Jakob Hjorth von Stemann, Joseph Dowsett, Rebecca Svanberg Teglgaard, Maria Didriksen, Frederikke Byron Pedersen, Mette Skou Bentsen, Andrea Barghetti, Maria Vispe Laguarda, Sara Louise Borregaard Larsen, Bente Glintborg, Ulrik Lassen, Ruth Frikke-Schmidt, Celeste Porsbjerg, Jens-Ulrik Stæhr Jensen, Thomas Werge, Andrew J Schork, Johan Skov Bundgaard, Henning Bundgaard, Torben Hansen, DBDS Genomic Consortium, Mie Topholm Bruun, Bitten Aagaard Jensen, Christina Mikkelsen, Hans-Jakob Hartling, Christian Erikstrup, Ole Birger Pedersen, Erik Sørensen, Morten Bagge Hansen, Sisse Rye Ostrowski
Anti-cytokine autoantibodies are increasingly recognized as modulators of immune function and determinants of disease risk, yet their genetic basis and population-level impact remain unclear. Here we perform genome-wide association studies of autoantibodies against IL-1α, IL-6, IL-10, IFN-α, IFN-β, IFN-γ and GM-CSF in 15,000 individuals from the Danish Blood Donor Study. We identify 52 genome-wide significant loci, implicating genes enriched in antigen-presentation pathways. Using these data, we derive cytokine-specific polygenic risk scores and evaluate their associations across 300,000 individuals in the Copenhagen Hospital Biobank. Genetic predisposition to IL-1α autoantibodies is associated with reduced risk of rheumatoid arthritis and certain cancers, whereas genetic predisposition to IL-6 autoantibodies is associated with increased risk of diabetes, mirroring prior clinical observations. These findings define the genetic architecture of anti-cytokine autoantibodies and indicate their divergent effects on human disease risk at population scale, providing a framework for mechanistic investigation and potential clinical stratification.