Abstract
Epilepsy is a common neurological disorder in domestic dogs. However, its complex mechanism involves multiple genetic and environmental factors that make it challenging to identify the real pathogenic factors contributing to epilepsy, particularly for idiopathic epilepsy. Conventional genome-wide association studies (GWASs) can detect various genes associated with epilepsy, although they primarily detect the effects of single-site mutations in epilepsy while ignoring their interactions. In this study, we used a systems genetics method combining both GWAS and gene interactions and obtained 26 significantly mutated subnetworks. Among these subnetworks, seven genes were reported to be involved in neurological disorders. Combined with gene ontology enrichment analysis, we focused on 4 subnetworks that included traditional GWAS-neglected genes. Moreover, we performed a drug enrichment analysis for each subnetwork and identified significantly enriched candidate anti-epilepsy drugs using a hypergeometric test. We discovered 22 potential drug combinations that induced possible synergistic effects for epilepsy treatment, and one of these drug combinations has been confirmed in the Drug Combination database (DCDB) to have beneficial anti-epileptic effects. The method proposed in this study provides deep insight into the pathogenesis of canine epilepsy and implications for anti-epilepsy drug discovery.
Highlights
Epilepsy is a common serious neurological disease, which does latent harm to human health [1]
Using the combination of genome-wide association studies (GWASs) and HotNet2, we identified 26 subnetworks associated with canine epilepsy
Through gene ontology (GO) enrichment analysis and a literature review, we focused on the relationship between gene mutations and epilepsy mechanisms in four subnetworks
Summary
Epilepsy is a common serious neurological disease, which does latent harm to human health [1]. Though a better understanding of the genetic targets and mechanisms of anti-seizure drug activity offers trusty direction in drug selection for individual patients, the experiments in need are ethically and technically difficult. For this reason, animal models are useful in anti-seizure drug research [3]. Animal models are useful in anti-seizure drug research [3] One such model organism is the dog, because both humans and companion animals suffer from epilepsy, which is a chronic neurologic disorder affecting nearly 50 million people and 0.5–5% of the canine population worldwide [4]. Models of anti-seizure medication targets and activities that are derived from humans are useful in epilepsy research in a canine context
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