Network-based analysis predicts interacting genetic modifiers from a meta-mapping study of spike–wave discharge in mice
Date
2024-03-05
Journal Title
Journal ISSN
Volume Title
Publisher
Genes, Brain and Behavior
Abstract
Absence seizures are characterized by brief lapses in awareness accompanied by a hallmark spike-and-wave discharge (SWD) electroencephalographic pattern and are common to genetic generalized epilepsies (GGEs). While numerous genes have been associated with increased risk, including some Mendelian forms with a single causal allele, most cases of GGE are idiopathic and there are many unknown genetic modifiers of GGE influencing risk and severity. In a previous meta-mapping study, crosses between transgenic C57BL/6 and C3HeB/FeJ strains, each carrying one of three SWD-causing mutations (Gabrg2tm1Spet(R43Q), Scn8a8j or Gria4spkw1), demonstrated an antagonistic epistatic interaction between loci on mouse chromosomes 2 and 7 influencing SWD. These results implicate universal modifiers in the B6 background that mitigate SWD severity through a common pathway, independent of the causal mutation. In this study, we prioritized candidate modifiers in these interacting loci. Our approach integrated human genome-wide association results with gene interaction networks and mouse brain gene expression to prioritize candidate genes and pathways driving variation in SWD outcomes. We considered candidate genes that are functionally associated with human GGE risk genes and genes with evidence for coding or non-coding allele effects between the B6 and C3H backgrounds. Our analyses output a summary ranking of gene pairs, one gene from each locus, as candidates for explaining the epistatic interaction. Our top-ranking gene pairs implicate microtubule function, cytoskeletal stability and cell cycle regulation as novel hypotheses about the source of SWD variation across strain backgrounds, which could clarify underlying mechanisms driving differences in GGE severity in humans.
Description
This article was originally published in Genes, Brain and Behavior. The version of record is available at: https://doi.org/10.1111/gbb.12879. © 2024 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.
Keywords
epilepsy, epistasis, functional networks, genetic generalized epilepsy, genetic modifiers, machine learning, network analysis, network-based functional prediction, quantitative genetics, spike and wave discharge
Citation
Lara MK, Brabec JL, Hernan AE, Scott RC, Tyler AL, Mahoney JM. Network-based analysis predicts interacting genetic modifiers from a meta-mapping study of spike–wave discharge in mice. Genes, Brain and Behavior. 2024; 23(2):e12879. doi:10.1111/gbb.12879