September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Genome-Wide Pathway Approach to Dissecting Primary Open-Angle Glaucoma
Author Affiliations & Notes
  • Jessica Cooke Bailey
    Case Western Reserve University, Cleveland Heights, Ohio, United States
  • Mariusz Butkiewicz
    Case Western Reserve University, Cleveland Heights, Ohio, United States
  • Louis R Pasquale
    Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
    Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Jae H Kang
    Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Michael A Hauser
    Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States
    Department of Medicine, Duke University, Durham, North Carolina, United States
  • Rand R Allingham
    Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States
  • Janey L Wiggs
    Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
  • Jonathan L Haines
    Case Western Reserve University, Cleveland Heights, Ohio, United States
  • Footnotes
    Commercial Relationships   Jessica Cooke Bailey, None; Mariusz Butkiewicz, None; Louis Pasquale, None; Jae Kang, None; Michael Hauser, None; Rand Allingham, None; Janey Wiggs, None; Jonathan Haines, None
  • Footnotes
    Support  NIH/NEI EY022305
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 817. doi:
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    • Get Citation

      Jessica Cooke Bailey, Mariusz Butkiewicz, Louis R Pasquale, Jae H Kang, Michael A Hauser, Rand R Allingham, Janey L Wiggs, Jonathan L Haines; Genome-Wide Pathway Approach to Dissecting Primary Open-Angle Glaucoma. Invest. Ophthalmol. Vis. Sci. 2016;57(12):817.

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

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Abstract

Purpose : Primary open angle glaucoma (POAG) accounts for approximately 75% of glaucoma in the Western world and is a phenotypically and genetically complex disease. Genetics play a significant role in POAG risk and more than a dozen loci have been identified that mediate risk for glaucoma and related endophenotypes. The NEIGHBORHOOD consortium has one of the largest collections worldwide of POAG cases and controls and one of our goals is to expand glaucoma genomics knowledge to better understand disease mechanisms and genetic architecture. In this study, we approached this goal by expanding the testable area of the genome beyond previous glaucoma genome-wide association studies (GWAS) through imputation, and by evaluating these results in the context of pathway analysis to elucidate potentially novel mechanisms of disease.

Methods : Single-variant results from the NEIGHBORHOOD meta-analysis were evaluated using the Pathway Analysis by Randomization Incorporating Structure program (PARIS) v2.4.0a4, a new Python implementation in the Biofilter 2.0 software suite using the Library of Knowledge Integration database, the CEU Region panel, 10,000 permutations, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database. Because PARIS minimizes multiple testing and type I error concerns by implementing empirical genomic randomization to estimate significance, we set a threshold of P<0.0001; pathways attaining this threshold were interrogated further to identify significant (P<0.0001) genes.

Results : Of the 293 KEGG pathways, 33 were significant; 1882 unique genes comprised the significant pathways. Approximately 77% of these genes were only observed once, while 449 genes were significant in ≥1 significant pathway. Of the significant genes that appeared in significant pathways, 78% were only observed once, and 42 genes were in >2 significant pathways. Over 60% of the genes were individually significant in three pathways: selenocompound metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis, and basal transcription factors.

Conclusions : Identifying novel POAG pathways will help to define the underlying mechanisms of POAG by identifying proteins and molecular pathways that influence pathogenesis. This information may help identify biomarkers for early molecular diagnosis and treatment and improve prevention strategies.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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