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Identifying Novel Drug Targets for Epilepsy Through a Brain Transcriptome-Wide Association Study and Protein-Wide Association Study with Chemical-Gene-Interaction Analysis

Epilepsy is a severe neurological condition affecting 50–65 million individuals worldwide that can lead to brain damage. Nevertheless, the etiology of epilepsy remains poorly understood. Meta-analyses of genome-wide association studies involving 15,212 epilepsy cases and 29,677 controls of the ILAE...

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Autores principales: Lu, Mengnan, Feng, Ruoyang, Zhang, Chenglin, Xiao, Yanfeng, Yin, Chunyan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10415436/
https://www.ncbi.nlm.nih.gov/pubmed/37246165
http://dx.doi.org/10.1007/s12035-023-03382-z
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author Lu, Mengnan
Feng, Ruoyang
Zhang, Chenglin
Xiao, Yanfeng
Yin, Chunyan
author_facet Lu, Mengnan
Feng, Ruoyang
Zhang, Chenglin
Xiao, Yanfeng
Yin, Chunyan
author_sort Lu, Mengnan
collection PubMed
description Epilepsy is a severe neurological condition affecting 50–65 million individuals worldwide that can lead to brain damage. Nevertheless, the etiology of epilepsy remains poorly understood. Meta-analyses of genome-wide association studies involving 15,212 epilepsy cases and 29,677 controls of the ILAE Consortium cohort were used to conduct transcriptome-wide association studies (TWAS) and protein-wide association studies (PWAS). Furthermore, a protein-protein interaction (PPI) network was generated using the STRING database, and significant epilepsy-susceptible genes were verified using chip data. Chemical-related gene set enrichment analysis (CGSEA) was performed to determine novel drug targets for epilepsy. TWAS analysis identified 21,170 genes, of which 58 were significant (TWAS(fdr) < 0.05) in ten brain regions, and 16 differentially expressed genes were verified based on mRNA expression profiles. The PWAS identified 2249 genes, of which 2 were significant (PWAS(fdr) < 0.05). Through chemical-gene set enrichment analysis, 287 environmental chemicals associated with epilepsy were identified. We identified five significant genes (WIPF1, IQSEC1, JAM2, ICAM3, and ZNF143) that had causal relationships with epilepsy. CGSEA identified 159 chemicals that were significantly correlated with epilepsy (P(cgsea) < 0.05), such as pentobarbital, ketone bodies, and polychlorinated biphenyl. In summary, we performed TWAS, PWAS (for genetic factors), and CGSEA (for environmental factors) analyses and identified several epilepsy-associated genes and chemicals. The results of this study will contribute to our understanding of genetic and environmental factors for epilepsy and may predict novel drug targets. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-023-03382-z.
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spelling pubmed-104154362023-08-12 Identifying Novel Drug Targets for Epilepsy Through a Brain Transcriptome-Wide Association Study and Protein-Wide Association Study with Chemical-Gene-Interaction Analysis Lu, Mengnan Feng, Ruoyang Zhang, Chenglin Xiao, Yanfeng Yin, Chunyan Mol Neurobiol Article Epilepsy is a severe neurological condition affecting 50–65 million individuals worldwide that can lead to brain damage. Nevertheless, the etiology of epilepsy remains poorly understood. Meta-analyses of genome-wide association studies involving 15,212 epilepsy cases and 29,677 controls of the ILAE Consortium cohort were used to conduct transcriptome-wide association studies (TWAS) and protein-wide association studies (PWAS). Furthermore, a protein-protein interaction (PPI) network was generated using the STRING database, and significant epilepsy-susceptible genes were verified using chip data. Chemical-related gene set enrichment analysis (CGSEA) was performed to determine novel drug targets for epilepsy. TWAS analysis identified 21,170 genes, of which 58 were significant (TWAS(fdr) < 0.05) in ten brain regions, and 16 differentially expressed genes were verified based on mRNA expression profiles. The PWAS identified 2249 genes, of which 2 were significant (PWAS(fdr) < 0.05). Through chemical-gene set enrichment analysis, 287 environmental chemicals associated with epilepsy were identified. We identified five significant genes (WIPF1, IQSEC1, JAM2, ICAM3, and ZNF143) that had causal relationships with epilepsy. CGSEA identified 159 chemicals that were significantly correlated with epilepsy (P(cgsea) < 0.05), such as pentobarbital, ketone bodies, and polychlorinated biphenyl. In summary, we performed TWAS, PWAS (for genetic factors), and CGSEA (for environmental factors) analyses and identified several epilepsy-associated genes and chemicals. The results of this study will contribute to our understanding of genetic and environmental factors for epilepsy and may predict novel drug targets. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-023-03382-z. Springer US 2023-05-29 2023 /pmc/articles/PMC10415436/ /pubmed/37246165 http://dx.doi.org/10.1007/s12035-023-03382-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Lu, Mengnan
Feng, Ruoyang
Zhang, Chenglin
Xiao, Yanfeng
Yin, Chunyan
Identifying Novel Drug Targets for Epilepsy Through a Brain Transcriptome-Wide Association Study and Protein-Wide Association Study with Chemical-Gene-Interaction Analysis
title Identifying Novel Drug Targets for Epilepsy Through a Brain Transcriptome-Wide Association Study and Protein-Wide Association Study with Chemical-Gene-Interaction Analysis
title_full Identifying Novel Drug Targets for Epilepsy Through a Brain Transcriptome-Wide Association Study and Protein-Wide Association Study with Chemical-Gene-Interaction Analysis
title_fullStr Identifying Novel Drug Targets for Epilepsy Through a Brain Transcriptome-Wide Association Study and Protein-Wide Association Study with Chemical-Gene-Interaction Analysis
title_full_unstemmed Identifying Novel Drug Targets for Epilepsy Through a Brain Transcriptome-Wide Association Study and Protein-Wide Association Study with Chemical-Gene-Interaction Analysis
title_short Identifying Novel Drug Targets for Epilepsy Through a Brain Transcriptome-Wide Association Study and Protein-Wide Association Study with Chemical-Gene-Interaction Analysis
title_sort identifying novel drug targets for epilepsy through a brain transcriptome-wide association study and protein-wide association study with chemical-gene-interaction analysis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10415436/
https://www.ncbi.nlm.nih.gov/pubmed/37246165
http://dx.doi.org/10.1007/s12035-023-03382-z
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