A genetic interaction network model of a complex neurological disease. (27th October 2014)

• Record Type: Journal Article
• Authors: Tyler, A. L.; McGarr, T. C.; Beyer, B. J.; Frankel, W. N.; Carter, G. W.
• Is Part Of: Genes, brain, and behavior. Volume 13:Number 8(2014:Nov.)
• Page Start: 831
• Page End: 840
• Publication Date: 2014-10-27
• Subjects: Behavior genetics -- Periodicals; Neurogenetics -- Periodicals; 616.8
• DOI: 10.1111/gbb.12178
• Languages: English
• ISSNs: 1601-1848

Abstract

<abstract abstract-type="main" id="gbb12178-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p id="gbb12178-para-0001">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.</p> </abstract>