A genome-wide analysis of nearly 45,000 people has identified 16 regions of DNA associated with epilepsy, 11 of which are newly identified.

The International League Against Epilepsy (ILAE) Consortium on Complex Epilepsies did the analysis, which involved DNA from 15,212 people with epilepsy and 29,677 people without the condition. It is the largest study of its kind. The analysis was published in the Dec 10, 2018, issue of Nature Communications.

Most of these identified genes are associated with generalized epilepsy. The genes have diverse biological functions, including coding for ion-channel subunits, transcription factors, and a vitamin B6 metabolism enzyme. Compared with focal epilepsies, generalized epilepsies appear to have a stronger heritable component; however, fewer single genes have been implicated in generalized epilepsies.

After pinpointing the regions of DNA associated with epilepsy, the group used several criteria to identify the 21 most likely epilepsy-associated genes in 9 of the 11 new regions. Some of these genes have not been associated with epilepsy before. The genes are:

• Seven ion-channel genes (SCN1A, SCN2A, SCN3A, GABRA2, KCNN2, KCNAB1 and GRIK1)
• Three transcription factors (ZEB2, STAT4, and BCL11A)
• The histone modification gene BRD7
• The synaptic transmission gene STX1B
• The pyridoxine (vitamin B6) metabolism gene PNPO
• FANCL, implicated in Fanconi anemia and certain cancers
• PCDH7, which codes for a membrane protein thought to function in cell-cell recognition
• SLC33A1, which codes for the acetyl co-A transporter 1 protein
• GJA1, which codes for a connexin, a component of gap junctions
• TTC21B, HEATR3, ATXN1, and C3orf33

The group identified and analyzed 492 significant single nucleotide polymorphisms (SNPs) from all epilepsy phenotypes. SNPs are the most common type of genetic variation among people. Each SNP represents a difference in a single nucleotide. For example, a SNP may have a thymine replacing a cytosine in a certain stretch of DNA.

SNPs occur normally throughout the genome, mostly in stretches of DNA outside genes (intergenic), or in stretches within genes that are removed during transcription (intronic). SNPs occurring within a gene—or in a regulatory region near a gene—may play a direct role in a disease or condition.

In this study, most SNPs were either intergenic (29%) or intronic (46%). The group employed RegulomeDB, a database that matches SNPs with known and predicted sections of human DNA involved in regulating when genes are turned on and off. The database showed that about half of the epilepsy-related SNPs showed some evidence for affecting gene transcription.

The ILAE group also assessed whether the stretches of DNA identified in the analysis contained any SNPs that are known to “rev up” gene transcription in certain body tissues. Using data from the Roadmap Epigenomics Project, the group found a strong skew toward brain tissues for all epilepsy phenotypes, and a correlation between genetic generalized epilepsy and enhanced gene activity in the dorsolateral prefrontal cortex. This is an evolutionarily recent area of the brain, found only in humans and non-human primates. It is involved in working memory and attention span.

"Genetics is becoming increasingly important in the evaluation of people with epilepsy,” said Samuel Berkovic, director of the Epilepsy Research Centre at University of Melbourne and chair of the ILAE consortium. “The role of common variants has not been well established. This study shows that such common variants are indeed important, particularly in the generalized epilepsies, and is an important step forward toward a full understanding of the genetic architecture of epilepsies.”

Evidence from this study and others suggests that genetic generalized epilepsy could stem from epigenetic regulation of gene expression in the dorsolateral prefrontal cortex. “The agreement of the genetic findings from previous and independent electrophysiological, cognitive, and functional imaging studies was striking in implicating frontal lobe dysfunction in generalized epilepsy,” said Berkovic.

Using the BrainSpan database, the group found that genes associated with focal epilepsy were “powered up” in late infancy and young adulthood; genes associated with genetic generalized epilepsy were dampened or shut down in early childhood.

BrainSpan includes gene expression data from post-mortem brains of various ages, ranging from 8 weeks post-conception to 40 years. Data are available for more than 15 areas of the brain, including the hippocampus, amygdala, and striatum. Researchers can use the database to look up a gene and see when and where it’s expressed during development and aging.

The Connectivity Map, or CMap, is a library of gene expression profiles in cultured human cells treated with specific drugs or small molecules. It uses matching algorithms to show connections among drugs, genes, and diseases. CMap tools identified 30 drugs that are predicted to affect the expression of at least one of the identified genes. The drugs have shown anti-epileptic promise in animal models and are already licensed for the treatment of other human diseases. CMap is managed by The Broad Institute, a partnership between Harvard University and MIT. “This library provides a novel mechanism of discovering potentially new therapies for epilepsy, which would then need to undergo formal clinical trials,” said Berkovic.

The Consortium on Complex Epilepsies was established in 2011 with the idea that collaboration and synergy are better able to drive progress in the genetics of epilepsy, compared with individual groups of researchers. The group’s first publication occurred in 2014 in Lancet Neurology, and other studies are underway.

"An important role of the ILAE is to help bring together groups of researchers from around the globe to enhance collaboration. The remarkable achievement of the ILAE Consortium on Complex Epilepsies demonstrates the power of collaboration and data sharing in genetics research in epilepsy," said ILAE President Samuel Wiebe, professor of neurology at the University of Calgary.