June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Exome-wide analyses of glaucoma-related endophenotypes in 19,700 individuals
Author Affiliations & Notes
  • Adriana I Iglesias
    Epidemiology , Erasmus MC, Rotterdam, Netherlands
  • Anthony P Khawaja
    Institute of Ophthalmology, NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL, London, United Kingdom
    Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
  • Pieter W.M. Bonnemaijer
    Epidemiology , Erasmus MC, Rotterdam, Netherlands
    Ophthalmology, Erasmus MC , Rotterdam, Netherlands
  • Abhishek Nag
    Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
  • Pirro G Hysi
    Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
  • Christopher J Hammond
    Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
  • Najaf Amin
    Epidemiology , Erasmus MC, Rotterdam, Netherlands
  • Caroline Klaver
    Ophthalmology, Erasmus MC , Rotterdam, Netherlands
  • Paul J Foster
    Institute of Ophthalmology, NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL, London, United Kingdom
  • Cornelia van Duijn
    Epidemiology , Erasmus MC, Rotterdam, Netherlands
  • Footnotes
    Commercial Relationships   Adriana I Iglesias, None; Anthony Khawaja, None; Pieter Bonnemaijer, None; Abhishek Nag, None; Pirro Hysi, None; Christopher Hammond, None; Najaf Amin, None; Caroline Klaver, None; Paul Foster, None; Cornelia van Duijn, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 2134. doi:
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      Adriana I Iglesias, Anthony P Khawaja, Pieter W.M. Bonnemaijer, Abhishek Nag, Pirro G Hysi, Christopher J Hammond, Najaf Amin, Caroline Klaver, Paul J Foster, Cornelia van Duijn; Exome-wide analyses of glaucoma-related endophenotypes in 19,700 individuals. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2134.

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

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Abstract

Purpose : Glaucoma is a heterogeneous optic neuropathy in which rare coding and common non-coding genetic variants play a key role. Although the over 70 identified non-coding variants may be implicated in glaucoma pathogenesis through gene regulation, most were discovered by genome-wide association without in-depth exploration of the region for coding variants. We conducted an exome-wide study in 19,700 persons of European descent to discover and replicate new coding variants implicated in the pathogenesis of glaucoma

Methods : We used exome-wide sequence and array data of three independent European cohorts: The Rotterdam Study (RS), The Erasmus Rucphen Family study and the EPIC study (N~11,400). Three glaucoma-related endophenotypes were examined: disc area, vertical cup-disc ratio (VCDR) and intraocular pressure (IOP). Fixed-effect meta-analyses were performed and variants with P <1.0x10-04 were selected for in silico replication in independent participants of the RS and the TwinsUK study (N~8300). To allow reliable replication of low-frequency variants, cohorts were imputed with the Haplotype Reference Consortium (HRC) reference panel. Based on the number of exonic variants in the discovery (N = 78,604), the P-value for exome-wide significance was 6.3x10-07

Results : We identified one novel low-frequency missense variant in the MITF gene significantly associated with disc area (P=1.9x10-07) and suggestive for VCDR (P= 1.1x10-05). Other common coding variants in previously known regions were also associated with optic nerve parameters. Significant association with VCDR was found in proximity to previously reported non-coding variants annotated to DUSP1, SIX6, and CHEK2. For IOP, novel rare coding variants in RUSC1 and OR4N2 reached exome-wide significance in the discovery but were not present in the HRC imputations. Also for IOP, we found common coding variants in previously reported regions, including ARHGEF12 and MADD

Conclusions : We identify a novel missense low-frequency variant in the MITF gene implicated in disc area and VCDR. MITF regulates the differentiation of the retinal pigmented epithelium and has been implicated in murine microphthalmia. For IOP, we discovered four novel exonic variants for which replication is ongoing. Our analysis provides further new biologically relevant insights of the annotation and functional relevance of genome-wide associated signals

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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