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GWAS Meta-Analysis Identifies 26 Risk Loci Linked to Epilepsy

NEW YORK A genome-wide association study (GWAS) meta-analysis by several international research teams has identified 26 risk loci and subtype-specific genetic architecture linked to epilepsy.

To uncover the variants associated with the condition, investigators from the International League Against Epilepsy Consortium, founded in 1909, conducted a meta-analysis on complex epilepsies, including 29,944 cases recruited from tertiary referral centers and 52,538 controls.

Common and rare genetic variations contribute to milder and common focal epilepsies (FE) and generalized epilepsies. This is especially true for generalized epilepsy mainly constituted by genetic generalized epilepsy (GGE), and previous studies have revealed only a few of these variants, the authors noted.

The researchers combined their previously published analyses with unpublished data from the Epi25 collaborative and four additional cohorts. The findings were published in Nature Genetics on Thursday, with the authors noting that the new analysis contained double the previous sample size.

In the post-GWAS analysis, the researchers focused on 29 genes linked to the newly identified risk loci using previously published tools such as FUMA and MAGMA. Many of these were monogenic epilepsy genes, including the calcium channel gene CACNA2D2, which is already the target of ten licensed drugs, including two antiseizure medications (gabapentin and pregabalin), the Parkinson's disease drug safinamide, and the nonsteroidal anti-inflammatory drug celecoxib, the authors noted.

Further gene-set analyses of GGE signals implicated synaptic processes in both excitatory and inhibitory neurons in the brain and the pituitary, suggesting a hormonal component to seizure susceptibility. The involvement of excitatory and inhibitory neurons was a contrast to other neurological diseases which typically involve multiple cell types, such as astrocytes, oligodendrocytes, or microglia.

The researchers also used their analysis to identify drugs that can be repurposed for epilepsy. This assessment was based on the predicted ability of each drug to modulate epilepsy-related changes in the function and abundance of proteins. Their results highlighted 20 drugs that are licensed for other conditions but may show benefits to generalized epilepsy, which will need to be clinically tested in the future.

Meanwhile, in their final experiment, the authors used data from several large-scale population biobanks and Decode Genetics to explore the consistency of the epilepsy loci in cohorts that were less intensely phenotyped. This did not substantially increase the signal despite almost doubling the sample size.

Of note was that GGE had a strong contribution from shared genetic variation, whereas FEs had only a minor contribution of common variants, with no variant reaching genome-wide significance. The authors believe focal epilepsies are more heterogeneous than GGE and may have a higher degree of polygenicity and likely lower contribution of common heritable risk variation.

"Our findings shed light on the enigmatic biology of generalized epilepsy and the importance of accurate syndromic phenotyping and may facilitate drug repurposing for new therapeutic approaches," they concluded.

Highlighting the limitations, the researchers noted that the biobank cases were phenotyped mostly based on the International Classification of Diseases codes, which could have led to misclassification.