Pathway-driven gene stability selection of two rheumatoid arthritis GWAS identifies and validates new susceptibility genes in receptor mediated signalling pathways

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.