Abstract
Epilepsy is a common neurological disorder that affects mammalian species including human beings and dogs. In order to discover novel drugs for the treatment of canine epilepsy, multiomics data were analyzed to identify epilepsy associated genes. In this research, the original ranking of associated genes was obtained by two high-throughput bioinformatics experiments: Genome Wide Association Study (GWAS) and microarray analysis. The association ranking of genes was enhanced by a re-ranking system, HPO-Shuffle, which integrated information from GWAS, microarray analysis and Human Phenotype Ontology database for further downstream analysis. After applying HPO-Shuffle, the association ranking of epilepsy genes were improved. Afterward, a weighted gene coexpression network analysis (WGCNA) led to a set of gene modules, which hinted a clear relevance between the high ranked genes and the target disease. Finally, WGCNA and connectivity map (CMap) analysis were performed on the integrated dataset to discover a potential drug list, in which a well-known anticonvulsant phensuximide was included.
Highlights
Epilepsy is a spectrum of neurological disorders characterized by epileptic seizures
We proposed a novel computational pipeline, HPO-Shuffle, which integrated multi-Omics data mining and human phenotype ontology, and showed effectiveness for the identification of compounds that could be repurposed for canine epilepsy treatment, as a preliminary case study
To avoid potential bias introduced by across-breed heterogeneity, we limited our study on idiopathic epilepsy (IE) in Irish Wolfhounds, which consisted of 202 subjects (34 cases and 168 controls) genotyped for 160,727 single-nucleotide polymorphisms (SNP)
Summary
Epilepsy is a spectrum of neurological disorders characterized by epileptic seizures. It brings considerable burden of disease, affecting nearly 50 million people and 0.5–5% of the canine population [1]. Epilepsy treatment mainly relies on medication with anticonvulsant drugs that include phenytoin, carbamazepine and valproate. Over half of epileptic cases respond to a single-agent or combined antiepileptic treatment, certain subjects show refractory seizures and/or relapse, and suboptimally controlled epilepsy brings severe damage to both physical and mental health. Anticonvulsant treatment generally requires long-term administration, and it brings major adverse effects that reduce quality of life. Development of more effective and less toxic antiepilepsy drugs is a task of great importance
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