title: Pathway-driven gene stability selection of two rheumatoid arthritis GWAS identifies and validates new susceptibility genes in receptor mediated signalling pathways.
abstract: Rheumatoid arthritis (RA) is the commonest chronic, systemic, inflammatory disorder affecting ∼1% of the world population. It has a strong genetic component and a growing number of associated genes have been discovered in genome-wide association studies (GWAS), which nevertheless only account for 23% of the total genetic risk. We aimed to identify additional susceptibility loci through the analysis of GWAS in the context of biological function. We bridge the gap between pathway and gene-oriented analyses of GWAS, by introducing a pathway-driven gene stability-selection methodology that identifies potential causal genes in the top-associated disease pathways that may be driving the pathway association signals. We analysed the WTCCC and the NARAC studies of ∼5000 and ∼2000 subjects, respectively. We examined 700 pathways comprising ∼8000 genes. Ranking pathways by significance revealed that the NARAC top-ranked ∼6% laid within the top 10% of WTCCC. Gene selection on those pathways identified 58 genes in WTCCC and 61 in NARAC; 21 of those were common (P(overlap)< 10(-21)), of which 16 were novel discoveries. Among the identified genes, we validated 10 known RA associations in WTCCC and 13 in NARAC, not discovered using single-SNP approaches on the same data. Gene ontology functional enrichment analysis on the identified genes showed significant over-representation of signalling activity (P< 10(-29)) in both studies. Our findings suggest a novel model of RA genetic predisposition, which involves cell-membrane receptors and genes in second messenger signalling systems, in addition to genes that regulate immune responses, which have been the focus of interest previously.
authors.affiliation: Department of Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London W2 1PG, UK. hariklia.eleftherohorinou06@imperial.ac.uk
authors.forename: Hariklia
authors.initials: H
authors.lastname: Eleftherohorinou
authors.forename: Clive J
authors.initials: CJ
authors.lastname: Hoggart
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Wright
authors.forename: Michael
authors.initials: M
authors.lastname: Levin
authors.forename: Lachlan J M
authors.initials: LJ
authors.lastname: Coin
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology