%0 Journal Article %J Am J Ophthalmol %D 2022 %T Gene Set Enrichment Analsyes Identify Pathways Involved in Genetic Risk for Diabetic Retinopathy %A Sobrin, Lucia %A Susarla, Gayatri %A Stanwyck, Lynn %A Rouhana, John M %A Li, Ashley %A Pollack, Samuela %A Igo, Robert P %A Jensen, Richard A %A Li, Xiaohui %A Ng, Maggie C Y %A Smith, Albert V %A Kuo, Jane Z %A Taylor, Kent D %A Freedman, Barry I %A Bowden, Donald W %A Penman, Alan %A Chen, Ching J %A Craig, Jamie E %A Adler, Sharon G %A Chew, Emily Y %A Cotch, Mary Frances %A Yaspan, Brian %A Mitchell, Paul %A Wang, Jie Jin %A Klein, Barbara E K %A Wong, Tien Y %A Rotter, Jerome I %A Burdon, Kathyrn P %A Iyengar, Sudha K %A Segrè, Ayellet V %K Diabetes Mellitus, Type 2 %K Diabetic Retinopathy %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %X 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 Americans with type 2 diabetes. Gene sets relevant to 5 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 4 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 <.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 regulation of the lipid catabolic process (2-fold enrichment, Pcorr = .014); nitric oxide biosynthesis (1.92-fold enrichment, 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. NOTE: Publication of this article is sponsored by the American Ophthalmological Society. %B Am J Ophthalmol %V 233 %P 111-123 %8 2022 01 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/34166655?dopt=Abstract %R 10.1016/j.ajo.2021.06.014