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

Abstract

SummaryGenomics-driven drug discovery framework holds promise in developing novel therapeutic targets. Here, we leveraged 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 potential therapeutic targets and identify opportunities for drug repositioning in rheumatoid arthritis (RA). We found that prioritized genes covering two approved RA treatment targets (IL6R and CD86), and five targets tested in clinical trials for RA. Eighteen proteins were identified as having causalities with RA risk, three out of them showed strong support for colocalization. Bromodomain-containing protein 2 (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 screening of candidate drug targets from different genetically informed approaches, and provided a comprehensive insight into therapeutic strategies for RA.