Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability.
Author
Ge, XiangyuFrank-Bertoncelj, Mojca
Klein, Kerstin
McGovern, Amanda
Kuret, Tadeja
Houtman, Miranda
Burja, Blaž
Micheroli, Raphael
Shi, Chenfu
Marks, Miriam
Filer, Andrew
Buckley, Christopher D
Orozco, Gisela
Distler, Oliver
Morris, Andrew P
Martin, Paul
Eyre, Stephen
Ospelt, Caroline
Publication date
2021-08-25
Metadata
Show full item recordAbstract
Background: Genome-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. Results: We 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. Conclusion: Overall, 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.Citation
Ge X, Frank-Bertoncelj M, Klein K, McGovern A, Kuret T, Houtman M, Burja B, Micheroli R, Shi C, Marks M, Filer A, Buckley CD, Orozco G, Distler O, Morris AP, Martin P, Eyre S, Ospelt C. Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability. Genome Biol. 2021 Aug 25;22(1):247. doi: 10.1186/s13059-021-02460-6Type
ArticleOther
Additional Links
https://genomebiology.biomedcentral.com/PMID
34433485Journal
Genome BiologyPublisher
BioMed Centralae974a485f413a2113503eed53cd6c53
10.1186/s13059-021-02460-6