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...

Full description

Saved in:
Bibliographic Details
Published in:Molecular neurobiology 2023-09, Vol.60 (9), p.5055-5066
Main Authors: Lu, Mengnan, Feng, Ruoyang, Zhang, Chenglin, Xiao, Yanfeng, Yin, Chunyan
Format: Article
Language:English
Subjects:
Biomedical and Life Sciences
Biomedicine
Brain injury
Cell Biology
Chemicals
Enrichment
Environmental factors
Epilepsy
Gene expression
Gene set enrichment analysis
Genes
Genetic factors
Genome-wide association studies
Genomes
Ketones
Neurobiology
Neurology
Neurosciences
PCB
Pentobarbital
Polychlorinated biphenyls
Protein interaction
Proteins
Therapeutic targets
Transcriptomes
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0893-7648
1559-1182
DOI:10.1007/s12035-023-03382-z