Analysis of Genetically Determined Gene Expression Suggests Role of Inflammatory Processes in Etiology of Exfoliation Syndrome

Abstract Exfoliation syndrome (XFS) is an age-related systemic disorder characterized by excessive production and progressive accumulation of abnormal extracellular material, with pathognomonic ocular manifestations. It is the most common cause of secondary glaucoma, resulting in widespread global blindness. We performed Transcriptomic Wide Association Studies using PrediXcan models trained in 48 GTEx tissues to identify genetically-determined gene expression changes associated with XFS risk, leveraging on results from a global GWAS that included 123,457 individuals from 24 countries. Twenty-eight genes in the chr15q22-25 region showed statistically significant associations in both single-tissue and multi-tissue analysis. Reduced models for these genes that excluded variants in LD with the known LOXL1 signal showed genome-wide significant association signals in nine genes, independently of LOXL1. Out of these ten genes, mRNA transcript levels for ARID3B, CD276, LOXL1, NEO1, SCAMP2, and UBL7 were significantly decreased in iris tissues from XFS patients compared to control samples. Genes with genetically determined expression changes in XFS were significantly enriched for genes associated with inflammatory conditions. We further explored the health consequences of high susceptibility to XFS using a large electronic health record and observed a higher incidence of XFS comorbidity with inflammatory and connective tissue diseases. Our results implicate a role for connective tissues and inflammation in the etiology of XFS. Targeting the inflammatory pathway may be a potential therapeutic option to reduce progression in XFS.