Identifying therapeutic targets for rheumatoid arthritis by genomics-driven integrative approaches

Abstract

Genomics-driven drug discovery holds significant promise in identifying and developing novel therapeutic targets. Here, we utilized large-scale genomic data including genome-wide association studies (GWAS), rare variant burden tests in exome sequencing studies (Exome), and protein quantitative trait loci (pQTL), to prioritize therapeutic targets or repurpose drugs in rheumatoid arthritis (RA). We found that prioritized genes covering two approved RA treatment targets (IL6R and CD86), along with several targets currently undergoing active clinical trials for RA. Fifteen proteins were identified as having causalities with RA risk, and three out of them showed strong support for colocalization. BRD2 was nominated as one of the most promising candidates for clinical translation as its wide expression in joint synovial tissues and validation in observational analyses associating with RA incidence. Collectively, our systematic prioritization of drug targets from different genetically informed approaches, and provided a comprehensive insight into therapeutic strategies for RA.