July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Identifying Genes that Underlie Exfoliation Syndrome using Genetically Determined Gene Expression
Author Affiliations & Notes
  • Jibril Hirbo
    Vanderbilt University School of Medicine, Clarksville, Tennessee, United States
  • Francesca Pasutto
    Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, Erlangen, Bavaria, Germany
  • Priyanka Pawar
    Vanderbilt Eye Institute, Nashville, Tennessee, United States
  • Julia Sealock
    Vanderbilt University School of Medicine, Clarksville, Tennessee, United States
  • Patrick Evans
    Vanderbilt University School of Medicine, Clarksville, Tennessee, United States
  • Eric Gamazon
    Vanderbilt University School of Medicine, Clarksville, Tennessee, United States
  • Ran Tao
    Vanderbilt University School of Medicine, Clarksville, Tennessee, United States
  • André Reis
    Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, Erlangen, Bavaria, Germany
  • Daniel Berner
    Ophthalmology, Universitätsklinikum Erlangen, Erlangen, Bavaria, Germany
  • Ursula Schlotzer-Schrehardt
    Ophthalmology, Universitätsklinikum Erlangen, Erlangen, Bavaria, Germany
  • Milam A Brantley
    Vanderbilt Eye Institute, Nashville, Tennessee, United States
  • Chiea Chuen Khor
    Singapore Eye Research Institute, Singapore
  • Nancy Cox
    Vanderbilt University School of Medicine, Clarksville, Tennessee, United States
  • Karen M Joos
    Vanderbilt Eye Institute, Nashville, Tennessee, United States
  • Footnotes
    Commercial Relationships   Jibril Hirbo, None; Francesca Pasutto, None; Priyanka Pawar, None; Julia Sealock, None; Patrick Evans, None; Eric Gamazon, None; Ran Tao, None; André Reis, None; Daniel Berner, None; Ursula Schlotzer-Schrehardt, None; Milam Brantley, None; Chiea Chuen Khor, None; Nancy Cox, None; Karen Joos, None
  • Footnotes
    Support  NHI/NEI EY021453, Interdisciplinary Center for Clinical Research (IZKF) at the University Hospital of the University of Erlangen-Nürnberg (project E23 to AR and USS), Joseph Ellis Family Research Fund, Suzanne Sousan Research Fund, NIH P30EY008126 to Vanderbilt Vision Research Center, and an Unrestricted Departmental Grant from Research to Prevent Blindness, Inc., N.Y. to the Vanderbilt Eye Institute
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 6072. doi:https://doi.org/
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    • Get Citation

      Jibril Hirbo, Francesca Pasutto, Priyanka Pawar, Julia Sealock, Patrick Evans, Eric Gamazon, Ran Tao, André Reis, Daniel Berner, Ursula Schlotzer-Schrehardt, Milam A Brantley, Chiea Chuen Khor, Nancy Cox, Karen M Joos; Identifying Genes that Underlie Exfoliation Syndrome using Genetically Determined Gene Expression. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6072. doi: https://doi.org/.

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

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Abstract

Purpose : Exfoliation syndrome (XFS) is an age-related systemic disorder characterized by excessive production and progressive accumulation of an abnormal extracellular material, with conspicuous ocular manifestation. It is the most common cause of secondary glaucoma resulting in widespread global blindness. The largest GWAS meta-analysis data of exfoliation syndrome of 123,457 individuals by Aung, et al., 2017, identified 7 loci with the strongest signal in chromosome 15 at LOXL1. Biological importance of coding mutations on LOXL1 were elucidated, but mechanisms underlying associations with other variants in the locus are not clear. We hypothesize that correlation of the genetically determined component of gene expression in XFS can provide a powerful method to identify genes involved in XFS.

Methods : We used gene-based method, PrediXcan, for correlating genetically determined gene expression with disease risk. We applied PrediXcan using models trained on 48 GTEx tissues to estimate individual gene expression from GWAS summary statistics of global XFS dataset from Aung, et al. Additionally, a subset of 8056 European-ancestry individual genetic data from Aung, et al., including 2000 new genetic data from Vanderbilt BioVU were analyzed.

Results : On chromosome 15, 23 genes showed statistically significant associations in both single-tissue and multi-tissue PrediXcan analyses. An additional 5 genes were associated in only multi-tissue analysis within the same chr15q22-25 region spanning 3 mb. Additionally, 7 genes on chromosomes 1 (2 genes), 6 (1), 8 (1), 10 (2) and 19 (1) were identified in multi-tissue analysis. PrediXcan in the available tissues supported 6p21 locus as PRRT1 but not the AGPAT1. Thirteen (12 on chromosome 15) of the 35 genes identified in the global dataset were confirmed in a subset of European-ancestry individuals. Conditional PrediXcan analysis of chr15q22-25 region in the European-ancestry dataset confirmed association signals in six genes: LOXL1, STOML1, UBL7, NEO1, SCAMP2 & INSYN1. All except INSYN1 have been identified in ocular tissues.

Conclusions : Gene-based strategies offer powerful methods to prioritize genes for therapeutic targets. Conditional PrediXcan analysis of genetic signals will be confirmed in individuals of Asian ancestry from Aung, et al. If confirmed, our findings would offer novel gene targets for understanding the pathogenesis of XFS and developing therapies.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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