Genome-Wide Association Study Reveals Genetic Architecture of Common Epilepsies.

Abstract

Epilepsy, affecting approximately 50 million individuals worldwide, exhibits a genetic heritability of 32%. While several genes/loci associated with epilepsy have been identified through candidate and genome-wide association studies (GWAS), exploration of population-specific markers remains underexplored. We conducted the first GWAS in north Indian population (~1500 samples) to identify genetic variants/loci associated with epilepsy risk, validated using targeted next-generation sequencing (NGS). Our GWAS revealed 30 variants across seven loci associated with epilepsy risk, including six novel loci. Subtype analysis based on etiology and seizure types, identified 57 variants across 11 loci, 10 of which are novel. Gene-set analysis unveiled enrichment in genes associated with glutathione synthesis and recycling and regulation of dopaminergic neuron differentiation pivotal in epilepsy pathophysiology. Furthermore, PRS analysis revealed a significant genetic contribution to the epilepsy with an R² of 0.00573. Additionally, targeted NGS showed ~95% concordance with GSA genotypes. Our study highlights six novel loci rs17031055/4q31.3(DCHS2), rs73182224/3q27.2(DGKG), rs9322462/6q25.2(CNKSR3), rs75328617/8q24.23(RNU1-35P), rs2938010/10q26.13(CTBP2) and rs11652575/17p11.2(SLC5A10) associated with epilepsy risk. These findings offer valuable insights into the genetic landscape of epilepsy in the north Indian population, providing foundation for future exploratory studies.