1. ¹Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
2. ²Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
3. ³Departmentof Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
4. ⁴Department of Epidemiology and Biostatistics Erasmus University Medical School, Rotterdam, The Netherlands

Correspondence: Dr I Meulenbelt, Molecular Epidemiology, Leiden University Medical Center, Einthovenweg 20, Postzone S-05-P, PO Box 9600, 2300 RC, Leiden, The Netherlands. Tel: +31 71 526 9734; Fax: +31 71 526 8280. E-mail: i.meulenbelt@lumc.nl

Received 3 April 2006; Revised 19 June 2006; Accepted 5 July 2006; Published online 16 August 2006.

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.