Substantial progress has been made recently in positional cloning of epilepsy susceptibility genes in unusual families with Mendelian forms of transmission. However, little is known about the magnitude of genetic effects on different epilepsy syndromes in the population, or the range of clinical phenotypes produced by specific genetic mechanisms. We propose to address these questions in a population-based study of the shared and distinct genetic influences on specific seizure disorders and epilepsy syndromes, using data from the Rochester-Olmsted County Records Linkage Project. Case probands will be all Rochester residents born in 1920 or later with incidence of epilepsy or an isolated unprovoked seizure from 1935-1994 (N=1056). Control probands will be individuals without unprovoked seizures, matched to the cases by birth year, ethnicity, and length of Rochester residency. Diagnosis and classification will be based on review of medical records, supplemented by semistructured diagnostic interviews to ensure that data are collected systematically on essential clinical features. Information on seizure disorders in the first-degree relatives of cases and controls will be collected by review of the medical records of the relatives, supplemented by proband interviews. Blood samples will be collected from living cases and controls for candidate gene association studies. The data will be used to assess which clinical features of epilepsy are most likely to predict a genetic susceptibility whether the genetic influences on epilepsy also raise risk for other seizure disorders (isolated unprovoked seizures, febrile convulsions, and other acute symptomatic seizures), and whether different clinically-defined epilepsy syndromes have shared or distinct genetic influences. Risks of seizure disorders in the offspring of female and male probands will be compared to explore the previously observed maternal effect in epilepsy. A set of candidate genes encoding either voltage-gated or ligand-gated ion channels will be investigated in both direct and indirect (haplotype or marker-based) association tests utilizing single nucleotide polymorphisms (SNPs).
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