Gene Set Enrichment Analyses Identify Pathways Involved in Genetic Risk for Diabetic Retinopathy.

ABSTRACT Purpose : To identify functionally related genes associated with diabetic retinopathy (DR) risk using gene set enrichment analyses (GSEA) applied to genome-wide association study (GWAS) meta-analyses. Methods: We analyzed DR GWAS meta-analyses performed on 3,246 Europeans and 2,611 African Americans with type 2 diabetes. Gene sets relevant to five key DR pathophysiology processes were investigated: tissue injury, vascular events, metabolic events and glial dysregulation, neuronal dysfunction, and inflammation. Keywords relevant to these processes were queried in four pathway 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 defined to be enriched for gene associations with DR if the P value corrected for multiple testing (Pcorr) was Results : Five gene sets were significantly enriched for multiple modest genetic associations with DR in one method (MAGENTA or MAGMA) and also at least nominally significant (uncorrected P 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.