Genome-wide association meta-analyses of drug-resistant epilepsy.

Authors

• Costin Leu
• Andreja Avbersek
• Remi Stevelink
• Helena Martins Custodio
• Siwei Chen
• Doug Speed
• Caitlin A Bennett
• Lina Jonsson
• Unnur Unnsteinsdóttir
• Andrea L Jorgensen
• Gianpiero L Cavalleri
• Norman Delanty
• John J Craig
• Chantal Depondt
• Michael R Johnson
• Bobby P C Koeleman
• Emadeldin Hassanin
• Maryam Erfanian Omidvar
• Roland Krause
• Holger Lerche
• Anthony G Marson
• Terence J O'Brien
• Josemir W Sander
• Graeme J Sills
• Pasquale Striano
• Federico Zara
• Hreinn Stefansson
• Kari Stefansson
• Patrick May
• Benjamin M Neale
• Dennis Lal
• Samuel F Berkovic
• Sanjay M Sisodiya

Publication/Presentation Date

5-1-2025

Abstract

BACKGROUND: Epilepsy is one of the most common neurological disorders, affecting over 50 million people worldwide. One-third of people with epilepsy do not respond to currently available anti-seizure medications, constituting one of the most important problems in epilepsy. Little is known about the molecular pathology of drug resistance in epilepsy, in particular, possible underlying genetic factors are largely unknown.

METHODS: We performed a genome-wide association study (GWAS) in two epilepsy cohorts of European ancestry, comparing drug-resistant (N = 4208) to drug-responsive individuals (N = 2618) followed by meta-analyses across the studies. Next, we performed subanalyses split into two broad subtypes: acquired or non-acquired focal and genetic generalized epilepsy.

FINDINGS: Our drug-resistant versus drug-responsive epilepsy GWAS meta-analysis showed no significant loci when combining all epilepsy types. Sub-analyses on individuals with focal epilepsy (FE) identified a significant locus on chromosome 1q42.11-q42.12 (lead SNP: rs35915186, P = 1·51 × 10

INTERPRETATION: We identified a contribution of common genetic variation to drug-resistant focal epilepsy. These findings provide insights into possible mechanisms underlying drug response variability in epilepsy, offering potential targets for personalised treatment approaches.

FUNDING: This work is part of the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 279062 (EpiPGX) and the Centers for Common Disease Genomics (CCDG) program, funded by the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI).

Volume

115

First Page

105675

Last Page

105675

ISSN

2352-3964

Published In/Presented At

Leu, C., Avbersek, A., Stevelink, R., Custodio, H. M., Chen, S., Speed, D., Bennett, C. A., Jonsson, L., Unnsteinsdóttir, U., Jorgensen, A. L., Cavalleri, G. L., Delanty, N., Craig, J. J., Depondt, C., Johnson, M. R., Koeleman, B. P. C., Hassanin, E., Omidvar, M. E., Krause, R., Lerche, H., … Sisodiya, S. M. (2025). Genome-wide association meta-analyses of drug-resistant epilepsy. EBioMedicine, 115, 105675. https://doi.org/10.1016/j.ebiom.2025.105675

Disciplines

Medicine and Health Sciences

PubMedID

40240269

Department(s)

Department of Medicine

Document Type

Article