Large international study discovers 11 new epilepsy genes

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.

Abstract

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy 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. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.

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Epilepsy is a common neurological condition with a controversial past. The cause was unknown and often shrouded in mystery. We now understand that the cause is largely genetic, however, little is known about the specific genes responsible for the most common forms of the disorder. This is particularly important when we consider that a third of the 65 million patients worldwide will not become seizure free using current treatment options. To find new epilepsy genes, a large study was undertaken by more than 150 researchers from multiple centres in the UK, Europe, USA, Brazil, Hong Kong and Australia as part of the International League Against Epilepsy Consortium on Complex Epilepsies.

The DNA of more than 15,000 people with epilepsy was compared to the DNA of 30,000 healthy controls. The results tripled the number of known genetic associations for epilepsy and importantly implicated 11 new genes. These genes have a number of different functions in the human body, including regulating signal transduction between brain cells, converting vitamin-B6 into its active form, and controlling expression of genes in the brain. The researchers found that the majority of current anti-epileptic drugs directly target one or more of the associated genes and identified an additional 166 drugs that do the same. These drugs are promising new candidates for epilepsy therapy as they directly target the genetic basis of the disease. With these findings, the researchers hope that in the future more people with epilepsy will achieve seizure freedom.

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