Genome‐wide association study of epilepsy in a Japanese population identified an associated region at chromosome 12q24

Abstract

Objective: Although a number of genes responsible for epilepsy have been identified through Mendelian genetic approaches, and genome-wide association studies (GWASs) have implicated several susceptibility loci, the role of ethnic-specific markers remains to be fully explored. We aimed to identify novel genetic associations with epilepsy in a Japanese population. Methods: We conducted a GWAS on 1825 patients with a variety of epilepsies and 7975 control individuals. Expression quantitative trait locus (eQTL) analysis of epilepsy-associated single nucleotide polymorphisms (SNPs) was performed using Japanese eQTL data. Results: We identified a novel region, which is ~2 Mb (lead SNP rs149212747, p = 8.57 × 10 −10 ), at chromosome 12q24 as a risk for epilepsy. Most of these loci were polymorphic in East Asian populations including Japanese, but monomorphic in the

CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate

“…Therefore, the CUX2 recurrent variant in EEs may not be enough to explain the genome-wide association with epilepsy at the 12q24 region in Japanese population. In our GWAS study 5 , sub-analyses for subtypes of epilepsies further revealed that a polymorphic marker at the 12q24 epilepsy-associated region showed genome-wide significant association with structural/metabolic epilepsy. Hippocampal sclerosis is the major entity for structural/metabolic epilepsy, and therefore the CUX2 variants in patients with TLE would contribute to the association with epilepsy at 12q24 in Japanese population.…”

“…All of these patients with CUX family variants showed symptoms of epileptic seizures, suggesting that the variants may contribute to the threshold for the triggering epileptic seizures through a facilitation of excitatory synaptic transmission from entorhinal cortex to hippocampus in epilepsies caused by CUX family variants. Our recent GWAS analysis of Japanese patients with variable epilepsies identified a region with genome-wide significance at chromosome 12q24 which harbors CUX2 5 . Although a recurrent de novo CUX2 variant p.E590K has been described in patients with EEs 6 , 7 , a previous whole exome sequencing study for Japanese patients with EEs 17 did not find the CUX2 pathogenic variant.…”

“…For the frequency calculation of c.3847G>A (p.E1283K) variant in CUX2 gene, additional DNA samples from independent 69 Japanese patients with TLE from 2 additional independent facilities were further recruited (Table S1 ). The patients' DNAs analyzed in our GWAS 5 were not used in the present study, because their epilepsy subtype information [TLE, etc.] were not available for those materials.…”

“…CUX2 controls neuronal proliferation, dendrite branching, spine morphology and synapse formation 3 , 4 . We recently reported a genome-wide association study (GWAS) on 1825 Japanese patients with variable epilepsies which identified an associated region at chromosome 12q24.11–12q24.13 harboring 24 transcripts including CUX2 gene 5 . In the region, CUX2 is only gene which has been reported to be relevant for epilepsy; a recurrent de novo variant (c.1768G>A, p.E590K) has been identified in patients with rare epileptic encephalopathies (EEs) 6 , 7 .…”

CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate

“…CUX2 controls neuronal proliferation, dendrite branching, spine morphology and synapse formation 3,4 . We recently reported a genome-wide association study (GWAS) on 1,825 Japanese patients with variable epilepsies which identified an associated region at chromosome 12q24.11 – 12q24.13 harboring 24 transcripts including CUX2 gene 5 . In the region, CUX2 is only gene which has been reported to be relevant for epilepsy; a recurrent de novo variant (c.1768G>A, p.E590K) has been identified in patients with rare epileptic encephalopathies (EEs) 6,7 .…”