Genomic network analysis links uveitis with systemic inflammatory diseases.

Purpose: Uveitis is a vision-threatening inflammatory eye disease for which the cause is unknown and response to current therapies is limited. To better understand the genetic architecture of ocular inflammatory disease, we performed a computational synthesis and comparative network analysis of previously published GWAS significant variants associated with 1) uveitis, 2) ocular conditions including age-related and inherited retinal degeneration and 3) extraocular immune-mediated inflammatory diseases (IMIDs). Methods: We 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. Results: Seventy-five percent of the putative causal genes for uveitis were also implicated in IMIDs, while no uveitis genes were 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. Conclusions: Overlapping causal genes and network similarity suggest that uveitis is predominantly an inflammatory disease, sharing genetic architecture with other IMIDs. Translational Relevance: These findings provide a genomic framework for understanding the genetic drivers of ocular inflammation in uveitis and generate testable hypothesis for future studies aimed at rationally repurposing drugs from IMIDs for patients with uveitis.