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

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 European population. This region harbors 24 transcripts including genes expressed in the brain such as CUX2, ATXN2, BRAP, ALDH2, ERP29, TRAFD1, HECTD4, RPL6, PTPN11, and RPH3A. The eQTL analysis revealed that the associated SNPs are also correlated to differential expression of genes at 12q24. Significance: These findings suggest that a gene or genes in the CUX2-RPH3A ~2-Mb region contribute to the pathology of epilepsy in the Japanese population.