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PLoS One. 2017 Mar 6;12(3):e0172427. doi: 10.1371/journal.pone.0172427. eCollection 2017.

Whole exome sequencing implicates eye development, the unfolded protein response and plasma membrane homeostasis in primary open-angle glaucoma.

Author information

Flinders University, Department of Ophthalmology, Bedford Park, South Australia, Australia.
University of Sydney Discipline of Ophthalmology, Sydney, Australia.
Glaucoma Unit, Sydney Eye Hospital, Sydney, Australia.
Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia.
University of Tasmania Menzies Institute for Medical Research, Hobart, Australia.
University of Western Australia Centre for Ophthalmology and Visual Science, Lions Eye Institute, Perth, Australia.
University of Adelaide, Discipline of Ophthalmology & Visual Sciences, Adelaide, Australia.
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.
University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Australia.
Statistical Genetics, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Australia.
EMBL Australia Group, Infection & Immunity Theme, South Australian Medical and Health Research Institute, Adelaide, Australia.
Flinders University, School of Medicine, Adelaide, Australia.



To identify biological processes associated with POAG and its subtypes, high-tension (HTG) and normal-tension glaucoma (NTG), by analyzing rare potentially damaging genetic variants.


A total of 122 and 65 unrelated HTG and NTG participants, respectively, with early onset advanced POAG, 103 non-glaucoma controls and 993 unscreened ethnicity-matched controls were included in this study. Study participants without myocilin disease-causing variants and non-glaucoma controls were subjected to whole exome sequencing on an Illumina HiSeq2000. Exomes of participants were sequenced on an Illumina HiSeq2000. Qualifying variants were rare in the general population (MAF < 0.001) and potentially functionally damaging (nonsense, frameshift, splice or predicted pathogenic using SIFT or Polyphen2 software). Genes showing enrichment of qualifying variants in cases were selected for pathway and network analysis using InnateDB.


POAG cases showed enrichment of rare variants in camera-type eye development genes (p = 1.40×10-7, corrected p = 3.28×10-4). Implicated eye development genes were related to neuronal or retinal development. HTG cases were significantly enriched for key regulators in the unfolded protein response (UPR) (p = 7.72×10-5, corrected p = 0.013). The UPR is known to be involved in myocilin-related glaucoma; our results suggest the UPR has a role in non-myocilin causes of HTG. NTG cases showed enrichment in ion channel transport processes (p = 1.05×10-4, corrected p = 0.027) including calcium, chloride and phospholipid transporters involved in plasma membrane homeostasis. Network analysis also revealed enrichment of the MHC Class I antigen presentation pathway in HTG, and the EGFR1 and cell-cycle pathways in both HTG and NTG.


This study suggests that mutations in eye development genes are enriched in POAG. HTG can result from aberrant responses to protein misfolding which may be amenable to molecular chaperone therapy. NTG is associated with impaired plasma membrane homeostasis increasing susceptibility to apoptosis.

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