penetrance by the sixth decade. Analysis of seven highly polymorphic markers from chromosome 18q21–22 showed positive summated two‐point log10 odds ratio (lodscores) of +2.97 with the marker D18S42 at a recombination fraction (θ) = 0.05, and of +2.95 with the marker D18S60 at θ = 0.00, values which are close to the cut‐off of +3.0, which is generally accepted as evidence of linkage. Segregation analysis of the haplotypes and formal statistical analysis using the HOMOG program provided evidence for genetic heterogeneity, however, with evidence for linkage in five families and against linkage in the remaining three families (chi square 8.82; df = 2; p < 0.025). Multipoint linkage analysis in the five linked families showed lodscores of above +3.5 across the whole susceptibility region and a maximum summated lodscore of 3.89 at the marker D18S465. In the three nonlinked families, negative multipoint results were obtained for the whole region, with lodscores below –2.0 in one family, excluding this as a candidate locus for the disease. Our studies demonstrate the importance of hereditary factors in the pathogenesis of Paget's disease and confirm evidence of linkage between Paget's disease and chromosome 18q21–22 in some families. This raises the possibility that Paget's disease and FEO may share a common molecular basis, perhaps due to different mutations in the same gene or family of genes. Data from three families did not support evidence of linkage to 18q21–22 however, indicating that Paget's disease is genetically heterogeneous and suggests the presence of at least one additional locus which remains to be discovered.Keywords
This publication has 17 references indexed in Scilit:
- Does Paget's Disease Really Have a Viral Aetiology? Letter to the Editor: Maybe NotJournal of Bone and Mineral Research, 1997
- Evidence for secular change in paget's diseaseBone, 1997
- Seeking the elusive etiology of paget disease: A progress reportJournal of Bone and Mineral Research, 1996
- Genetic dissection of complex traits: guidelines for interpreting and reporting linkage resultsNature Genetics, 1995
- Genetic linkage of familial expansile osteolysis to chromosome 18qHuman Molecular Genetics, 1994
- Familial aggregation of paget's disease of boneJournal of Bone and Mineral Research, 1991
- Familial Expansile OsteolysisPublished by Wolters Kluwer Health ,1989
- Published by Wiley ,1988
- A family study of Paget's disease of bone.Journal of Epidemiology and Community Health, 1983
- European distribution of Paget's disease of bone.BMJ, 1982