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Gene set enrichment analyses identify pathways involved in genetic risk for diabetic retinopathy


Sobrin, L and Susarla, G and Stanwyck, L and Rouhana, JM and Li, A and Pollack, S and Igo Jr, RP and Jensen, RA and Li, X and Ng, MCY and Smith, AV and Kuo, JZ and Taylor, KD and Freedman, BI and Bowden, DW and Penman, A and Chen, CJ and Craig, JE and Adler, SG and Chew, EY and Frances Cotch, M and Yaspan, B and Mitchell, P and Wang, JJ and Klein, BEK and Wong, TY and Rotter, JI and Burdon, KP and Iyengar, SK and Segre, AV, Gene set enrichment analyses identify pathways involved in genetic risk for diabetic retinopathy, American Journal of Ophthalmology ISSN 0002-9394 (2021) [Refereed Article]

DOI: doi:10.1016/j.ajo.2021.06.014


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.

Item Details

Item Type:Refereed Article
Keywords:retinopathy, ophthalmology, GWAS, GSEA
Research Division:Biomedical and Clinical Sciences
Research Group:Ophthalmology and optometry
Research Field:Ophthalmology
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biomedical and clinical sciences
UTAS Author:Burdon, KP (Professor Kathryn Burdon)
ID Code:145316
Year Published:2021
Funding Support:National Health and Medical Research Council (1059954)
Deposited By:Menzies Institute for Medical Research
Deposited On:2021-07-15
Last Modified:2021-07-19

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