Genetics of common Epilepsies: Innovating methods for detection of genetic risk factors for common diseases.
11 / 2005 - unknown
IGE (Idiopathic Generalized Epilepsy) is the most common form of epilepsy, and consists of distinct epilepsy phenotypes, such as Juvenile Myoclonic Epilepsy (JME), PhotoSensitive Epilepsy (PSE), and Juvenile Absence Epilepsy (JAE). In some families only one distinct IGE phenotypes is segregating, but in other families different IGE phenotypes are present, even within single patients. It is therefore believed that specific genetic risk factors may exist that are common for the different IGE phenotypes, but that polygenic inheritance determines the phenotypic expression of the disease. Several genes have been reported to be involved in the susceptibility for IGE, but mutations in coding regions of these genes only account for a minority of IGE patients. This observation suggests that either mild noncoding variants are present in the detected genes, or alternatively, that other genes are implicated in the remainder of patients. To further clarify this, I propose a comprehensive search for genetic factors involved in common epilepsies, and within this framework innovate our current methodology for detecting genetic risk factors for common disease. I propose to fine-map the disease loci detected by previous linkage screens and to perform a association studies of these regions and functional candidate genes, improve statistical methods for detecting genetic risk factors for common disease, apply new approaches to identify functional non-coding genetic variants, and, when a genetic risk factor has been detected, to perform biological assays to assess its functionality. I expect the above strategy to lead to identification of genetic variants that show strong genetic and biological evidence for being associated with IGE.