We propose to continue our long-term study of the genetic contributions to epilepsy by performing genetic linkage analysis. Our previous analyses indicate that in most families containing multiple individuals with epilepsy, the mode of inheritance is uncertain. Thus in the proposed study, we shall use analytic approaches that do not require assumptions about mode of inheritance. Approximately 195 families containing equal to or greater than 2 living individuals with idiopathic/cryptogenic epilepsy with onset prior to age 25 will be included in the study (23 families already collected from our original database, 22 additional families containing affected sibling pairs from our original database, and 150 families to be ascertained from the patient resources at our medical center). Genotypes in family members will be determined at approximately 400 microsatellite markers spaced at an average of 10 centimorgan intervals throughout the genome. Analysis of marker alleles shared identical-by-descent (IBD) in affected relatives will be used to identify genomic regions likely, and exclude regions unlikely, to contain genes raising risk for idiopathic/cryptogenic epilepsy with onset prior to age 25. In genomic regions with suggestive evidence for linkage, we will use multipoint linkage analysis association analysis to assess the evidence further. If evidence for linkage is obtained, we will explore the phenotypes most likely to result from the mapped susceptibility genes by analysis of the effect on allele sharing when the phenotype is restricted to specific clinical subgroups (e.g., generalized epilepsy, localization-related epilepsy).
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