To identify disease-causative variants, we intersected the published results of a metaanalysis of genome-wide association studies (GWAS) for rheumatoid arthritis (RA) with the set of enhancer regions for 71 primary cell types that was provided by the FANTOM consortium. We first retrieved all single nucleotide polymorphisms (SNPs) that are associated (P < 5 x 10(8)) with RA in the GWAS meta-analysis and that are located in any of these enhancer regions. After excluding the major histocompatibility complex (MHC) region, we identified 50 such RA-associated SNPs that are located in enhancer regions. Enhancer sets from different cell types were then compared with each other for their number of RA-associated SNPs by permutation analysis. This analysis showed that RA-associated SNPs are preferentially located in enhancers from several immunological cell types. In particular, we see a strong relative enrichment in enhancer regions that are active in T cells (P < 0.001) and NK cells (P < 0.001). Several loci display multiple RA-associated SNPs in tight linkage disequilibrium that are located within the same or neighboring enhancers. These haplotypes may have a greater likelihood to influence enhancer activity than any SNP on its own. Taken together, these results support the hypothesis that RA-causative variants often act through altering the activity of immune cell enhancers. The enrichment in T-cell and NK-cell enhancer regions indicates that expression changes in these cell types are particularly relevant for the pathogenesis of RA. The specific SNPs that account for this enrichment can be used as a basis for focused genotype-phenotype studies of these cell types.
Faculty; Northwell Researcher
School of Medicine; Northwell Health
General Internal Medicine