title: Strong linkage on 2q33.3 to familial early-onset generalized osteoarthritis and a consideration of two positional candidate genes.
abstract: A genomewide screen was performed in four extended families with early-onset generalized osteoarthritis (FOA) without dysplasia. The FOA phenotype within these families shows a dominant Mendelian inheritance pattern and may represent common osteoarthritis (OA) at later ages. An initial locus was confirmed by three additional families and refined by 14 markers to a two-point logarithm of odds score of 6.05 (theta=0.00) for marker D2S155 at chromosome 2q33.3. This locus coincided with the highest multipoint nonparametric linkage score of 4.70 (P-value=0.0013) at marker D2S2358. Haplotype analysis of family members delineated a narrow region with a number of possible positional candidates, of which we investigate here the two most likely ones: PTHR2, encoding parathyroid hormone receptor 2, and FZD5, encoding frizzled receptor 5. For FZD5, we did not observe a segregating variant, however, for PTHR2, a missense variant (A225S) cosegregated with FOA in one family. The frequency of the PTHR2 variant was rare in a population-based sample, aged 55-70 years (N=1228, 0.4%). Of the 11 carriers, 36% showed generalized radiographic OA as compared to 23% in the remaining population. None of the other families that contributed to the linkage revealed a segregating variant. Together, we have identified a locus on chromosome 2q33.3 for FOA. Candidate gene analysis suggested a possible association of a PTHR2 variant with generalized radiographic OA; it is, however, unlikely the major disease gene for the observed linkage to the FOA phenotype.
authors.affiliation: Molecular Epidemiology, Leiden University Medical Center, Einthovenweg 20, 2300 RC Leiden, The Netherlands. i.meulenbelt@lumc.nl
authors.forename: Ingrid
authors.initials: I
authors.lastname: Meulenbelt
authors.forename: Josine L
authors.initials: JL
authors.lastname: Min
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Margreet
authors.initials: M
authors.lastname: Kloppenburg
authors.forename: Ferdinand C
authors.initials: FC
authors.lastname: Breedveld
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
mesh_terms: D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D005260:Female; D051157:Frizzled Receptors / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D016678:Genome; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010003:Osteoarthritis / Q000235:genetics*; D010375:Pedigree; D044183:Receptor, Parathyroid Hormone, Type 2 / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*
chemical_list: C498589:FZD5 protein, human; D051157:Frizzled Receptors; D044183:Receptor, Parathyroid Hormone, Type 2; D043562:Receptors, G-Protein-Coupled