GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Abstract

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

Fig. 1. Manhattan plot of multi-ancestry all epilepsy (n = 29,944), focal epilepsy (n = 16,384) and genetic generalized epilepsy (n = 7,407) genome-wide meta-analyses, obtained by fixed-effects meta-analysis weighted by effective sample sizes.

The red line shows the genome-wide significance threshold (5 × 10⁻⁸). Chromosome and position are displayed on the x axis, and two-sided −log₁₀ P value is on the y axis. New genome-wide significant loci are highlighted in red, and loci previously associated with epilepsy in orange. New loci were those previously unreported as GWAS significant in previous epilepsy GWASs. Annotated genes are those implicated by our gene prioritization analyses. See Supplementary Fig. 7 for QQ plots. QQ plots, quantile–quantile plot.

Fig. 2. Genetic correlations of epilepsy with other phenotypes.

The genetic correlation coefficient was calculated with LDSC and is denoted by color scale from −1 (red; negatively (anti-)correlated) to +1 (blue; positively correlated). The square size relates to the absolute value of the corresponding correlation coefficient. Single asterisk indicates two-sided P < 0.05 and double asterisk indicates two-sided P < 0.0009 (Bonferroni corrected). Source data