A microRNA-328 binding site in PAX6 is associated with centrotemporal spikes of rolandic epilepsy

Objective: Rolandic epilepsy is a common genetic focal epilepsy of childhood characterized by centrotemporal sharp waves on electroencephalogram. In previous genome-wide analysis, we had reported linkage of centrotemporal sharp waves to chromosome 11p13, and fine mapping with 44 SNPs identified the ELP4-PAX6 locus in two independent US and Canadian case–control samples. Here, we aimed to find a causative variant for centrotemporal sharp waves using a larger sample and higher resolution genotyping array. Methods: We fine-mapped the ELP4-PAX6 locus in 186 individuals from rolandic epilepsy families and 1000 population controls of European origin using the Illumina HumanCoreExome-12 v1.0 BeadChip. Controls were matched to cases on ethnicity using principal component analysis. We used generalized estimating equations to assess association, followed up with a bioinformatics survey and literature search to evaluate functional significance. Results: Homozygosity at the T allele of SNP rs662702 in the 3′ untranslated region of PAX6 conferred increased risk of CTS: Odds ratio = 12.29 (95% CI: 3.20–47.22), P = 2.6 × 10⁻⁴ and is seen in 3.9% of cases but only 0.3% of controls. Interpretation: The minor T allele of SNP rs662702 disrupts regulation by microRNA-328, which is known to result in increased PAX6 expression in vitro. This study provides, for the first time, evidence of a noncoding genomic variant contributing to the etiology of a common human epilepsy via a posttranscriptional regulatory mechanism.