Common and pleiotropic genetic factors in epileptogenesis

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Previous studies on identifying genetic risk loci implicated in epileptogenesis have usually employed standard genetic risk models under which these variants act, namely single common variants under a multiplicative (i.e. additive in the number of alleles) model (GWAS studies) or several subsets of rare variants acting together as a genetic burden (exome studies). In the 1st funding period, we (1) identified 2 novel suceptibility loci for GGE (NCAM1, MAP3K9), (2) described an aberrant ALDH5A1 promoter regulation, and (3, formerly P2) conducted a benchmarking study for common-variant pleiotropy detection and applied such methods to GWAS datasets from ILAE2. In the 2nd period, project P3 will pursue different statistical and bioinformatic approaches in parallel to identify epilepsy-related genetic variants that act under non-standard risk models or those which require additional information, including external epigenomic data or information on related traits, to achieve sufficient power for their successful identification. This involves widened pleiotropy detection, Bayesian GWAS, polygenic risk scores (PRS) profiling and improved epilepsy sub-phenotype delineation, systematic investigation of compound heterozygous risk models and of pairwise epistasis as well as several approaches based on integration of transcriptional and epigenetic data. We will focus on generalized genetic epilepsies (GGEs) while also considering focal epilepsies (FEs) as well as developmental and epileptic encephalopathies (DEEs). Project P3 will share novel candidate loci with P1, P2 and the experimental projects P4-P8.