Identification of rheumatoid arthritis causal genes using functional genomics (360G-Wellcome-207491_Z_17_Z)

Genome-wide association studies (GWAS) have been used to great effect to identify genetic variants that predispose to rheumatoid arthritis (RA). 90% of associated variants are non-coding and thought to be involved in transcriptional regulation, but their functional role has been under explored. I will perform functional characterization of RA risk loci with the aim of translating GWAS findings into biological disease mechanisms and suggesting therapeutic targets. My key goals are: 1. To identify the genes that cause RA. I will identify chromatin interactions between RA loci and their targets using capture Hi-C in primary CD4+ T-cells and synovial fibroblasts from RA patients. I will explore whether associated SNP genotypes are correlated with differential expression of the genes they interact with. 2. To elucidate the mechanism by which RA-associated SNPs alter their target genes. Regulatory elements containing disease-associated SNPs will be identified in primary cells from patients and their functional importance will be verified using CRISPR/Cas9 genome editing. 3. To translate research findings into patient benefit. Identified causal genes and pathways will be intersected with known drug targets to identify existing drugs whose safety and efficacy has been proven in other diseases and which could potentially be re-purposed to treat RA.