Genome-Wide Genetic Interaction Analysis of Glaucoma Using Expert Knowledge Derived From Human Phenotype Networks

Hu, Ting; Darabos, Christian; Cricco, Maria E.; Kong, Emily; Moore, Jason H.

doi:10.1142/9789814644730_0021

Cited by 3 publications

(3 citation statements)

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“…GJA8 and CRYBA4 are both crystalline lens-associated genes implicated in the formation of cataract. While it is well known that cataracts can contribute to the pathogenesis of angle-closure glaucoma, pathway analyses with GWAS SNPs[ 35 ] have identified associated SNPs in genes CDK4PS , NFYAP1 , and LGMNP1 shared between the POAG and cataract phenotypes, suggesting a potential genetic connection between these conditions. GJA8 has been linked to ocular developmental abnormalities of microcornea[ 36 ] and microphthalmia[ 37 ], both of which may be related to glaucoma.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…All three studies found intriguing relationships between SNP interactions and phenotypes, highlighting potential interactions between gene products while also providing biological context for the interactions behind the identified associations. In a separate study, bipartite networks were used to build a human phenotype network within a glaucoma dataset in which epistatic interactions among prioritized SNPs were identified using a statistical epistasis network [90] .…”

Section: Genetic Variation: Snps To Copy Number Variants Epistasis Amentioning

confidence: 99%

Phenome-Wide Association Studies: Embracing Complexity for Discovery

et al. 2015

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“…Generally, it cannot be cured, but it can be controlled [ 25 ]. Some reported glaucoma interaction networks were based on genome wide association studies (GWAS) [ 26 , 27 ] while others focused on interaction networks from genome wide expression studies (GWES) [ 28 , 29 ] but none have yet been based solely on text mining of the vast swath of PMC literature, where all types of glaucoma studies are covered. Such a network is expected to have a wider coverage than prior efforts because it will not be inferred from a particular type of study but rather from all types of studies related to glaucoma.…”

Section: Introductionmentioning

confidence: 99%

Building a glaucoma interaction network using a text mining approach

2016

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BackgroundThe volume of biomedical literature and its underlying knowledge base is rapidly expanding, making it beyond the ability of a single human being to read through all the literature. Several automated methods have been developed to help make sense of this dilemma. The present study reports on the results of a text mining approach to extract gene interactions from the data warehouse of published experimental results which are then used to benchmark an interaction network associated with glaucoma. To the best of our knowledge, there is, as yet, no glaucoma interaction network derived solely from text mining approaches. The presence of such a network could provide a useful summative knowledge base to complement other forms of clinical information related to this disease.ResultsA glaucoma corpus was constructed from PubMed Central and a text mining approach was applied to extract genes and their relations from this corpus. The extracted relations between genes were checked using reference interaction databases and classified generally as known or new relations. The extracted genes and relations were then used to construct a glaucoma interaction network. Analysis of the resulting network indicated that it bears the characteristics of a small world interaction network. Our analysis showed the presence of seven glaucoma linked genes that defined the network modularity. A web-based system for browsing and visualizing the extracted glaucoma related interaction networks is made available at http://neurogene.spd.louisville.edu/GlaucomaINViewer/Form1.aspx.ConclusionsThis study has reported the first version of a glaucoma interaction network using a text mining approach. The power of such an approach is in its ability to cover a wide range of glaucoma related studies published over many years. Hence, a bigger picture of the disease can be established. To the best of our knowledge, this is the first glaucoma interaction network to summarize the known literature. The major findings were a set of relations that could not be found in existing interaction databases and that were found to be new, in addition to a smaller subnetwork consisting of interconnected clusters of seven glaucoma genes. Future improvements can be applied towards obtaining a better version of this network.Electronic supplementary materialThe online version of this article (doi:10.1186/s13040-016-0096-2) contains supplementary material, which is available to authorized users.

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Genome-Wide Genetic Interaction Analysis of Glaucoma Using Expert Knowledge Derived From Human Phenotype Networks

Cited by 3 publications

References 50 publications

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

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

Phenome-Wide Association Studies: Embracing Complexity for Discovery

Building a glaucoma interaction network using a text mining approach

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