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

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Zhou, T, Souzeau, E, Sharma, Shiwani, Landers, J, Mills, R, Goldberg, I, Healey, PR, Graham, S, Hewitt, AW

, Mackey, DA, Galanopoulos, A, Casson, RJ, Ruddle, JB, Ellis, J, Leo, P, Brown, MA, MacGregor, S, Lynn, DJ, Burdon, KP

and Craig, JE 2017 , 'Whole exome sequencing implicates eye development, the unfolded protein response and plasma membrane homeostasis in primary open-angle glaucoma' , PLoS ONE, vol. 12, no. 3 , pp. 1-18 , doi: https://doi.org/10.1371/journal.pone.0172427.

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Official URL: http://dx.doi.org/10.1371/journal.pone.0172427

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 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.

Item Type:	Article
Authors/Creators:	Zhou, T and Souzeau, E and Sharma, Shiwani and Landers, J and Mills, R and Goldberg, I and Healey, PR and Graham, S and Hewitt, AW and Mackey, DA and Galanopoulos, A and Casson, RJ and Ruddle, JB and Ellis, J and Leo, P and Brown, MA and MacGregor, S and Lynn, DJ and Burdon, KP and Craig, JE
Journal or Publication Title:	PLoS ONE
Publisher:	Public Library of Science
ISSN:	1932-6203
DOI / ID Number:	https://doi.org/10.1371/journal.pone.0172427
Copyright Information:	Copyright 2017 Zhou et al. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) http://creativecommons.org/licenses/by/4.0/
Related URLs:	Google Scholar: Hewitt, AW UTAS Profile: Hewitt, AW Google Scholar: Burdon, KP UTAS Profile: Burdon, KP
Item Statistics:	View statistics for this item

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