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

PubMed ID: 34166655

Author(s): Sobrin L, Susarla G, Stanwyck L, Rouhana JM, Li A, Pollack S, Igo RP Jr, Jensen RA, Li X, Ng MCY, Smith AV, Kuo JZ, Taylor KD, Freedman BI, Bowden DW, Penman A, Chen CJ, Craig JE, Adler SG, Chew EY, Cotch MF, Yaspan B, Mitchell P, Wang JJ, Klein BEK, Wong TY, Rotter JI, Burdon KP, Iyengar SK, Segrè AV. Gene Set Enrichment Analyses Identify Pathways Involved in Genetic Risk for Diabetic Retinopathy. Am J Ophthalmol. 2021 Jun 21. pii: S0002-9394(21)00336-6. doi: 10.1016/j.ajo.2021.06.014. [Epub ahead of print] PMID 34166655

Journal: American Journal Of Ophthalmology, Jun 2021

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 <.05.

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 <.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.