IntroductionSubstantial links between autoimmune diseases have been shown by an increasing number of studies, and one hypothesis for this comorbidity is that there is a common genetic cause.MethodsIn this paper, a large-scale cross-trait Genome-wide Association Studies (GWAS) was conducted to investigate the genetic overlap among rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and type 1 diabetes.Results and discussionThrough the local genetic correlation analysis, 2 regions with locally significant genetic associations between rheumatoid arthritis and multiple sclerosis, and 4 regions with locally significant genetic associations between rheumatoid arthritis and type 1 diabetes were discovered. By cross-trait meta-analysis, 58 independent loci associated with rheumatoid arthritis and multiple sclerosis, 86 independent loci associated with rheumatoid arthritis and inflammatory bowel disease, and 107 independent loci associated with rheumatoid arthritis and type 1 diabetes were identified with genome-wide significance. In addition, 82 common risk genes were found through genetic identification. Based on gene set enrichment analysis, it was found that shared genes are enriched in exposed dermal system, calf, musculoskeletal, subcutaneous fat, thyroid and other tissues, and are also significantly enriched in 35 biological pathways. To verify the association between diseases, Mendelian randomized analysis was performed, which shows possible causal associations between rheumatoid arthritis and multiple sclerosis, and between rheumatoid arthritis and type 1 diabetes. The common genetic structure of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and type 1 diabetes was explored by these studies, and it is believed that this important discovery will lead to new ideas for clinical treatment.