June 2020
Volume 61, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2020
Gene set enrichment analysis implicates vascular endothelial growth factor pathway in genetic risk of developing proliferative diabetic retinopathy
Author Affiliations & Notes
  • Gayatri Susarla
    Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Richard Jensen
    Cardiovascular Health Research Unit, Department of Medicine, Epidemiology and Health Services, University of Washington, Seattle, Washington, United States
  • Albert V. Smith
    University of Michigan, Michigan, United States
  • Mary Frances Cotch
    Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States
  • Brian Yaspan
    Genentech Inc., South San Francisco, California, United States
  • Donald Bowden
    Wake Forest School of Medicine, Center for Genomics and Personalized Medicine Research, Winston-Salem, North Carolina, United States
    Wake Forest School of Medicine, Department of Biochemistry, Winston-Salem, North Carolina, United States
  • Ronald Klein
    Department of Opthalmology and VIsual Sciences, University of Wisconsin, Wisconsin, United States
  • Barbara Klein
    Department of Opthalmology and VIsual Sciences, University of Wisconsin, Wisconsin, United States
  • Tien Y. Wong
    Duke-NUS Medical School, Singapore
    Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  • Jie Jin Wang
    Duke-NUS Medical School, Singapore
    Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia
  • Kathryn P Burdon
    Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
  • Xiaohui Li
    Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, California, United States
  • Sudha K Iyengar
    Department of Population and Quantitative Health Sciences, Case Western University, Cleveland, Cleveland, Ohio, United States
  • Lucia Sobrin
    Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Ayellet Segrè
    Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Gayatri Susarla, None; Richard Jensen, None; Albert Smith, None; Mary Cotch, None; Brian Yaspan, Genentech Inc. (E); Donald Bowden, None; Ronald Klein, None; Barbara Klein, None; Tien Wong, None; Jie Jin Wang, None; Kathryn Burdon, None; Xiaohui Li, None; Sudha Iyengar, None; Lucia Sobrin, None; Ayellet Segrè, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 1900. doi:
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      Gayatri Susarla, Richard Jensen, Albert V. Smith, Mary Frances Cotch, Brian Yaspan, Donald Bowden, Ronald Klein, Barbara Klein, Tien Y. Wong, Jie Jin Wang, Kathryn P Burdon, Xiaohui Li, Sudha K Iyengar, Lucia Sobrin, Ayellet Segrè; Gene set enrichment analysis implicates vascular endothelial growth factor pathway in genetic risk of developing proliferative diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1900.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To gain statistical discovery power and biological insight into the genetic architecture of diabetic retinopathy (DR), we tested for enrichment of multiple genetic variant associations with DR in gene sets or pathways related to DR pathophysiology, rather than inspecting variants individually.

Methods : We applied the gene set enrichment analysis (GSEA) method, Meta-Analysis Gene-set Enrichment of variaNT Associations (MAGENTA), to four previously published DR genome-wide association study (GWAS) analyses adjusted for duration of diabetes and glycemic control. These GWAS were performed separately in patients of African American (AA) and European (EU) ancestry, using one of two DR case-control definitions: (1) PDR analysis: cases (n=1495) had proliferative DR (PDR) and controls (n=4362) had any level of non-proliferative DR or no DR and (2) Extremes of DR analysis: cases (n=1495) had PDR and controls (n=2911) had no DR. From a literature review, we identified key DR-associated biological processes including angiogenesis, glial dysregulation, neuronal dysfunction, and inflammation. Gene sets representing these pathways were extracted from four gene set databases: Gene Ontology (n=144 pathways extracted), Kyoto Encyclopedia of Genes and Genomes (KEGG, n=13 pathways extracted), Reactome (n=10 pathways extracted), and Mouse Phenotype Ontology (MGI, n=79 pathways extracted). Multiple hypothesis correction based on false discovery rate (FDR) was applied to gene sets from each database separately.

Results : MAGENTA identified one statistically significant pathway from KEGG, the vascular endothelial growth factor (VEGF) signaling pathway, for the PDR analysis in the AA population. Significance was based on a 75th percentile enrichment cutoff (Gene set enrichment P=0.0015, FDR=0.0159). This analysis suggests 11 new DR-associated genes (1.6 fold-enrichment) based on their confounder-adjusted gene association P values, with the variant DR P values ranging between 2x10-5 and 0.001. No significant enrichment was found among these genes in the EU extremes of DR analysis.

Conclusions : Genetic variation in the VEGF signaling pathway may be associated with PDR risk in the AA population. Replication of this finding with alternate GSEA analysis methods and in independent DR GWAS are needed to confirm these results and to determine if the significance is AA-specific.

This is a 2020 ARVO Annual Meeting abstract.

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