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Rare variation at the TNFAIP3 locus and susceptibility to rheumatoid arthritis.

Bowes, John; Lawrence, Robert; Eyre, Stephen; Panoutsopoulou, Kalliope; Orozco, Gisela; Elliott, Katherine S; Ke, Xiayi; Morris, Andrew P; UKRAG; Thomson, Wendy; Worthington, Jane; Barton, Anne; Zeggini, Eleftheria

Human genetics. 2010;128(6):627-633.

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Abstract

Genome-wide association studies (GWAS) conducted using commercial single nucleotide polymorphisms (SNP) arrays have proven to be a powerful tool for the detection of common disease susceptibility variants. However, their utility for the detection of lower frequency variants is yet to be practically investigated. Here we describe the application of a rare variant collapsing method to a large genome-wide SNP dataset, the Wellcome Trust Case Control Consortium rheumatoid arthritis (RA) GWAS. We partitioned the data into gene-centric bins and collapsed genotypes of low frequency variants (defined here as MAF ≤0.05) into a single count coupled with univariate analysis. We then prioritised gene regions for further investigation in an independent cohort of 3,355 cases and 2,427 controls based on rare variant signal p value and prior evidence to support involvement in RA. A total of 14,536 gene bins were investigated in the primary analysis and signals mapping to the TNFAIP3 and chr17q24 loci were selected for further investigation. We detected replicating association to low frequency variants in the TNFAIP3 gene (combined p = 6.6 × 10(-6)). Even though rare variants are not well-represented and can be difficult to genotype in GWAS, our study supports the application of low frequency variant collapsing methods to genome-wide SNP datasets as a means of exploiting data that are routinely ignored.

Bibliographic metadata

Type of resource:
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Published date:
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Volume:
128
Issue:
6
Start page:
627
End page:
633
Digital Object Identifier:
10.1007/s00439-010-0889-1
Pubmed Identifier:
20852893
Access state:
Active

Record metadata

Manchester eScholar ID:
uk-ac-man-scw:92370
Created by:
Ingram, Mary
Created:
11th October, 2010, 10:39:50
Last modified by:
Ingram, Mary
Last modified:
18th December, 2013, 19:38:43

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