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Epilepsy Genetics Group

Epilepsy encompasses a group of heterogeneous brain diseases that affect more than 50 million people worldwide. Based initially on family and twin studies, emerging evidence suggests that genetic factors play a major role in the etiology of at least 50% of epilepsies. Genetic generalized epilepsies (GGEs) represent the most common form of genetically determined epilepsies (PMID:29741207). Up to date, the genetic basis of common GGE syndromes remains largely unsolved due to their prominent polygenic predisposition and extensive genetic heterogeneity. Our current knowledge of the complex genetic architecture of common GGE syndromes suggests that rare deleterious gene mutations and common polygenic variation act synergistically and converge on shared gene networks controlling excitability and synchronization of neural circuits underlying epileptogenesis. Heritability analyses implicate that at least 35% of GGE susceptibility is determined by single nucleotide polymorphisms (SNPs). Based on the common disease – common variants (CDCV) hypothesis, our research group aims to disentangle the complex genetics basis of common GGE syndromes, using genome-wide linkage, copy number variation (CNV), SNP-based association (GWAS) and whole exome sequencing (WES) studies (DFG Research Group 2715: Epileptogenesis of Genetic Epilepsies). Given that most GGE-associated SNPs reside in non-coding genomic regions, we are exploring the prevailing view that causal SNPs in non-coding regions exert a regulatory effect on the transcriptional activity of adjacent genes by an allelic functional alteration of cis-acting epigenetic elements, such as promoters, enhancers and insulators. Accordingly, epigenomic profiling of GGE-associated rSNPs will gain critical insights into temporospatial neurobiological processes of epileptogenesis. Predictive modeling of key pathways of epileptogenesis and delineation of individual epigenomic risk profiles of GGE may be of relevance towards precision medicine (PMID:32413583).

Selected publications

Linkage analyses

Prüss H, Gessner G, Heinemann SH, et al. (2019). Linkage evidence for a two-locus inheritance of LQT-associated seizures in a multigenerational LQT family with a novel loss-of-function mutation. Front Neurol 10, 648.

EPICURE Consortium, Leu C, de Kovel CG, et al. (2012). Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies. Epilepsia 53, 308-318.

Hempelmann A, Lenzen KP, Heils A, et al. (2006). Exploration of the genetic architecture of idiopathic generalized epilepsies. Epilepsia 10, 1682-1690.

GWAS

Wolking S, Schulz H, Nies AT, et al. (2020). Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study. Pharmacogenomics 21, 325-335.

International League Against Epilepsy Consortium on Complex Epilepsies, et al. (2018). Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat Commun 9, 5269.

International League Against Epilepsy Consortium on Complex Epilepsies, et al. (2014). Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurol 13, 893-903.

EPICURE Consortium, EMINet Consortium, Steffens M, et al. (2012). Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32. Hum Mol Genet. 21, 5359-5372.

CNV analyses

Lal D, Ruppert AK, Trucks H, et al. (2015). Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. PLoS Genet 11, e1005226.

Dejanovic B, Lal D, Catarino CB, et al. (2014). Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy. Neurobiol Dis 67, 88-96.

Lal D, Trucks H, Moller RS, et al. (2013). Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy. Epilepsia 54, 265-271.

Mullen SA, Carvill GL, Bellows S, et al. (2013). Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology 81, 1507-1514.

de Kovel CG, Trucks H, Helbig I, et al. (2010). Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain. 133, 23-32.

Helbig I, Mefford HC, Sharp AJ, et al. (2009) 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet 1, 160-162.

Sequencing analyses

May P, Girard S, Harrer M, et al. (2018). Rare coding variants in genes encoding GABA(A) receptors in genetic generalised epilepsies: an exome-based case-control study. Lancet Neurol 17, 699-708.

Lal D, Neubauer BA, Toliat MR, et al. (2016). Increased probability of co-occurrence of two rare diseases in consanguineous families and resolution of a complex phenotype by next generation sequencing. PLoS ONE 11, e0146040.

Galizia EC, Myers CT, Leu C, et al. (2015). CHD2 variants are a risk factor for photosensitivity in epilepsy. Brain 138, 1198-1207.

Striano P, Weber YG, Toliat MR, et al. (2012). GLUT1 mutations are a rare cause of familial idiopathic generalized epilepsy. Neurology 78, 557-562.

Epigenetic analyses

Schulz H, Ruppert AK, Zara F, et al. (2019). No evidence for a BRD2 promoter hypermethylation in blood leukocytes of Europeans with juvenile myoclonic epilepsy. Epilepsia 60, e31-e36.

Schulz H, Ruppert AK, Herms S, et al. (2017). Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus. Nat Commun 8, 1511.

Pernhorst K, van Loo KMJ, von Lehe M, et al. (2013). Rs6295 promoter variants of the serotonin type 1A receptor are differentially activated by c-Jun in vitro and correlate to transcript levels in human epileptic brain tissue. Brain Res 1499, 136-144.