Integrating human plasma proteomes with genome-wide association data implicates novel proteins and drug targets for Rheumatoid arthritis

Background Genome-wide association studies (GWAS) have uncovered over 100 loci associated with Rheumatoid arthritis (RA) risk. However, how these loci contribute to RA risk remains largely unknown, which has hampered the development of new therapeutics. To identify genes contributing to RA risk through their effects on protein abundance, we conducted the first large-scale proteome-wide association study (PWAS) by integrating the largest up-to-date RA GWAS results with human plasma proteomes. Methods The PWAS was perform using RA GWAS summary statistics from discovery (22,350 RA cases and 74,823 controls) and replication (31,313 RA cases and 995,377 controls) cohorts, by leveraging precomputed protein expression weights generated from ARIC (N = 7,213) and INTERVAL (N = 3,301) studies. Then, Mendelian randomization (MR) and colocalization analyses were employed to investigate causal relationships between PWAS proteins and RA. Druggable targets exploration were finally conducted to prioritize potential therapeutic targets for RA. Results We identified 21 genes whose genetically regulated protein abundances were associated with RA risk. Of note, 10 genes were potentially causal and were prioritized as candidate RA genes. Among the 10 causal genes, six genes ( OLFML3 , PAM , ICOSLG , FCRL3 , ERAP2 , IL6R ) were also associated to RA at transcriptome level, including the three novel genes ( ICOSLG , FCRL3 , ERAP2 ) that were not implicated in the original GWAS, which were regarded as novel candidate genes for RA. Druggable targets exploration identified 120 drug-gene interactions involving in 7 causal PWAS genes, including seven drugs or compounds targeting novel PWAS gene ERAP2 and ICOSLG , which possesses superior anti-inflammatory and anti-rheumatic activity in autoimmune diseases, hence might be candidates for treating RA. Conclusions Our results provide novel insights into RA pathogenesis and promising targets for further mechanistic investigations and drug development of RA.