EXTENDED REPORT

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

Gregory Livshits^1,2, Bernet S Kato², Guangju Zhai², Deborah J Hart², David Hunter^2,3, Alex J MacGregor^2,4, Frances M K Williams², Tim D Spector²

¹ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
² Twin Research and Genetic Epidemiology Unit, St Thomas’ Hospital, King’s College London, London, UK
³ Boston University School of Medicine, Boston, Massachusetts, USA
⁴ School of Medicine, University of East Anglia, Norwich, UK

Correspondence to:
Dr T D Spector
Twin Research and Genetic Epidemiology Unit, King’s College London, St Thomas’ Hospital Campus, London SE1 7EH, UK; tim.spector{at}kcl.ac.uk

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.

Abbreviations: DIP, distal interphalangeal; DZ, dizygous; GLM, generalised linear modelling; IR, iterative regression; JSN, joint space narrowing; KL, Kellgren and Lawrence; LOD, logarithmic odds ratio; MPL, multipoint linkage; OA, osteoarthritis; OSP, osteophyte; Tot-KL, Kellgren–Lawrence score for both hands

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