June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
New evidence for enrichment of metabolic, signaling, and inflammatory pathways in age-related macular degeneration
Author Affiliations & Notes
  • Andrea R Waksmunski
    Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland , Ohio, United States
  • Jessica Cooke Bailey
    Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States
  • Margaret A Pericak-Vance
    Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States
  • William K Scott
    Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States
  • Jonathan L Haines
    Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States
    Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, United States
  • Footnotes
    Commercial Relationships   Andrea Waksmunski, None; Jessica Cooke Bailey, None; Margaret Pericak-Vance, None; William Scott, None; Jonathan Haines, None
  • Footnotes
    Support  1X01HG006934-01 and R01 EY022310
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 1851. doi:
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      Andrea R Waksmunski, Jessica Cooke Bailey, Margaret A Pericak-Vance, William K Scott, Jonathan L Haines; New evidence for enrichment of metabolic, signaling, and inflammatory pathways in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1851.

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

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Abstract

Purpose : The disease etiology of age-related macular degeneration (AMD) is largely unknown. We aimed to identify biological pathways, gene and protein interactions, protein families, and regulatory regions consistently enriched for genetic variations nominally associated with AMD.

Methods : We performed pathway analysis using the Pathway Analysis by Randomization Incorporating Structure (PARIS, V2.4) software tool on 445,115 common and rare variants genotyped as a part of the International AMD Genomics Consortium (IAMDGC). The samples used to generate these data were from 16,144 advanced AMD cases and 17,832 controls. PARIS groups variants into features based on linkage disequilibrium and assigns significance to a pathway based on permutations of the genome. We performed 10,000 permutations. A feature was considered significant if it contained at least one variant with p-value<0.05. To acquire a more comprehensive understanding of which curated biological and genomic entities contribute to AMD risk, we performed PARIS using multiple biological function databases including KEGG, Reactome, GO, NetPath, BioGRID, MINT, Pfam, and ORegAnno. Entities with p-value<0.0001 were prioritized for further investigation.

Results : Preliminary results confirmed several pathways previously implicated in AMD, including the complement cascade, Wnt signaling, and inflammation pathways. Genes previously implicated in the pathogenesis of AMD, such as SYN3, were consistently enriched for significant interactions and regulatory regions identified by PARIS. Preliminary results also showed that 2 genes, PLCG2 and CYP1A1, had significant signals across multiple immune, metabolic, and signaling pathways among the NetPath, KEGG, and Reactome databases. These anchor genes nominate multiple biological pathways and processes in the etiology of AMD.

Conclusions : Variants potentially associated with AMD were enriched in multiple metabolic, signaling, and inflammatory pathways. Further examination is underway to identify the “driver” genes among these phenomena and determine how they may be contributing to AMD pathophysiology. This analysis highlights how the combination of genome-wide genotyping and statistical pathway analysis incorporating in silico functional data can be used to elucidate the genetic architecture of complex ocular diseases like AMD.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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