Pharmacoresponse in Genetic Generalized Epilepsy: A Genome-Wide Association Study
Stefan Wolking, Herbert Schulz, Anne T. Nies, Mark McCormack, Elke Schaeffeler, Pauls Auce, Andreja Avberšek, Felicitas Becker, Karl Martin Klein, Martin Krenn, Rikke S. Møller, Marina Nikanorova, Sarah Weckhuysen, EpiPGx Consortium, Gianpiero L. Cavalleri, Norman Delanty, Chantal Depondt, Michael R. Johnson, Bobby P.C. Koeleman, Wolfram S. Kunz, Anthony G Marson, Josemir W. Sander, Graeme J. Sills, Pasquale Striano, Federico Zara, Fritz Zimprich, Yvonne Weber, Roland Krause, Sanjay M. Sisodiya, Matthias Schwab, Thomas Sander, Holger Lerche
Abstract
Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials & methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE – responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10-5) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.