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Purpose: Exfoliation syndrome (XFS) is an age-related systemic disorder characterized by excessive production and progressive accumulation of abnormal extracellular material, with pathognomonic ocular manifestation. It is the most common cause of secondary glaucoma resulting in widespread global blindness. Global multi-ethnic genome-wide association (GWAS) summary data of XFS in 123,457 individuals identified 7 loci with strongest signal in chromosome 15 involving 54 potentially causal variants near LOXL1 gene. While the biological importance of the coding mutations on LOXL1 were elucidated, the mechanisms underlying associations with non-coding variants are not clear. The non-coding variants might play a regulatory role, thus we hypothesized that the correlation of genetically determined components of gene expression with XFS may provide a powerful method to identify additional genes involved in the etiology of the XFS.

Methods: We applied S-PrediXcan using models trained on 48 GTEx tissues to estimate the correlation of genetically determined gene expression with XFS risk by leveraging multi-ethnic GWAS summary statistics. We then analyzed GWAS data from 13,202 individuals from 4 European ancestry populations conditioning on predicted gene expressions of strongest association signals. We did enrichment analysis of the XFS associated genes. We further performed functional validation in diseased and normal human iris tissues of the top prioritized genes. Finally, we explored other health consequences of high genetic risk to XFS in a large electronic health record.

Results: A total of 28 genes on chr15 showed …