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Largest study of its kind reveals risk genes for epilepsy development

Over 50 million people worldwide are currently living with epilepsy. However, one third of patients are resistant to common antiseizure medications. A new study published in Nature Genetics combines research from 150 groups worldwide to establish the key genes involved in epilepsy development, providing opportunities to repurpose existing drugs for use in its treatment.

The largest study of its kind

Epilepsy is generally characterised by its debilitating seizures, although a number of subtypes with varying symptoms exist, which are clinically defined by deep phenotyping. As is the case for other common neurodevelopmental disorders, epilepsy is linked to genetic variations. Specific gene variations can be linked to each subtype, but only a limited number of identifiable genes have been found so far.

To determine which genes could be involved in epilepsy development, researchers from around the world completed the largest complex epilepsy-based genome-wide association study (GWAS) meta-analysis to date, as part of the International League Against Epilepsy (ILAE) Consortium. This study compared 29,944 deeply phenotyped cases to 52,538 healthy controls, doubling previous sample sizes in this type of study.

Key genes

The study uncovered 26 common epilepsy risk loci, 16 of which had not been previously reported. Genetic generalized epilepsy (GGE) was found to have the strongest contribution from genetic variation, with 19 of these risk loci specific to this type of disease. The results also suggested notable differences in genetic architecture between the focal (within one area of the brain) and generalised (in both sides of the brain) forms of epilepsy. Using further post-GWAS analysis methods, 29 individual key epilepsy development genes were identified.

“This identification of epilepsy-associated genetic changes will allow us to improve diagnosis and classification of different epilepsy subtypes” said Professor Colin Doherty, Consultant Neurologist at St James’s Hospital, co-author of the paper and clinical investigator at the SFI FutureNeuro Centre based in Dublin, Ireland. “This in turn will guide clinicians in selecting the most beneficial treatment strategies, minimising seizures.”

Repurposing existing medications

Antiseizure medications are generally used to treat epilepsy. However, despite 25 treatments being licenced around the world, many patients are resistant and continue to experience seizures. Surgery, neuromodulation and changes in diet are currently recommended in these cases; however, if an understanding of a patient’s specific genetic variations could be established, other medicines that target key epilepsy genes, but are not usually used to treat the condition, could be recommended.

Using the study results, researchers were able to highlight epilepsy genes that are targeted by drugs licenced for other conditions, which could be beneficial for patients who are resistant to antiseizure medications. For example, CACNA2D2, a calcium voltage-gated channel encoding and established epileptic encephalopathy gene, is directly targeted by 10 currently licensed drugs, including the Parkinson’s disease drug safinamide and the nonsteroidal anti-inflammatory drug celecoxib, both of which have evidence of antiseizure activity.

Taken together, this study reveals significant differences in the genetic architecture of epilepsy subtypes. Characterising the genetic variation in epileptic patients could therefore provide opportunities to identify and repurpose existing drugs originally designed for other diseases, increasing the potential for effective treatment.

More on these topics

Epilepsy / epilepsy drugs / GWAS