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.
Highlights
Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide. [1] Epidemiological evidence has demonstrated a strong genetic component to POAG with a heritability of 0.81[2] and a 9.2-fold familial increase in disease risk among first-degree relatives of an affected individual.[3]
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
Summary
Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide. [1] Epidemiological evidence has demonstrated a strong genetic component to POAG with a heritability of 0.81[2] and a 9.2-fold familial increase in disease risk among first-degree relatives of an affected individual.[3]. [1] Epidemiological evidence has demonstrated a strong genetic component to POAG with a heritability of 0.81[2] and a 9.2-fold familial increase in disease risk among first-degree relatives of an affected individual.[3] Historically, POAG was thought to be solely a disease of raised intraocular pressure (IOP); this concept does not capture the full spectrum of the disease.[4, 5] Wide phenotypic heterogeneity exists within the disorder—despite the majority of patients exhibiting elevated IOP (high-tension glaucoma (HTG)), many others develop vision loss with no recorded elevation in their IOP (normal-tension glaucoma (NTG)) This is a reflection of the complex gene-environment interactions which drive the pathophysiology. Mutations in MYOC and CYP1B1 are causative for HTG, [7, 8] while mutations in OPTN and copy-number variations of TBK1 cause NTG.[4, 5, 9] Despite these successes, highly penetrant Mendelian mutations in genes discovered to date only account for around 5% of all cases of POAG.[6]
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