Genome-wide scan for Paget's disease of bone in French-Canadian families. N. Laurin1, V. Raymond1, A. Duchesne1, C. Brousseau2, D. Huot2, Y. Lacourcière2, G. Drapeau2, J. Verreault2, J.P. Brown2, J. Morissette1. 1) Molecular Endocrinology and Oncology, CHUL (Laval University Medical Ctr) Research Ctr, Quebec city, Qc., Canada; 2) Rheumatology-Immunology, CHUL Research Ctr, Quebec city, Qc., Canada.
Page'ts disease of bone is a chronic skeletal disorder characterized by an excessive increase of bone turnover. The pathologic basis of the disease is still unknown. Recent pedigree studies have shown that the modes of genetic transmission of Paget's disease of bone include both autosomal dominant inheritance with reduced penetrance and multifactorial inheritance. To understand the genetic components underlying the disorder, we performed a genome-wide scan on three family nuclei selected from 24 French-Canadian kindreds in which Paget's was transmitted as an autosomal dominant trait. These nuclei comprised 27 affected and 17 non-affected subjects. Diagnoses were based on total serum alkaline phosphatase, total body bone scan and skull and pelvis X-rays. We genotyped 400 microsatellite markers located at an average spacing of 10 cM. Linkage analyses were done by FASTLINK 4.1P and GENEHUNTER 2.0. Haplotypes were phased by SIMWALK 2.6. With a phenocopy rate fixed at 5% for people up to 50 years old, the highest lod score values were observed at D19S414 (Z=3.03), D3S3681 (Z=1.37), D15S153 (Z=1.27), D4S422 (Z=1.22) and D1S2890 (Z=1.16). Heterogeneity was observed for several markers between the families. When families were analyzed separately, a few chromosome regions showed positive lod score values between 0.75 and 2.00 at independent loci. Multipoint analyses were subsequently performed within regions of interest. Some consecutive markers (between 3 to 7) gave positive lod score values on chromosomes 3, 4, 9, 10, 13, 16, 19 and 20 in one or more families. These data therefore suggest that Paget's disease of bone may be genetically heterogeneous. The seven most interesting regions are now being investigated for linkage with the disease using additional markers and the 21 other families not included in our genome-wide scan.