title: Rare variation at the TNFAIP3 locus and susceptibility to rheumatoid arthritis.
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 prioritized 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.
authors.affiliation: Arthritis Research UK, Epidemiology Unit, University of Manchester, Manchester, UK.
authors.forename: John
authors.initials: J
authors.lastname: Bowes
authors.forename: Robert
authors.initials: R
authors.lastname: Lawrence
authors.forename: Stephen
authors.initials: S
authors.lastname: Eyre
authors.forename: Kalliope
authors.initials: K
authors.lastname: Panoutsopoulou
authors.forename: Gisela
authors.initials: G
authors.lastname: Orozco
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Elliott
authors.forename: Xiayi
authors.initials: X
authors.lastname: Ke
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Morris
authors.forename: Wendy
authors.initials: W
authors.lastname: Thomson
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D004268:DNA-Binding Proteins; D020022:Genetic Predisposition to Disease; D005821:Genetic Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D015201:Meta-Analysis as Topic; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3