Abstracts

Rationale: Genome-wide association studies (GWAS) in epilepsy and the two largest clinical subgroups - genetic generalized epilepsy (GGE) and focal epilepsy - have had only limited success in identifying risk loci. The largest GWAS in epilepsy up to date, comprising 8,696 individuals with epilepsy and 26,157 controls, identified two susceptibility loci shared by all epilepsies, one susceptibility locus for genetic generalized epilepsy, and no association signal for focal epilepsy. Methods: Here we report a new large-scale genome-wide meta-analysis in epilepsy in the largely independent Epi25 cohort, currently the largest sequencing project in the epilepsies, with 14,671 sequenced and genotyped epilepsy samples. Results: In the European subsample of the Epi25 cohort comprising 10,497 individuals with epilepsy and 15,610 controls, we replicated the susceptibility locus for all epilepsies at 4p15.1 in proximity to PCDH7 (rs4692500, P=2.2*10^-11), and a previously replicated susceptibility locus for GGE at 2p16.1 in a 706kb region encompassing VRK2 and FANCL (rs2717004, P=2.0*10^-9). In addition, we identified three credible new susceptibility loci at 5q22.1 near NREP (rs112832534, P=4.2*10^-8), 16p12.1 near TNRC6A (rs2112783, P=1.7*10^-8), and 19q13.33 near GLTSCR1 (rs2914006, P=2.2*10^-8). Subgroup analysis identified two new susceptibility loci for GGE at 2q12.1 in proximity to TMEM182 (rs1379430, P=7.7*10^-12), and at 12q13.13 near ACVR1B (rs114131287, P=1.6*10^-12). Conclusions: Consistent to previous results, no genome-wide significant association signal could be observed for focal epilepsy. Our study provides further insights on the shared etiology of all common epilepsies, despite clinically different manifestations. We further provide additional evidence for a significant genotypic and phenotypic heterogeneity of the focal epilepsies, and a challenge for improvement of the actual clinical classification. Funding: NIH funded.