Epilepsy is a complex genetic disease with a prevalence of about 1% worldwide. So far, only a few epilepsy genes have been identified in unusually large, high-density pedigrees. However, their contribution in the general epilepsy population appears to be limited and many mutations seem to raise seizure susceptibility unspecifically, since divergent seizure types are associated with them.
Our aims for this grant are to look for further genes for epilepsy but also specifically for genetic elements that determine the absence seizures in a clinically distinct subform of epilepsy, i.e. Childhood Absence Epilepsy (CAE). Using a novel statistical approach, we have already identified areas containing genes with high biological relevance to epilepsy in a genome wide association study (GWAS). In a pathway analysis we found that a majority of identified genes map to a network involving Cell-To-Cell Signaling and Interaction, Nervous System Development and Function, and Cell Death. Furthermore, we have identified association peaks in highly conserved intergenic chromosomal regions, raising the possibility of the involvement of regulatory elements in CAE. We will confirm our findings in an independent sample of CAE patients and in addition, we will also investigate the involvement of chromosomal structural variants in CAE. We will then determine the sequence variants underlying these association results by Next-Gen sequencing. We will be in an excellent position to discover novel pathways that lead to epileptogenesis that go beyond the already established mechanisms of membrane excitability and synaptic transmission.
Epilepsy is a common, genetically complex disease with a prevalence of about 1% worldwide. So far, only a few epilepsy genes have been identified in unusually large, high-density pedigrees. However, their contribution in a general epilepsy population is minimal and mutations seem to raise seizure susceptibility unspecifically.
Our aims for this grant are to look for further genes for epilepsy but also specifically for genes that determine the absence seizures in a clinically distinct subform of epilepsy, i.e. Childhood Absence Epilepsy (CAE).
|Wittkowski, Knut M; Sonakya, Vikas; Song, Tingting et al. (2013) From single-SNP to wide-locus: genome-wide association studies identifying functionally related genes and intragenic regions in small sample studies. Pharmacogenomics 14:391-401|
|Vierck, Esther; Cauley, Ryan; Kugler, Steven L et al. (2010) Polyspike and waves do not predict generalized tonic-clonic seizures in childhood absence epilepsy. J Child Neurol 25:475-81|
|Chioza, Barry A; Aicardi, Jean; Aschauer, Harald et al. (2009) Genome wide high density SNP-based linkage analysis of childhood absence epilepsy identifies a susceptibility locus on chromosome 3p23-p14. Epilepsy Res 87:247-55|
|Everett, Kate; Chioza, Barry; Aicardi, Jean et al. (2007) Linkage and mutational analysis of CLCN2 in childhood absence epilepsy. Epilepsy Res 75:145-53|
|Pal, Deb K; Durner, Martina; Klotz, Irene et al. (2006) Complex inheritance and parent-of-origin effect in juvenile myoclonic epilepsy. Brain Dev 28:92-8|
|Greenberg, David A; Cayanis, Eftihia; Strug, Lisa et al. (2005) Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy. Am J Hum Genet 76:139-46|
|Pal, Deb K; Evgrafov, Oleg V; Tabares, Paula et al. (2003) BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy. Am J Hum Genet 73:261-70|
|Pal, D K; Durner, M; Greenberg, D A (2001) Effect of misspecification of gene frequency on the two-point LOD score. Eur J Hum Genet 9:855-9|
|Durner, M; Keddache, M A; Tomasini, L et al. (2001) Genome scan of idiopathic generalized epilepsy: evidence for major susceptibility gene and modifying genes influencing the seizure type. Ann Neurol 49:328-35|
|Greenberg, D A; Durner, M; Keddache, M et al. (2000) Reproducibility and complications in gene searches: linkage on chromosome 6, heterogeneity, association, and maternal inheritance in juvenile myoclonic epilepsy. Am J Hum Genet 66:508-16|