Abstract
BackgroundAlthough rheumatoid arthritis has been shown to have moderately strong genetic component, both linked loci identified in linkage analyses and susceptibility variants from association studies are short of adequately accounting for a comprehensive catalogue of the molecular factors underlying this complex disease. The objective of this study was to use supplementary phenotype based on cumulative hazard of rheumatoid arthritis to identify linkage evidence for new and additional rheumatoid arthritis loci in a genome-wide linkage analysis of 342 affected sibling pair families from the United Kingdom.MethodsUsing proportional hazards model, we estimated cumulative hazard of rheumatoid arthritis and then used it as a quantitative trait in a non-parametric multipoint variance component linkage analysis with 353 microsatellite markers distributed across the 22 autosomal chromosomes.ResultsWe identified 3 new loci with genome-wide suggestive linkage evidence for rheumatoid arthritis on 9q21.13, 15p11.1 and 20q13.33. Our results also confirmed previously reported linkage evidence in the HLA-DRB1 region on chromosome 6 and on locus 1q32.1.ConclusionThis study demonstrates the potential for information gain through the use of supplementary phenotypes in genetic study of complex diseases to identify new and additional potential linked loci that are not detected by linkage analysis of traditional phenotypes; and our results provide further evidence of the involvement of multiple loci in the genetic aetiology of rheumatoid arthritis.
Highlights
Rheumatoid arthritis has been shown to have moderately strong genetic component, both linked loci identified in linkage analyses and susceptibility variants from association studies are short of adequately accounting for a comprehensive catalogue of the molecular factors underlying this complex disease
The Rheumatoid arthritis (RA) affected sibling pair families used in this study were part of the UK National Repository of Multicase Rheumatoid Arthritis Families maintained by the Arthritis Research Campaign
logarithm of odds (LOD) scores which were defined as the logarithm to base 10 of likelihood ratio of the data assuming linkage versus the analysis model assuming no linkage, were used to summarize the evidence in favour of linkage and these plotted by chromosome against the genetic marker positions
Summary
Rheumatoid arthritis has been shown to have moderately strong genetic component, both linked loci identified in linkage analyses and susceptibility variants from association studies are short of adequately accounting for a comprehensive catalogue of the molecular factors underlying this complex disease. In addition to evidence from familial aggregation, results from twin studies [6,7,8], segregation analysis [9] and genome-wide association studies [10,11,12] all indicate evidence of genetic influence in the aetiology of RA This evidence is further strengthened by the relatively high heritability of RA, estimated to be about 65% [13] from twin studies; and by reported linkage evidence for regions on chromosomes 2 and 11 [14], and 6 and 16 [15]. The implication is that it is likely that a number of other loci involved in the genetic susceptibility to RA exist and are yet to be identified and their individual roles quantified; the complete role of genetic factor in the aetiology of this complex disease remains to be clearly understood
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