Progress in understanding the genetics of epilepsies

13.02.2019 | Epilepsy | Rare Neurological Diseases

Epilepsies affect around 65 million people worldwide and are clinically a heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsies, most probably due to relatively small sample sizes and insufficient power. In 2011, the International League Against Epilepsy (ILAE) launched the Consortium on Complex Epilepsies, to facilitate meta-analysis in epilepsy genomics. In 2014, the first such meta-analysis was reported comprising 8696 cases and 26,157 controls. This led to the identification of 2q24.3, 4p15.1, and 2p16.1 as epilepsy loci (1). Most recent study reported a genome-wide mega-analysis involving 15,212 individuals with epilepsies and 29,677 controls. It revealed 16 genome-wide significant loci, of which 11 were novel. Using various prioritization criteria, the study pinpointed the 21 most likely epilepsy genes at these loci, with the majority in idiopathic or "genetic" generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Moreover, the results showed there was substantial genetic correlation between the generalized syndromes. It is possible that the different subtypes share a large part of the genetic susceptibility for generalized epilepsies, with specific modifying factors determining the specific syndrome.In conclusion, increasing evidence indicates that the common variants associated with epilepsies play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Together, these findings give hope for epilepsy therapies based on underlying pathophysiology mechanisms.

1) International League Against Epilepsy Consortium on Complex Epilepsies. Electronic address: epilepsy-austin@unimelb.edu.au. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurol. 2014 Sep;13(9):893-903.

2) International League Against Epilepsy Consortium on Complex Epilepsies. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat Commun. 2018 Dec 10;9(1):5269.

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