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.

Integrative analysis of epilepsy-associated genes reveals expression-phenotype correlations

“…Lastly, genetic mosaicism has been increasingly recognized to contribute to phenotypic diversity in human diseases, including epilepsy 49 , 50 . Genetic mosaicism refers to the accumulation of somatic mutations in the genome that arise during the developing stages after gametogenesis.…”

A concerted neuron–astrocyte program declines in ageing and schizophrenia

“…We used summary statistics from the following studies in Supplementary Fig. 12 : ADHD 112 , ALS 113 , Alzheimer’s disease 114 , age of smoking initiation 115 , autism 116 , bipolar disorder (all, type I, and type II) 117 , cigarettes per day 115 , educational attainment 118 , epilepsy (all, focal, generalized) 119 , height 120 , IQ 121 , insomnia 122 , neuroticism 123 , OCD 124 , schizophrenia 22 , PTSD 125 , risk 126 , subjective well-being 127 , smoking cessation 115 , smoking initiation 115 , Tourette’s 128 and ulcerative colitis 129 .…”

Idiopathic Generalized Epilepsy

“…A large genome-wide association study identified 22 “IGE” loci. 10 Complex inheritance underlies many heritable human traits, such as height, but can create an illusion of understanding. Most cases with IGE have no known cause, and attribution to multiple genes is likely in many cases, but remains unproven, and can minimize consideration of other mechanisms.…”