Update on the genetic architecture of rheumatoid arthritis

Key Points The highly polygenic aetiology of rheumatoid arthritis (RA) is well characterized in population genetic studies, with >100 susceptibility loci reported Genetic variants affecting the structure of epitope-binding sites of HLA molecules exhibit the strongest contributions to RA development; log-additive and non-log-additive effects of HLA alleles explain HLA–RA associations The majority of non-HLA associations are mapped at noncoding variants that colocalize with cell-type-specific characteristics (for example, histone markers or enhancers) in CD4 + T cells Pinpointing a single causal gene in a locus that contains multiple genes usually requires additional 'omics' data RA-risk loci generally contain genes related to T-cell and B-cell pathways, cytokine signalling pathways, proliferation and/or impaired haematopoietic and immune systems Many proteins encoded within RA-risk loci, and their interaction partners, are the targets of currently approved therapies, implicating a potential guiding role for human RA genetics data in drug discovery and repurposing Genetic association studies have uncovered more than 100 genetic loci related to susceptibility to rheumatoid arthritis. This Review discusses the latest insights into rheumatoid arthritis pathogenesis gained from genetic studies and their application for drug discovery and development. Human genetic studies into rheumatoid arthritis (RA) have uncovered more than 100 genetic loci associated with susceptibility to RA and have refined the RA-association model for HLA variants. The majority of RA-risk variants are highly shared across multiple ancestral populations and are located in noncoding elements that might have allele-specific regulatory effects in relevant tissues. Emerging multi-omics data, high-density genotype data and bioinformatic approaches are enabling researchers to use RA-risk variants to identify functionally relevant cell types and biological pathways that are involved in impaired immune processes and disease phenotypes. This Review summarizes reported RA-risk loci and the latest insights from human genetic studies into RA pathogenesis, including how genetic data has helped to identify currently available drugs that could be repurposed for patients with RA and the role of genetics in guiding the development of new drugs.