A group of genes linked with a heightened risk of rheumatoid arthritis have been discovered in a new study, reshaping understanding of what causes the disease and pointing to possible treatments. A new study led by Usher's Paul McKeigue, with Athina Spiliopoulou, Andrii Iakovliev and colleagues from other institutions, has identified 16 genes linked to increased risk of rheumatoid arthritis – reshaping understanding of the disease and highlighting new treatment targets. Six of these genes produce immune checkpoint proteins which, when malfunctioning, can cause the immune system to attack the body’s own cells. Targeting these checkpoints with drugs could offer more effective treatments – or even a cure – for the 400,000 people in the UK affected by this painful and debilitating condition.Core genesTo pinpoint the core genes for rheumatoid arthritis, researchers from the University of Edinburgh looked at genetic data from 450,000 individuals in the UK Biobank. They used a new approach to add up the small effects of hundreds of common mutations on each gene.The main core gene they identified produces an immune checkpoint called programmed death protein 1 (PD-1). Drugs that target the protein to prevent the immune system over-reaction have proved effective in treating rheumatoid arthritis in recent trials, though these drugs are not yet licensed for use in patients. The research team will now study whether the activity of these core genes can help guide treatment decisions for people with the disease.Combined effectPrevious genetic studies have identified specific differences in the DNA of people with and without the condition, but studying genes near these mutations has failed to discover new treatments. Recently, scientists proposed that small changes in many genes could combine to affect a few core genes directly linked with the disease. Experts say this helps explain why genes found in earlier studies are not the best drug targets as they affect the main genes but do not directly cause the disease. This work reshapes our understanding of the causes of rheumatoid arthritis. We expect drugs that target the causes of the disease to be more effective than the drugs used now, which only target inflammation. We’re encouraged by the promising results of trials of drugs that target PD-1 in rheumatoid arthritis. Our research can help identify which other autoimmune diseases these drugs are likely to be effective in. Professor Paul McKeigue Professor of Genetic Epidemiology and Statistical Genetics, Usher Institute The study was funded by the UK Medical Research Council and also involved researchers from the University of Manchester and Queen Mary University London. Cite asSpiliopoulou A, Iakovliev A, Plant D et al. Genome-wide aggregated trans effects analysis identifies genes encoding immune checkpoints as core genes for rheumatoid arthritis. Arthritis Rheumatol 2025. https://doi.org/10.1002/art.43125Further informationRead the study in the journal Arthritis and Rheumatology Publication date 07 Jul, 2025
