A genetic interaction network model of a complex neurological disease

Genes Brain Behav. 2014 Nov;13(8):831-40. doi: 10.1111/gbb.12178. Epub 2014 Oct 27.


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.

Keywords: Complex trait; epilepsy; epistasis; genetic interaction; genetic network; mouse model; pleiotropy; quantitative trait analysis; spike-wave discharge; statistical genetics.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Epilepsy, Absence / genetics*
  • Epistasis, Genetic*
  • Gene Regulatory Networks*
  • Humans
  • Mice
  • Models, Genetic*
  • Phenotype
  • Quantitative Trait Loci