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

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

doi:10.2217/pgs-2019-0179

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

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 KunzAnthony 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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	325-335
Number of pages	11
Journal	Pharmacogenomics
Volume	21
Issue number	5
DOIs	https://doi.org/10.2217/pgs-2019-0179
Publication status	Published - Apr 2020

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Wolking, S., Schulz, H., Nies, A. T., McCormack, M., Schaeffeler, E., Auce, P., Avbersek, A., Becker, F., Klein, K. M., Krenn, M., Møller, R. S., Nikanorova, M., Weckhuysen, S., Consortium, EG., Cavalleri, G. L., Delanty, N., Depondt, C., Johnson, M. R., Koeleman, B. P., ... Lerche, H. (2020). Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study. Pharmacogenomics, 21(5), 325-335. https://doi.org/10.2217/pgs-2019-0179

Pharmacoresponse in genetic generalized epilepsy : a genome-wide association study. / Wolking, Stefan; Schulz, Herbert; Nies, Anne T; McCormack, Mark; Schaeffeler, Elke; Auce, Pauls; Avbersek, Andreja; Becker, Felicitas; Klein, Karl M; Krenn, Martin; Møller, Rikke S; Nikanorova, Marina; Weckhuysen, Sarah; Consortium, EpiPGx; Cavalleri, Gianpiero L; Delanty, Norman; Depondt, Chantal; Johnson, Michael R; Koeleman, Bobby Pc; Kunz, Wolfram S; Marson, Anthony G; Sander, Josemir W; Sills, Graeme J; Striano, Pasquale ; Zara, Federico; Zimprich, Fritz; Weber, Yvonne G; Krause, Roland; Sisodiya, Sanjay; Schwab, Matthias; Sander, Thomas; Lerche, Holger.

In: Pharmacogenomics, Vol. 21, No. 5, 04.2020, p. 325-335.

Research output: Contribution to journal › Article › peer-review

Wolking, S, Schulz, H, Nies, AT, McCormack, M, Schaeffeler, E, Auce, P, Avbersek, A, Becker, F, Klein, KM, Krenn, M, Møller, RS, Nikanorova, M, Weckhuysen, S, Consortium, EG, Cavalleri, GL, Delanty, N, Depondt, C, Johnson, MR, Koeleman, BP, Kunz, WS, Marson, AG, Sander, JW, Sills, GJ, Striano, P , Zara, F, Zimprich, F, Weber, YG, Krause, R, Sisodiya, S, Schwab, M, Sander, T & Lerche, H 2020, 'Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study', Pharmacogenomics, vol. 21, no. 5, pp. 325-335. https://doi.org/10.2217/pgs-2019-0179

Wolking, Stefan ; Schulz, Herbert ; Nies, Anne T ; McCormack, Mark ; Schaeffeler, Elke ; Auce, Pauls ; Avbersek, Andreja ; Becker, Felicitas ; Klein, Karl M ; Krenn, Martin ; Møller, Rikke S ; Nikanorova, Marina ; Weckhuysen, Sarah ; Consortium, EpiPGx ; Cavalleri, Gianpiero L ; Delanty, Norman ; Depondt, Chantal ; Johnson, Michael R ; Koeleman, Bobby Pc ; Kunz, Wolfram S ; Marson, Anthony G ; Sander, Josemir W ; Sills, Graeme J ; Striano, Pasquale ; Zara, Federico ; Zimprich, Fritz ; Weber, Yvonne G ; Krause, Roland ; Sisodiya, Sanjay ; Schwab, Matthias ; Sander, Thomas ; Lerche, Holger. / Pharmacoresponse in genetic generalized epilepsy : a genome-wide association study. In: Pharmacogenomics. 2020 ; Vol. 21, No. 5. pp. 325-335.

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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.",

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

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AU - Wolking, Stefan

AU - Schulz, Herbert

AU - Nies, Anne T

AU - McCormack, Mark

AU - Schaeffeler, Elke

AU - Auce, Pauls

AU - Avbersek, Andreja

AU - Becker, Felicitas

AU - Klein, Karl M

AU - Krenn, Martin

AU - Møller, Rikke S

AU - Nikanorova, Marina

AU - Weckhuysen, Sarah

AU - Consortium, EpiPGx

AU - Cavalleri, Gianpiero L

AU - Delanty, Norman

AU - Depondt, Chantal

AU - Johnson, Michael R

AU - Koeleman, Bobby Pc

AU - Kunz, Wolfram S

AU - Marson, Anthony G

AU - Sander, Josemir W

AU - Sills, Graeme J

AU - Striano, Pasquale

AU - Zara, Federico

AU - Zimprich, Fritz

AU - Weber, Yvonne G

AU - Krause, Roland

AU - Sisodiya, Sanjay

AU - Schwab, Matthias

AU - Sander, Thomas

AU - Lerche, Holger

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N2 - 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.

AB - 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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SN - 1462-2416

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

Abstract

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