Objective: Until recently there has been little agreement between conflicting OA linkage results. The purpose of this study was to conduct a whole-genome linkage scan to identify susceptibility loci for idiopathic hand osteoarthritis (OA) in a large, population-based sample of females.
Methods: Two OA-related radiographic phenotypes: DIP-OA (distal interphalangeal joints) and Tot-KL (Kellgren-Lawrence score for both hands) chosen a priori were examined on 592 monozygous (MZ) and 1292 Dizygous (DZ) females. A genomewide scan using microsatellite markers spaced every 10 cM was performed on 1018 DZ twins. First, heritability of the two OA phenotypes was estimated. Next, multipoint linkage analysis was conducted using a modified version of the Haseman-Elston method in a generalized linear model.
Results: Heritability for DIP-OA and Tot-KL were found to be 47.6% and 67.4%, respectively. A genomewide scan produced reliable evidence of significant linkage of DIP-OA on chromosome 2 at 90 cM (LOD=2.90) and for Tot-KL on chromosome 19 at 65cM (LOD=4.26). These results are in agreement with data previously published. Several other significant linkage peaks were observed, e.g. on chromosomes 1 at 250, 3 at 30cM and some others, but were less reliably confirmed.
Conclusion: This is one of the largest OA linkage studies performed to date and provides clear evidence for linkage at two QTLs (on Ch 2 at 90cM and Ch 19 at 65 cM). Since the results were robust and replicated in previous smaller studies, the fine mapping of these regions is a logical next step to pinpoint potential susceptibility gene(s) of interest.
- Haseman-Elston method
- Kellgren-Lawrence scores
- LOD score
- distal interphalangeal joints
- multipoint linkage analysis