Linkage to nodal osteoarthritis: quantitative and qualitative analyses of data from a whole-genome screen identify trait-dependent susceptibility loci

Greig, Carolyn; Spreckley, Kristian; Aspinwall, Richard; Gillaspy, Emma; Grant, Mark; Ollier, WE; John, Sujit; Doherty, Michael; Wallis, Gillian A.

doi:10.1136/ard.2005.048165

Cited by 23 publications

(11 citation statements)

References 38 publications

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“…Leppavuori's team, 17 in a small family-based sample, found a significant association of DIP to 116 cM near the IL1R1gene cluster. Greig et al, 18 using a modest sample of affected families from a similar ethnic background to ours, found significant linkage to markers mapped to the 103.7 cM position on this chromosome. As the CIs are wide for model-free linkage methods, 16 it is possible that these areas coincide and represent a replication.…”

Section: Discussionsupporting

confidence: 74%

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

Livshits

Kato

Zhai

et al. 2007

Annals of the Rheumatic Diseases

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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.

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Section: Discussionsupporting

confidence: 74%

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

Livshits

Kato

Zhai

et al. 2007

Annals of the Rheumatic Diseases

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“…If, however, the study aim is to identify risk factors for incident RHOA, the choice of definition may have a major impact on the results, because risk factors may differ between different phenotypes of RHOA (i.e., hypertrophic and atrophic) (12,26,27). Recent work also suggests that genetic susceptibility loci may be associated preferentially with changes predominantly in JSN (28) or osteophytosis (28,29). Thus, a composite measure such as the presence of both osteophytes and JSN, which displays a greater overlap with the other definitions, would appear to be a good option for identifying the complete spectrum of risk factors for hip OA.…”

Section: Discussionmentioning

confidence: 99%

Defining incident radiographic hip osteoarthritis for epidemiologic studies in women

Arden¹,

Lane²,

Parimi³

et al. 2009

Arthritis & Rheumatism

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Objectives To evaluate definitions of radiographic hip osteoarthritis (RHOA) for use in longitudinal epidemiologic studies of disease incidence in women. Methods We studied 5,839 women from the Study of Osteoporotic Fractures who had had serial pelvic radiographs obtained (mean of 8.3 years apart) and who were followed up (mean followup 7.1 years from the time of the second radiograph) for evaluation of clinical outcomes. Definitions of RHOA were assessed for construct validity (association with symptoms and signs at the time of the second radiograph) and predictive validity (association with total hip replacement [THR] and signs and symptoms a mean of 7.1 years later). Odds ratios (ORs) and 95% confidence intervals were calculated to assess the strength of association using logistic regression. Results The cumulative incidence of RHOA ranged from 2.2% to 11.7%. All definitions displayed significant construct validity; the most consistent was found for composite definitions that required the concurrent presence of 2 or more individual radiographic features and definitions based on stringent criteria for joint space narrowing. All definitions except minimum joint space ≤2.5 mm displayed consistent predictive validity. Composite definitions had the strongest associations with THR (OR 10.5–18.5) and hip pain (OR 2.6–2.9). The hips identified as having OA by each definition varied, with especially small overlap between findings using definitions based on osteophytes and those using definitions based on joint space narrowing alone. Conclusions Most definitions of incident RHOA display good construct and predictive validity. Composite definitions have the best overall performance, and definitions requiring the presence of both osteophytes (in particular, femoral osteophytes) and joint space narrowing would be recommended for most epidemiologic and genetic studies.

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“…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.…”

Section: Genome-wide Linkage Studiesmentioning

confidence: 99%

Genetic Association and Linkage Studies in Osteoarthritis

Näkki¹,

Männikkö²,

Saarela³

2012

Principles of Osteoarthritis- Its Definition, Character, Derivation and Modality-Related Recognition

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Linkage to nodal osteoarthritis: quantitative and qualitative analyses of data from a whole-genome screen identify trait-dependent susceptibility loci

Abstract: The ASP and quantitative analyses of the cohort with nodal osteoarthritis suggest that multiple susceptibility loci for osteoarthritis influence the traits, which combine to form the osteoarthritis phenotype, and that these loci may not act exclusively on the joints of the hand.

Cited by 23 publications

References 38 publications

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

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

Defining incident radiographic hip osteoarthritis for epidemiologic studies in women

Genetic Association and Linkage Studies in Osteoarthritis

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