Gene Set Enrichment Analsyes Identiify Pathways Involved in Genetic Risk for Diabetic Retinopathy

PURPOSE: To identify functionally related genes associated with diabetic retinopathy (DR) risk using gene set enrichment analyses applied to genome-wide association study meta-analyses. METHODS: We analyzed DR GWAS meta-analyses performed on 3246 Europeans and 2611 African Ameri-cans with type 2 diabetes. Gene sets relevant to 5 key DR pathophysiology processes were investigated: tissue injury, vascular events, metabolic events and glial dys-regulation, neuronal dysfunction, and inflammation. Key-words relevant to these processes were queried in 4 path-way and ontology databases. Two GSEA methods, Meta-Analysis Gene set Enrichment of variaNT Associations (MAGENTA) and Multi-marker Analysis of GenoMic Annotation (MAGMA), were used. Gene sets were de-fined to be enriched for gene associations with DR if the P value corrected for multiple testing (Pcorr) was < .05. RESULTS: Five gene sets were significantly enriched for numerous modest genetic associations with DR in one method (MAGENTA or MAGMA) and also at least nominally significant (uncorrected P < .05) in the other method. These pathways were regula-tion of the lipid catabolic process (2-fold enrichment, Pcorr = .014); nitric oxide biosynthesis (1.92-fold en-richment, Pcorr = .022); lipid digestion, mobilization, and transport (1.6-fold enrichment, P = .032); apoptosis (1.53-fold enrichment, P = .041); and retinal ganglion cell degeneration (2-fold enrichment, Pcorr = .049). The interferon gamma (IFNG) gene, previously implicated in DR by protein-protein interactions in our GWAS, was among the top ranked genes in the nitric oxide pathway (best variant P = .0001). CONCLUSIONS: These GSEA indicate that variants in genes involved in oxidative stress, lipid transport and catabolism, and cell degeneration are enriched for genes associated with DR risk. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

This study identified functionally related genes associated with diabetic retinopathy risk using gene set enrichment analyses in genome-wide association study meta-analyses. The variants in genes involved in oxidative stress, lipid transport and catabolism, and cell degeneration were found to be enriched for genes associated with DR risk.