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

Abstract

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

Genome-wide Expression Profiling and Pathway Analysis in Cyclic Stretched Human Trabecular Meshwork Cells

“…Reducing ER stress and unfolded protein response in TM cells chemically can prevent dexamethasone-induced ocular hypertension in mice (49). Rare variants in key regulators of unfolded protein response ( ACADVL, EXOSC3, KDELR3, SHC1, SRPRB, SYVN1, TATDN2 , and TPP1 ) were found to be significantly enriched in POAG patients with elevated IOP (51). Differentially expressed miRNAs miR-455-5p, miR-34a-5p, miR-199a-5p, miR-221-5p, miR-494-3p, miR-29a-3p, miR-93-5p, miR-25-3p, and miR-30a have been known to target the regulators of unfolded protein response (52, 53).…”

Physiological function of myocilin and its role in the pathogenesis of glaucoma in the trabecular meshwork (Review)

“…Normally, myocilin is intra-cellularly cleaved within the endoplasmic reticulum (ER) of TM cells and secreted into the aqueous humor (33,38). C-terminal myocilin fragments have been detected in the TM and the aqueous humor (23,33).…”

Identification of candidate genes and pathways in retinopathy of prematurity by whole exome sequencing of preterm infants enriched in phenotypic extremes

“…retinitis pigmentosa) and also in multifactorial diseases (e.g. glaucoma 19 – 22 , age-related macular degeneration 23 – 25 ) in ophthalmology. Also, combining WES and pathway analysis has enabled researchers to find novel biological pathways or polygenic burdens associated with disease in small to moderate-scale sequencing studies 19 , 26 – 28 .…”

“…glaucoma 19 – 22 , age-related macular degeneration 23 – 25 ) in ophthalmology. Also, combining WES and pathway analysis has enabled researchers to find novel biological pathways or polygenic burdens associated with disease in small to moderate-scale sequencing studies 19 , 26 – 28 . This study aimed to identify potentially pathogenic genes and biological pathways associated with ROP by analyzing whole exome sequencing data from 100 preterm infants enriched in phenotypic extremes, by analyzing the variants both by rare variant methods and common variant methods.…”