title: A genetic interaction network model of a complex neurological disease.
abstract: Absence epilepsy (AE) is a complex, heritable disease characterized by a brief disruption of normal behavior and accompanying spike-wave discharges (SWD) on the electroencephalogram. Only a handful of genes has been definitively associated with AE in humans and rodent models. Most studies suggest that genetic interactions play a large role in the etiology and severity of AE, but mapping and understanding their architecture remains a challenge, requiring new computational approaches. Here we use combined analysis of pleiotropy and epistasis (CAPE) to detect and interpret genetic interactions in a meta-population derived from three C3H × B6J strain crosses, each of which is fixed for a different SWD-causing mutation. Although each mutation causes SWD through a different molecular mechanism, the phenotypes caused by each mutation are exacerbated on the C3H genetic background compared with B6J, suggesting common modifiers. By combining information across two phenotypic measures - SWD duration and frequency - CAPE showed a large, directed genetic network consisting of suppressive and enhancing interactions between loci on 10 chromosomes. These results illustrate the power of CAPE in identifying novel modifier loci and interactions in a complex neurological disease, toward a more comprehensive view of its underlying genetic architecture.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Tyler
authors.forename: T C
authors.initials: TC
authors.lastname: McGarr
authors.forename: B J
authors.initials: BJ
authors.lastname: Beyer
authors.forename: W N
authors.initials: WN
authors.lastname: Frankel
authors.forename: G W
authors.initials: GW
authors.lastname: Carter
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004832:Epilepsy, Absence / Q000235:genetics*; D004843:Epistasis, Genetic; D053263:Gene Regulatory Networks; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D010641:Phenotype; D040641:Quantitative Trait Loci
keywords: Complex trait; epilepsy; epistasis; genetic interaction; genetic network; mouse model; pleiotropy; quantitative trait analysis; spike-wave discharge; statistical genetics