Identifying Genetic Modifiers of Epilepsy Resilience and Susceptibility

Gianna Durante

Document Type

Article

Publication Date

8-9-2024

Keywords

JMG

JAX Location

In: Student Reports, Summer 2024, The Jackson Laboratory

Abstract

Epilepsy is a family of diseases characterized by hyper-synchronized brain activity resulting in seizures. Most epilepsy is polygenic, meaning it is caused by several genetic and environmental factors. Due to the large amount of genetic variation between individuals with polygenic epilepsy, it is difficult to understand the underlying mechanisms of epilepsy risk and resilience. In contrast to human studies, mouse studies on epilepsy allow experimental induction of epilepsy to map genetic factors driving resilience. Meta- analysis of multiple genome-wide association studies (GWAS) further allows for the identification of single nucleotide polymorphisms (SNPs) that affect epilepsy prevalence and seizure severity across many such studies, and hence general mechanisms of risk and resilience. In this study, we conduct a GWAS meta-analysis on a collection of mouse studies, a network-based functional prediction of genes involved in epilepsy, and Genomic Evolutionary Rate Profiling (GERP) conservational analysis to identify the genes responsible for differential epilepsy phenotypes in our studied mouse populations. [Bl We discovered that 5 genes Tenm4, Dtna, /gsf21, Cadps2, and ltpk1 have mutations within highly conserved transcription factor binding motifs. These mutations are predicted to result in a significantly lower predicted transcription factor binding affinity, and thus a predicted decrease in gene expression. These genes are involved in neural development and decreased ability to adapt to adverse stimuli, providing insights into potential therapeutic targets.

Please contact the Joan Staats Library for information regarding this document.

COinS