Abstracts

Most common human epilepsies have multifactorial etiologies and their development depends on a combination of both genetic and environmental factors. While significant progress has been made in gene identification for monogenic epilepsies, failure to identify and measure environmental risk factors has hindered progress in gene identification for multifactorial epilepsies. In this study, we analyzed the role of environmental factors on gene identification for multifactorial epilepsy in the EL mouse. The EL mouse is a model for age-dependent generalized idiopathic epilepsy and expresses complex partial seizures with secondary generalization. The inheritance of seizures was analyzed in the seizure susceptible EL (E) and seizure resistant ABP/LeJ (A) parental strains, and in their AEF1 and AEF2 hybrid offspring using a gentle handling-induced seizure susceptibility test paradigm. The seizure tests were administered in three environments that included: test initiation once/month beginning at 30 days and ending at 141 days ([underline]Environment I[/underline]); a single test initiated at 150 days ([underline]Environment II[/underline]); test initiation once/month beginning at 150 days and ending at 261 days ([underline]Environment III[/underline]). Quantitative trait loci (QTL) were analyzed using simple sequence length polymorphisms and Mapmaker/QTL software. A total of 691 mice were analyzed. The inheritance of seizure susceptibility appeared dominant in Environments I and III, but appeared recessive in Environment II. Significant QTL, which were associated with repetitive seizure testing, were found on Chromosomes 2 and 9 and co-localized with the previously mapped [italic] El2 [/italic] and [italic] El4 [/italic] genes, respectively. Significant gender effects on gene mapping were detected only in Environment I. A novel QTL, [italic] El-N [/italic] ([italic] Epilepsy-Na[iuml]ve [/italic] quantitative trait locus), for age-dependent predisposition to seizures was found only in Environments II and III on proximal Chromosome 9 and differed from the previously identified [italic] El1 [/italic]. Environmental risk factors including age, gender, and recurrent seizures influence the inheritance and genetic architecture of seizure susceptibility in EL mice. The findings suggest that QTL for multifactorial epilepsy and possibly other age-dependent complex traits should be defined in terms of the environment in which they are expressed. (Supported by NIH grants NS23355 and HD39722, the Boston College Research Fund, and the Epilepsy Foundation.)