Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/105429
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Type: Journal article
Title: Whole exome sequencing implicates eye development, the unfolded protein response and plasma membrane homeostasis in primary open-angle glaucoma
Author: Zhou, T.
Souzeau, E.
Sharma, S.
Landers, J.
Mills, R.
Goldberg, I.
Healey, P.
Graham, S.
Hewitt, A.
Mackey, D.
Galanopoulos, A.
Casson, R.
Ruddle, J.
Ellis, J.
Leo, P.
Brown, M.
MacGregor, S.
Lynn, D.
Burdon, K.
Craig, J.
Citation: PLoS ONE, 2017; 12(3):e0172427-1-e0172427-18
Publisher: Public Library Science
Issue Date: 2017
ISSN: 1932-6203
1932-6203
Statement of
Responsibility: 
Tiger Zhou, Emmanuelle Souzeau, Shiwani Sharma, John Landers, Richard Mills, Ivan Goldberg, Paul R. Healey, Stuart Graham, Alex W. Hewitt, David A. Mackey, Anna Galanopoulos, Robert J. Casson, Jonathan B. Ruddle, Jonathan Ellis, Paul Leo, Matthew A. Brown, Stuart MacGregor, David J. Lynn, Kathryn P. Burdon, Jamie E. Craig
Abstract: Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.
Keywords: Glaucoma; apoptosis; cell cycle and cell division; gene ontologies; genetic networks; major histocompatibility complex; network analysis; eye development
Rights: © 2017 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
RMID: 0030066601
DOI: 10.1371/journal.pone.0172427
Grant ID: http://purl.org/au-research/grants/nhmrc/1023911
http://purl.org/au-research/grants/nhmrc/1107098
http://purl.org/au-research/grants/nhmrc/1065433
Appears in Collections:Medicine publications

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