- Sobrin, Lucia;
- Susarla, Gayatri;
- Stanwyck, Lynn;
- Rouhana, John M;
- Li, Ashley;
- Pollack, Samuela;
- Igo, Robert P;
- Jensen, Richard A;
- Li, Xiaohui;
- Ng, Maggie CY;
- Smith, Albert V;
- Kuo, Jane Z;
- Taylor, Kent D;
- Freedman, Barry I;
- Bowden, Donald W;
- Penman, Alan;
- Chen, Ching J;
- Craig, Jamie E;
- Adler, Sharon G;
- Chew, Emily Y;
- Cotch, Mary Frances;
- Yaspan, Brian;
- Mitchell, Paul;
- Wang, Jie Jin;
- Klein, Barbara EK;
- Wong, Tien Y;
- Rotter, Jerome I;
- Burdon, Kathyrn P;
- Iyengar, Sudha K;
- Segrè, Ayellet V
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.