Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability

Genome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis, and there loci have been shown to be enriched in immune cell-specific enhancers, we add Synovial fibroblasts (FLS), the local stromal cells of joints to this analysis. We integrated ChIP-seq, Hi-C, Capture Hi-C, ATAC-seq and RNA-seq datasets from FLS , with genetic fine-mapping of RA loci. From this we identified putative casual variants, enhancers and genes for 30-60% of RA loci and demonstrated that FLS regulatory elements accounts for up to 24% of RA heritability. We also examined the effects of TNF stimulation on the chromatin landscape of FLS, and we found there are significant alterations in the organization of topologically associated domains, chromatin interactions and the expression of several putative causal genes. Examine the enrichment of RA signals in FLS functional elements, assign putative gene targets for these RA signals in FLS, and quantify the effects of TNF stimulation on FLS.