Abstracts

Rationale: The preferential association of febrile convulsions (FC) with epilepsy remains unclear. Although there is a significant association between a febrile convulsion in early childhood and epilepsy, the contradictory findings also indicate a complex relationship of genetic and environmental factors. And some genes have been identified for some epilepsy syndromes, but genetic risk factors for the relevance to FC with epilepsy have been elusive. We aimed to identify risk loci through meta-analysis of genome-wide association studies (GWAS) among epilepsy patients with a history of FC.

Methods: We obtained the data of 125 epilepsy patients from epilepsy clinic in Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. All subjects were of Korean descent. Of 125 subjects, 28 epilepsy patients with a history of FC (case) and 97 epilepsy patients without a history of FC (control) were analyzed in our study. We explored associations between a history of febrile convulsions and single nucleotide polymorphisms (SNPs) through samples. We analyzed genome-wide association data of all samples with the GeneChip Human Mapping 500K Array Set (Affymetrix) using the standard protocol recommended by the manufacturer. Quality control and association analyses for our data were performed using the PLINK software. We imputed the genotypes of 28 case patients and 97 control subjects passing stringent quality control filters using IMPUTE2. In total, 288,394 SNPs with an estimated imputation accuracy of >0.95 and minor allele frequency (MAF) of >0.01 were included in the association analysis.

Results: Of the 23 candidate SNPs, 2 SNPs (rs6438756, rs496892) with P< 1x10^-4 were excluded, and 21 SNPs were included in the replication study. Finally, based on a significance value of less than 0.05 in the replication stage, we identified the one susceptible locus associated with FC and epilepsy: rs7554295 (P=2.2 x 10^-5) on 1q24. The rs7554295 locus was located near LINC00538/PROX1 which was replicated in an independent cohort.

Conclusions: Overall, our findings support the proposition that a history of febrile convulsions with implications for our understanding of the preferential association with epilepsy. Though little is known about the functions of mentioned genes in the brain, they may suggest that specific loci can act pleiotropically raising risk for epilepsy broadly, or can have effects limited to a specific. For example, as PROX1 is known as a critical intrinsic regulator of neurogenesis in the dentate gyrus of the hippocampus, it may be a good candidate marker for predicting relevance between FC and epilepsy. Future genetic analyses might benefit from both lumping (i.e., grouping of epilepsy types together) or splitting (i.e., analysis of specific clinical subtypes).

Funding: Please list any funding that was received in support of this abstract.: None.