CHOP Experts Help Discover 11 Genes Newly Linked to Epilepsy

Children’s Hospital of Philadelphia (CHOP) scientists participated in a large international research consortium to discover and analyze genetic influences on common forms of epilepsy. The findings may provide useful leads for future precision-medicine based therapies to help control seizures in children and adults.

Over 150 researchers from five continents contributed to the study by the International League Against Epilepsy Consortium on Complex Epilepsies (ILAE Consortium), which published its results Dec. 10, 2018, in Nature Communications.

The co-corresponding authors of the paper were Gianpero Cavellari, PhD, of the Royal College of Surgeons in Ireland, and Samuel F. Berkovic, MD, of the Epilepsy Research Centre at the University of Melbourne, Australia. The ILAE consortium performed a genome-wide association study (GWAS), comparing DNA from 15,000 patients with epilepsy to DNA from 30,000 healthy control subjects, to discover genetic locations linked to epilepsy risk. The DNA, from 24 different cohorts, came from Caucasian, Asian and African-American populations.

Hakon Hakonarson, MD, PhD Of the 24 collections of DNA, the largest group was the Philadelphia Cohort, led by CHOP. That cohort contributed DNA from 1,734 cases and 9,337 controls, drawn from Caucasian and African-American populations recruited by the Center for Applied Genomics (CAG) at CHOP. “This study illustrates the importance of multicenter consortia,” said co-author Hakon Hakonarson, MD, PhD, Director of the CAG. “No individual cohort would provide enough samples with the statistical power to find associations such as you can obtain from this mega-analysis with tens of thousands of samples.”

Study findings

The genome-wide study revealed 16 significant loci, 11 of which had not previously been associated with epilepsy. These risk loci were common variants, and the majority were associated with genetic generalized epilepsy. These risk variants led the researchers to 21 candidate genes most likely to have a role in epilepsy. The study team identified various biological functions among those genes, such as regulating signal transmission between brain cells, metabolizing vitamin-B6, and controlling gene expression in the brain.

Ingo Helbig, MD The researchers found that 13 out of 24 currently licensed anti-epilepsy drugs target genes that were implicated in the current study. Notably, they identified 166 other known drugs that target some of their candidate genes, offering the potential to identify further targets for epilepsy treatments. “Studies at this scale allow us to better understand biological mechanisms that we are not aware of yet,” said study co-author Ingo Helbig, MD, an attending physician and epilepsy genetics researcher in CHOP’s Neurogenetics Program. “This will be important in finding pathways to target with new medications.”

About epilepsy

Epilepsy is one of the most common neurological disorders in children and adults, and CHOP is the regional leader in the Pennsylvania-New Jersey-Delaware area in treating children with epilepsy. “Up to 30 percent of children with epilepsy have difficult-to-treat seizures in which new strategies are urgently needed,” said co-author Dennis Dlugos, MD, Director of CHOP’s Pediatric Epilepsy Program. “It is our hope that this new knowledge will help researchers to develop targeted therapies to control seizures in the future. This is an area of active development.”

Additional resources

Multiple grants, from the National Institutes of Health, several European research ministries, and private foundations, supported this research.

International League Against Epilepsy Consortium on Complex Epilepsies, “Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies,” Nature Communications, published online Dec. 10, 2018.  

Also see the posting by Helbig on this study on Beyond the Ion Channel, the official blog of the Genetics Commission of the International League Against Epilepsy.