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- DOI: 10.1002/art.30315
- PMID: 21370227
- UKPMCID: 21370227
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Examining the overlap between genome-wide rare variant association signals and linkage peaks in rheumatoid arthritis.
Ke, X; Eyre, S; Lawrence, R; Bowes, J; Panoutsopoulou, K; Barton, A; Thomson, W; Worthington, J; Zeggini, E
Arthritis and rheumatism. 2011;63(6):1522-1526.
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Full-text held externally
- DOI: 10.1002/art.30315
- PMID: 21370227
- UKPMCID: 21370227
Abstract
OBJECTIVE: With the exception of the MHC and STAT4, no other rheumatoid arthritis (RA) linkage peak has been successfully fine-mapped to date. This apparent failure to identify association under peaks of linkage could be ascribed to the examination of common variation, as linkage is likely to be driven by rare variants. We investigated the overlap between genome-wide rare variant RA association signals from the Wellcome Trust Case Control Consortium (WTCCC) study and 11 replicating RA linkage peaks, defined as regions with evidence for linkage in more than one study. METHODS: The WTCCC dataset contained 40,482 variants with minor allele frequency ≤0.05 in 1,860 RA cases and 2,938 controls. Genotypes of all rare variants within a given gene region were collapsed into a single locus and a global p value was calculated per gene. RESULTS: The distribution of rare variant signals (association p≤10(-5) ) was found to differ significantly between regions with and without linkage evidence (Fisher's exact p=2x10(-17) ). No significant difference was observed after data from the MHC region were removed or when the effect of the HLA-DRB1 locus was accounted for. CONCLUSION: The results suggest that rare variant association signals are significantly over-represented under linkage peaks in RA, but the effect is driven by the MHC. This is the first study to examine the overlap between linkage peaks and rare variant association signals genome-wide in a complex disease.