Genomic network analysis links uveitis with systemic inflammatory diseases

ObjectiveTo determine whether uveitis shares genetic similarity with extraocular immune-mediated inflammatory diseases (IMIDs), we performed network analysis of putative causal genes associated with ocular inflammatory disease, IMIDs and eye-specific diseases, including age-related macular degeneration and monogenic disorders. MethodsWe identified putative causal genes for genome-wide significance variants from uveitis, IMIDs and ocular diseases using OpenTargets and published studies. To assess the gene-level pleiotropy between disease groups, we quantified the causal gene overlap between groups, and the Jaccard Similarity Indices for individual disease pairs. We then used a network approach to assess the molecular genetic similarity between diseases at a biological pathway level and comparative statistics to identify diseases with greater network similarity to uveitis. ResultsSeventy-five percent of the putative causal genes for uveitis are also causal for IMIDs, while no uveitis genes are shared with primary ocular disorders. Network analysis revealed that 1) uveitis genes are more closely networked with systemic IMIDs disease genes than with ocular-specific disease genes; and 2) significant network similarity links uveitis and specific IMIDs, such as ankylosing spondylitis and sarcoidosis. ConclusionsOverlapping causal genes and network similarity indicate that uveitis is predominantly an inflammatory disease, sharing genetic architecture with other IMIDs. Future studies aimed at dissecting genetic heterogeneity within uveitis may determine whether subgroups share common immune pathways that could nominate endotype-specific therapeutic approaches.