Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability

Xiangyu Ge,Andrew P Morris,Stephen Eyre,Oliver Distler,Gisela Orozco,Miriam Marks,Kerstin Klein,Paul Martin,Blaž Burja,Raphael Micheroli,Amanda Mcgovern,Tadeja Kuret,Mojca Frank-Bertoncelj,Caroline Ospelt,Chenfu Shi,Christopher D Buckley,Miranda Houtman,Andrew Filer

doi:10.1186/s13059-021-02460-6

Abstract

BackgroundGenome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis (RA). These loci are shown to be enriched in immune cell-specific enhancers, but the analysis so far has excluded stromal cells, such as synovial fibroblasts (FLS), despite their crucial involvement in the pathogenesis of RA. Here we integrate DNA architecture, 3D chromatin interactions, DNA accessibility, and gene expression in FLS, B cells, and T cells with genetic fine mapping of RA loci.ResultsWe identify putative causal variants, enhancers, genes, and cell types for 30–60% of RA loci and demonstrate that FLS account for up to 24% of RA heritability. TNF stimulation of FLS alters the organization of topologically associating domains, chromatin state, and the expression of putative causal genes such as TNFAIP3 and IFNAR1. Several putative causal genes constitute RA-relevant functional networks in FLS with roles in cellular proliferation and activation. Finally, we demonstrate that risk variants can have joint-specific effects on target gene expression in RA FLS, which may contribute to the development of the characteristic pattern of joint involvement in RA.ConclusionOverall, our research provides the first direct evidence for a causal role of FLS in the genetic susceptibility for RA accounting for up to a quarter of RA heritability.

Highlights

Genome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis (RA)
These studies have demonstrated an enrichment of RA genetic risk variants in immune cell enhancers [3], but omitted the analysis of synovial fibroblasts or fibroblast-like synoviocytes (FLS), the resident stromal cells of the joints, even though they are responsible for the production of many immune-related cytokines and chemokines [6, 7]
We identified A/B compartments and Topologically Associating Domains (TADs) and determined significant chromatin interactions

Summary

Introduction

Genome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis (RA). Potential gene regulatory functions of these noncoding genetic risk variants have been investigated in immune cells based on genome-wide mapping of epigenetic modifications [3], chromatin interactions [4], correlation with variation in gene expression (eQTLs) [5], or linear proximity to coding genes in DNA sequence [2] These studies have demonstrated an enrichment of RA genetic risk variants in immune cell enhancers [3], but omitted the analysis of synovial fibroblasts or fibroblast-like synoviocytes (FLS), the resident stromal cells of the joints, even though they are responsible for the production of many immune-related cytokines and chemokines [6, 7]

Methods

Results

Conclusion