BackgroundJuvenile idiopathic arthritis (JIA) is an autoimmune joint disease that frequently co-occurs with other complex phenotypes, including cancers and other autoimmune diseases. Despite the identification of numerous risk variants through genome-wide association studies (GWAS), the affected genes, their connection to JIA pathogenesis, and their role in the development of associated traits remain unclear. This study aims to address these gaps by elucidating the gene-regulatory mechanisms underlying JIA pathogenesis and exploring its potential role in the emergence of associated traits.MethodsA two-sample Mendelian Randomization (MR) analysis was conducted to identify blood-expressed genes causally linked to JIA. A curated protein interaction network was subsequently used to identify sets of single-nucleotide polymorphisms (i.e., spatial eQTL SNPs) that regulate the expression of JIA causal genes and their protein interaction partners. These SNPs were cross-referenced against the GWAS catalog to identify statistically enriched traits associated with JIA.ResultsThe two-sample MR analysis identified 52 genes whose expression changes in the blood are putatively causal for JIA. These genes (e.g., HLA, LTA, LTB, IL6ST) participate in a range of immune-related pathways (e.g., antigen presentation, cytokine signalling) and demonstrate cell type-specific regulatory patterns across different immune cell types (e.g., PPP1R11 in CD4+ T cells). The spatial eQTLs that regulate JIA causal genes and their interaction partners were statistically enriched for GWAS SNPs linked with 95 other traits, including both known and novel JIA-associated traits. This integrative analysis identified genes whose dysregulation may explain the links between JIA and associated traits, such as autoimmune/inflammatory diseases (genes at 6p22.1 locus), Hodgkin lymphoma (genes at 6p21.3 [FKBPL, PBX2, AGER]), and chronic lymphocytic leukemia (BAK1).ConclusionOur approach provides a significant advance in understanding the genetic architecture of JIA and associated traits. The results suggest that the burden of associated traits may differ among JIA patients, influenced by their combined genetic risk across different clusters of traits. Future experimental validation of the identified connections could pave the way for refined patient stratification, the discovery of new biomarkers, and shared therapeutic targets.