Genome-wide association meta-analysis of 88,250 individuals highlights pleiotropic mechanisms of five ocular diseases in UK Biobank

Xue, Zhengbo; Yuan, Jian; Chen, Fukun; Yao, Yinghao; Xing, Shilai; Yu, Xiangyi; Li, Kai; Wang, Chenxiao; Bao, Jinhua; Qu, Jia; Su, Jianzhong; Chen, Hao

doi:10.1016/j.ebiom.2022.104161

Cited by 26 publications

(36 citation statements)

References 78 publications

(121 reference statements)

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“…Several putative target genes of the highest-ranked miRNAs were previously associated with eye diseases in genome-wide association studies (GWAS). Also, a GNAS gene was associated with HM (Tideman et al, 2021), TRAM1, CTNNB1, TENM3 and RUNX with myopia and/or refractive error (Han et al, 2020;Hysi et al, 2020;Xue et al, 2022), and EIF4B with low myopia/ hyperopia (Tideman et al, 2021) Overrepresentation analyses of miRNAs' targets revealed enrichment in biological pathways/processes related to eye structure and function, such as axon guidance, transcription, focal adhesion, insulin signaling, and signaling pathways of TGFβ, MAPK, and EGF-EGFR. Similarly, Mei et al also revealed significant enrichment of target genes of differentially expressed miRNAs in murine eyes with form-deprivation myopia in such processes as regulation of transcription, axon guidance, and TGF-β signaling pathway (Mei et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Differential methylation of microRNA encoding genes may contribute to high myopia

et al. 2023

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Introduction: High myopia (HM), an eye disorder with a refractive error ≤−6.0 diopters, has multifactorial etiology with environmental and genetic factors involved. Recent studies confirm the impact of alterations in DNA methylation and microRNAs (miRNAs) on myopia. Here, we studied the combined aspects evaluating to the role of methylation of miRNA encoding genes in HM.Materials and Methods: From the genome-wide DNA methylation data of 18 Polish children with HM and 18 matched controls, we retrieved differentially methylated CG dinucleotides localized in miRNA encoding genes. Putative target genes of the highest-ranked miRNAs were obtained from the miRDB and included in overrepresentation analyses in the ConsensusPathDB. Expression of target genes was assessed using the RNA sequencing data of retinal ARPE-19 cell line.Results: We identified differential methylation of CG dinucleotides in promoter regions of MIR3621, MIR34C, MIR423 (increased methylation level), and MIR1178, MIRLET7A2, MIR885, MIR548I3, MIR6854, MIR675, MIRLET7C, MIR99A (decreased methylation level) genes. Several targets of these miRNAs, e.g. GNAS, TRAM1, CTNNB1, EIF4B, TENM3 and RUNX were previously associated with myopia/HM/refractive error in Europeans in genome-wide association studies. Overrepresentation analyses of miRNAs’ targets revealed enrichment in pathways/processes related to eye structure/function, such as axon guidance, transcription, focal adhesion, and signaling pathways of TGF-β, insulin, MAPK and EGF-EGFR.Conclusion: Differential methylation of indicated miRNA encoding genes might influence their expression and contribute to HM pathogenesis via disrupted regulation of transcription of miRNAs’ target genes. Methylation of genes encoding miRNAs may be a new direction in research on both the mechanisms determining HM and non-invasive indicators in diagnostics.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differential methylation of microRNA encoding genes may contribute to high myopia

et al. 2023

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“…Optineurin (E50K) mutant astrocytes caused neurodegeneration in healthy RGCs ( Gomes et al, 2022 ). Xue et al (2022) investigated the common genetic causes of age-related macular degeneration, diabetic retinopathy, glaucoma, retinal detachment, and myopia, they found that genes associated with common genetic sites were involved in neuronal differentiation and eye development systems. Single-cell RNA sequencing data showed that their gene expression from pluripotent progenitor cells into retinal cells increased during retinal development ( Xue et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

A bibliometric analysis of the application of stem cells in glaucoma research from 1999 to 2022

Tao

Zhang

Mao

et al. 2023

Front. Cell Dev. Biol.

