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

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

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)111-123
Number of pages13
JournalAmerican Journal of Ophthalmology
Publication statusPublished - Jan 2022


  • Diabetic Retinopathy
  • Genome-wide association study
  • GWAS


Dive into the research topics of 'Gene Set Enrichment Analsyes Identiify Pathways Involved in Genetic Risk for Diabetic Retinopathy'. Together they form a unique fingerprint.

Cite this