Exploring the Genetic Association and Genetic Architecture of Iridocyclitis and Extraocular Autoimmune Diseases

Purpose: Our objective was to explore the shared genetic risks between iridocyclitis and extraocular autoimmune diseases, as well as refine the regulatory network of genetic and environmental mechanisms by incorporating endocrine-disrupting chemicals (EDCs). Methods: Using summary statistics reporting genome-wide association study findings within European ancestry, we first investigated the genetic associations between iridocyclitis and extraocular autoimmune diseases. We then performed causal inference using Mendelian randomization (MR). By integrating genetic and causal associations, we explored the comorbid genetic structure and shared risk genes between iridocyclitis and ulcerative colitis (UC) through cross-trait analysis and a transcriptome-wide association study (TWAS). Finally, we constructed an interaction network between EDCs and shared risk genes by combining chemical-genetic interaction data. Results: Linkage disequilibrium score regression identified significant positive genetic correlations between iridocyclitis and psoriasis (rg = 0.219, P = 3.15e-03) and ulcerative colitis (rg = 0.248, P = 9.21e-04). Local genetic correlation analysis revealed genetic overlap on chromosomes 1 and 6. No significant genetic association was found between iridocyclitis and seven other autoimmune diseases. MR identified bidirectional causality only between UC and iridocyclitis. Genetic analysis identified 11 independent shared single-nucleotide polymorphisms between UC and iridocyclitis, and colocalization analysis identified a shared causal variant (rs17369215). Subsequent TWAS identified three shared risk genes for UC and iridocyclitis, and an interaction network involving 25 EDCs and shared risk genes was constructed based on chemical-genetic interaction data. Conclusions: This study identified the shared genetic structure and key genes between iridocyclitis and UC, highlighting the significant role of EDCs through gene-environment interactions in the comorbidity of iridocyclitis and UC. Translational Relevance: This study reveals a common genetic association between iridocyclitis and extraocular autoimmune diseases.