Document Type
Article
Publication Date
4-1-2024
Original Citation
Lara M,
Brabec J,
Hernan A,
Scott R,
Tyler AL,
Mahoney J.
Network-based analysis predicts interacting genetic modifiers from a meta-mapping study of spike-wave discharge in mice. Genes Brain Behav. 2024;23(2):e12879.
Keywords
JMG, Humans, Animals, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Genome-Wide Association Study, Patient Discharge, Alleles, NAV1.6 Voltage-Gated Sodium Channel
JAX Source
Genes Brain Behav. 2024;23(2):e12879.
ISSN
1601-183X
PMID
38444174
DOI
https://doi.org/10.1111/gbb.12879
Grant
U.S. National Library of Medicine, Grant/Award Number: R21LM012615; National Institute of General Medical Sciences, Grant/Award Number: 1P20 GM130454
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 modi- fiers 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 (Gabrg2 tm1Spet(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 interac- tion 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 ana- lyses output a summary ranking of gene pairs, one gene from each locus, as candi- dates for explaining the epistatic interaction. Our top-ranking gene pairs implicate microtubule function, cytoskeletal stability and cell cycle regulation as novel hypothe- ses about the source of SWD variation across strain backgrounds, which could clarify underlying mechanisms driving differences in GGE severity in humans.
Comments
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2024 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.