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Background: Glaucoma, a neurodegenerative disease of the retina, is the leading cause of irreversible blindness. Stem cells have therapeutic potential for glaucoma. However, few bibliometric studies have been published in this field. Concerning a visual map, this article aims to characterize the research context, cooperation relationship, hotspots, and trends concerning the application of stem cells in glaucoma research.Methods: Publications focusing on stem cell research and glaucoma were retrieved from the Web of Science Core Collection. VOSviewer, CiteSpace, Microsoft Excel, and Scimago Graphica were used to map the contributions of countries or regions, authors, organizations, and journals. Journal Impact Factor data were obtained from the Web of Science Core Collection. We analyzed the tendencies, hotspots, and knowledge networks using VOSviewer, and CiteSpace.Results: We analyzed 518 articles published from 1999 through 2022. In the first decade, the number of articles in this field increased slowly, and there was a marked acceleration in publication frequency after 2010. The United States, China, and England were the main contributors. Yiqin Du was the most prolific author, and among the top 10 prolific writers, Keith R. Martin’s work was cited most frequently. Investigative Ophthalmology and Visual Science, Experimental Eye Research, and Cornea published the most articles in this domain. The three most commonly co-cited journals were Investigative Ophthalmology and Visual Science, Experimental Eye Research, and Proceedings of the National Academy of Sciences of the United States of America. The Central South University, the University of Pittsburgh, and the National Institutes of Health National Eye Institute were highly prolific institutions in this research area. Our keywords analysis with VOSviewer suggested directions of future research and yielded the following recent key themes, extracellular vesicles, exosomes, mitochondria, growth factors, oxidative stress, and ocular diseases. Four co-cited references had a citation burst duration until 2022.Conclusion: With improvements in overall quality of life and demographic transitions toward population aging, research and clinical focus on eye care has increased, with glaucoma as a key area of emphasis. This study added to our understanding of the global landscape and Frontier hotspots in this field.

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“…The results of our study should be inspected considering its theoretical nature and the limitations and strength of this approach. We explored shared pathways between proteomics of “advanced DR” from an Asian population and genomics of “any DR” from a mostly European population (the UKBiobank does not identify DR subclasses, so individuals with early and advanced DR are all included in one category 71 ). It should be noted that this is not a comparative study; thus, the genotypical and phenotypical diversity of the two groups does not invalidate the results.…”

Section: Discussionmentioning

confidence: 99%

Probable Treatment Targets for Diabetic Retinopathy Based on an Integrated Proteomic and Genomic Analysis

Valdivia

Ren

et al. 2023

Trans. Vis. Sci. Tech.

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Purpose Using previously approved medications for new indications can expedite the lengthy and expensive drug development process. We describe a bioinformatics pipeline that integrates genomics and proteomics platforms to identify already-approved drugs that might be useful to treat diabetic retinopathy (DR). Methods Proteomics analysis of vitreous humor samples from 12 patients undergoing pars plana vitrectomy for DR and a whole genome dataset (UKBiobank TOPMed-imputed) from 1330 individuals with DR and 395,155 controls were analyzed independently to identify biological pathways associated with DR. Common biological pathways shared between both datasets were further analyzed (STRING and REACTOME analyses) to identify target proteins for probable drug modulation. Curated target proteins were subsequently analyzed by the BindingDB database to identify chemical compounds they interact with. Identified chemical compounds were further curated through the Expasy SwissSimilarity database for already-approved drugs that interact with target proteins. Results The pathways in each dataset (proteomics and genomics) converged in the upregulation of a previously unknown pathway involved in DR (RUNX2 signaling; constituents MMP-13 and LGALS3), with an emphasis on its role in angiogenesis and blood–retina barrier. Bioinformatics analysis identified U.S. Food and Drug Administration (FDA)-approved medications (raltitrexed, pemetrexed, glyburide, probenecid, clindamycin hydrochloride, and ticagrelor) that, in theory, may modulate this pathway. Conclusions The bioinformatics pipeline described here identifies FDA-approved drugs that can be used for new alternative indications. These theoretical candidate drugs should be validated with experimental studies. Translational Relevance Our study suggests possible drugs for DR treatment based on an integrated proteomics and genomics pipeline. This approach can potentially expedite the drug discovery process by identifying already-approved drugs that might be used for new indications.

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Genome-wide association meta-analysis of 88,250 individuals highlights pleiotropic mechanisms of five ocular diseases in UK Biobank

Cited by 26 publications

References 78 publications

Differential methylation of microRNA encoding genes may contribute to high myopia

Differential methylation of microRNA encoding genes may contribute to high myopia

A bibliometric analysis of the application of stem cells in glaucoma research from 1999 to 2022

Probable Treatment Targets for Diabetic Retinopathy Based on an Integrated Proteomic and Genomic Analysis

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