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Epilepsy GWAS Leads to New Loci, Potential Drug Targets

NEW YORK (GenomeWeb) – A new genome-wide association study by members of the "International League Against Epilepsy Consortium on Complex Epilepsies" has uncovered 16 new or known risk loci for common epilepsies, leading to a set of candidate epilepsy genes that included current drug targets.

"Discovering these new genes for epilepsy provides important information towards novel treatments for the condition," co-corresponding author Gianpiero Cavalleri, a researcher in the Department of Molecular and Cellular Therapeutics at the Royal College of Surgeons in Ireland (RCSI) and deputy director of the FutureNeuro Research Center, said in a statement.

The team's GWAS, based on array-based genotyping profiles for 15,212 individuals with epilepsy and 29,677 without, led to five loci implicated in epilepsy in the past, along with 11 loci not previously associated with the seizure condition. When the group focused on the 21 suspected epilepsy genes flagged by these risk variants, it saw an over-representation of genes involved in sodium ion channel, transcription factor, synaptic transmission, and other pathways.

"In addition to the biological insights provided by the findings, this study will encourage researchers to develop personalized and precision therapies for patients with difficult and complex epilepsy," co-author Norman Delanty, a consultant neurologist and researcher affiliated with RCSI, FutureNeuro, and Dublin's Beaumont Hospital, said in a statement. "This will provide better seizure control and will enable improved quality of life for patients and families."

The researchers explored the associations in more detail using a transcriptome-wide association study, expression quantitative trait locus information, Hi-C chromatin interaction, and other data. For example, they saw signs that a significant proportion of epilepsy risk variants overlap with histone marks influencing brain gene expression. Also, their results offered clues to the distinct shared and subtype-specific genetic factors contributing to the epilepsy subtypes considered in the study, which was published online yesterday in Nature Communications.

Broadly speaking, the epilepsy cases included in the team's "mega-analysis" spanned three disease types — focal epilepsy, genetic generalized epilepsy, and unclassified epilepsy — and seven subtypes, in individuals of European, Asian, or African American ancestry. Most of the risk loci identified showed ties to the genetic generalized form of the disease, though some additional associations turned up.

With the help of publicly available drug-gene target databases, the researchers saw that 13 of the two dozen anti-epileptic drugs that are used clinically today target at least one of the candidate genes identified in the study. Even so, they noted that another 166 more drugs showed potential ties to the GWAS genes, perhaps offering an avenue for future treatment strategies.

"The next steps would be expanding these results in an even larger sample, which is underway, and then drilling down on specific groups of patients and the genes that influence their type of epilepsy to trial new therapies," co-corresponding author Samuel Berkovic, a clinical neurologist and director of the University of Melbourne's Epilepsy Research Centre, said in a statement.