A Genetic Interaction Network Model of a Complex Neurological Disease

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 x B6 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 B6, suggesting common modifiers. By combining information across two phenotypic measures – SWD duration and frequency – CAPE revealed 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, towards a more comprehensive view of its underlying genetic architecture.