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 ¼ 0.00) for marker D2S155 at chromosome 2q33.3. This locus coincided with the highest multipoint nonparametric linkage score of 4.70 (P-value ¼ 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 ¼ 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.

Mutation analysis of candidate genes within the 2q33.3 linkage area for familial early-onset generalised osteoarthritis

“…We also analysed the presence of ROA among carriers in the random population as quantitative trait using a sum score of the number of affected joints 16 which revealed similar findings (data not shown).…”

“…16 In brief, significant linkage was observed at 2q33.3 -2q34 between markers D2S1384 and D2S2178 implicating a 5 cM interval (4.6 Mb). 16 Recombinant haplotypes were constructed for all families that contributed positively to the linkage. In families 2 and 4, most affected individuals carry identical heterozygous haplotypes resulting in two possible haplotypes explaining the linkage (Figure 1).…”

“…15 Previously, we mapped a locus for early-onset osteoarthritis (familial OA, FOA) in seven families to 2q33.3 -2q34. 16 The high LOD score in the early-onset OA families and absence of variants in the two most promising genes (FZD5 and PTHR2) prompted us to perform an extended systemic mutation analysis of candidate genes in the 2q33.3-2q34 linkage area. Additionally, we screened for mutations in the FRZB gene, which is localised at 2q32, slightly outside our linkage region.…”

Variation in the PTH2R gene is associated with age-related degenerative changes in the lumbar spine

“…These changes occur most commonly at the bone--cartilage transition line and interestingly, the PTH2R gene is known to be involved in endochondral bone formation [12]. Evidence for linkage of the 2q33 locus, in which the PTH2R gene resides, for familial early--onset generalised osteoarthritis (FOA) has been reported [22]. Although a rare missense mutation in the PTH2R gene (c.786G>T; p.A225S) co--segregating with FOA was discounted as contributing significantly to the FOA phenotype, there was nevertheless evidence of a possible association with generalised radiographic osteoarthritis in the general population.…”

Genetic Association and Linkage Studies in Osteoarthritis

“…The first genome-wide linkage studies in OA families were published over ten years ago (Leppävuori et al 1999;Loughlin et al 1999). They were followed by a number of twin, sib pair, and family-based studies and their meta-analysis, which together have identified at least fifteen OA loci with a genome-wide significant logarithm of odds score (LOD ≥ 3.3) (Leppävuori et al 1999;Loughlin et al 1999;Ingvarsson et al 2001;Demissie et al 2002;Loughlin et al 2002b;Stefansson et al 2003;Forster et al 2004b;Hunter et al 2004;Southam et al 2004;Greig et al 2006;Lee et al 2006;Mabuchi et al 2006;Meulenbelt et al 2006;Livshits et al 2007;Min et al 2007;Meulenbelt et al 2008). Of these, loci in 2p23-p24, 2q31-q33, 4q31-q32, 7q34-q36, and 19q13 have been implicated also in other independent studies.…”