Genomewide linkage scan of hand osteoarthritis in female twin pairs showing replication of quantitative trait loci on chromosomes 2 and 19

Abstract

Background and objective: Until recently, there has been little agreement between conflicting results of osteoarthritis (OA) linkage. The purpose of this study was to conduct a whole-genome linkage scan to identify susceptibility loci for idiopathic hand OA in a large, population-based sample of females. Methods: Two OA-related radiographic phenotypes DIP (distal interphalangeal joints)-OA and Tot-KL (Kellgren-Lawrence score for both hands) chosen a priori were examined on 538 (269 pairs) monozygous and 1256 (628 pairs) dizygous (DZ) females. A genome-wide scan using microsatellite markers spaced 10 cM apart was performed on 1028 DZ twins. First, the 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 generalised linear model. Results: Heritability for DIP-OA and Tot-KL was found to be 47.6% and 67.4%, respectively. A genome-wide scan produced reliable evidence of significant linkage of DIP-OA on chromosome 2 at 90 cM (logarithmic odds ratio (LOD) = 2.90) and for Tot-KL on chromosome 19 at 65 cM (LOD = 4.26). These results are in agreement with data published previously. Several other significant linkage peaks were observed-for example, on chromosome 1 at 250 cM and on chromosome 3 at 30 cM-but were confirmed less reliably. Conclusion: This is one of the largest OA linkage studies performed to date and provides clear evidence for linkage at two quantitative trait loci (on chromosome 2 at 90 cM and on chromosome 19 at 65 cM). As 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.

Osteoarthritis of the Distal Interphalangeal Joint

“…[25][26][27][28][29][30] Specific patterns of osteoarthritic joint appearance have been observed yet remain without uniform agreement. 16,[31][32][33] Several studies have shown that OA of the DIP joint is more common and more severe in middle-aged women.…”

Heritability estimates and linkage analysis of 23 short tandem repeat loci on chromosomes 2, 11, and 12 in an endemic osteochondropathy in China

“…KBD has a common pathological feature, arthritic hyaline cartilage damage, with osteoarthritis (OA) (11)(12)(13). Predisposing STR loci of OA have been identified on chromosomes 2p, 2q, 11q, 12p, and 12q by association and linkage analysis (14)(15)(16)(17), and the biological mechanisms linking these genes with OA may be related to the cartilage extracellular matrix, structural genes, or genes related to bone density and cytokines (18)(19)(20)(21). However, few studies have identified regions of the genome that contain genes predisposed to KBD.…”

Genetic Association and Linkage Studies in Osteoarthritis

“…No OA predisposing variants have been identified. A region on 4q31-q32 has provided significant evidence for linkage with DIP (Stefansson et al 2003) and hand OA (Livshits et al 2007). Further, the locus on 19q13 has shown significant evidence for linkage with hand and DIP OA (19q13.2 and 19q13.4, respectively, (Livshits et al 2007) and this locus was also supported by a family based earlier linkage screen (Demissie et al 2002).…”

“…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.…”

“…The heritability of radiographic hand OA has been shown to vary between 47.6 % and 67.4 % in an UK population-based study sample of females. The lower value was for DIP OA based on joint space narrowing and osteophytes, and the upper value the total Kellgren and Lawrence value for all 30 hand joints (Livshits et al 2007). …”