Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study

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Stefan Wolking , Herbert Schulz, Anne T Nies, Mark McCormack, Elke Schaeffeler, Pauls Auce, Andreja Avbersek, Felicitas Becker, Karl M Klein, Martin Krenn, Rikke S Møller, Marina Nikanorova, Sarah Weckhuysen, EpiPGx Consortium‡, Gianpiero L Cavalleri, Norman Delanty, Chantal Depondt, Michael R Johnson, Bobby PC Koeleman, Wolfram S Kunz, Anthony G Marson, Josemir W Sander, Graeme J Sills, Pasquale Striano, Federico Zara, Fritz Zimprich, Yvonne G Weber, Roland Krause , Sanjay Sisodiya, Matthias Schwab, Thomas Sander & Holger Lerche

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.


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