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

Stefan Wolking^{1

2}, Herbert Schulz³, Anne T Nies^{4

5}, Mark McCormack⁶, Elke Schaeffeler^{4

5}, Pauls Auce⁷, Andreja Avbersek⁸, Felicitas Becker¹, Karl M Klein⁹, Martin Krenn¹⁰, Rikke S Møller^{11

12}, Marina Nikanorova¹¹, Sarah Weckhuysen^{13

14

15}, EpiPGx Consortium, Gianpiero L Cavalleri^{6

16}, Norman Delanty^{6

17

18}, Chantal Depondt¹⁹, Michael R Johnson¹⁶, Bobby Pc Koeleman²⁰, Wolfram S Kunz²¹, Anthony G Marson²², Josemir W Sander^{8

23}, Graeme J Sills²², Pasquale Striano^{24

25}, Federico Zara²⁶, Fritz Zimprich¹⁰, Yvonne G Weber¹, Roland Krause²⁷, Sanjay Sisodiya⁸, Matthias Schwab^{4

28

29}, Thomas Sander³, Holger Lerche¹

Affiliations

¹ Department of Neurology & Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
² Department of Neurosciences, CHUM Research Center, University of Montreal, Montreal, H2X 0A9, Canada.
³ Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
⁴ Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.
⁵ University of Tübingen, 72076 Tübingen, Germany.
⁶ Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, D02 YN77, Ireland.
⁷ Walton Centre NHS Foundation Trust, Liverpool, L33 4YD, UK.
⁸ Department of Clinical & Experimental Epilepsy, UCL Queen Square Institute of Neurology, London & Chalfont Centre for Epilepsy, London, SL9 0RJ, UK.
⁹ Epilepsy Center Frankfurt Rhine-Main, University Hospital Frankfurt, Goethe University Frankfurt, 60590 Frankfurt, Germany.
¹⁰ Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria.
¹¹ Danish Epilepsy Centre - Filadelfia, 4293 Dianalund, Denmark.
¹² Department of Regional Health Research, University of Southern Denmark, 5000 Odense, Denmark.
¹³ Neurogenetics Group, Center for Molecular Neurology, VIB-University of Antwerp, 2650 Edegem, Belgium.
¹⁴ Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2650 Edegem, Belgium.
¹⁵ Department of Neurology, Antwerp University Hospital, 2650 Edegem, Belgium.
¹⁶ Division of Brain Sciences, Imperial College Faculty of Medicine, London, SW2 2AZ, UK.
¹⁷ Division of Neurology, Beaumont Hospital, Dublin 9, Ireland.
¹⁸ The FutureNeuro Research Centre, Royal College of Surgeons in Ireland, Dublin, D02 YN77, Ireland.
¹⁹ Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium.
²⁰ Department of Genetics, University Medical Center Utrecht, 3584 Utrecht, The Netherlands.
²¹ Institute of Experimental Epileptology & Cognition Research & Department of Epileptology, University of Bonn, 53127 Bonn, Germany.
²² Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 7ZB, UK.
²³ Stichting Epilepsie Instellingen Nederland (SEIN), 2103 Heemstede, The Netherlands.
²⁴ Pediatric Neurology & Muscular Diseases Unit, IRCCS 'G. Gaslini' Institute, 16147 Genova, Italy.
²⁵ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal & Child Health, University of Genova, 16147 Genova, Italy.
²⁶ Laboratory of Neurogenetics and Neuroscience, IRCCS 'G. Gaslini' Institute, 16147 Genova, Italy.
²⁷ Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg.
²⁸ Department of Clinical Pharmacology, University Hospital Tübingen, 72076 Tübingen, Germany.
²⁹ Department of Pharmacy & Biochemistry, University Tübingen, 72076 Tübingen, Germany.

PMID: 32308125
DOI: 10.2217/pgs-2019-0179

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

Stefan Wolking et al. Pharmacogenomics. 2020 Apr.

. 2020 Apr;21(5):325-335.

doi: 10.2217/pgs-2019-0179. Epub 2020 Apr 20.

Authors

Affiliations

¹ Department of Neurology & Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
² Department of Neurosciences, CHUM Research Center, University of Montreal, Montreal, H2X 0A9, Canada.
³ Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
⁴ Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.
⁵ University of Tübingen, 72076 Tübingen, Germany.
⁶ Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, D02 YN77, Ireland.
⁷ Walton Centre NHS Foundation Trust, Liverpool, L33 4YD, UK.
⁸ Department of Clinical & Experimental Epilepsy, UCL Queen Square Institute of Neurology, London & Chalfont Centre for Epilepsy, London, SL9 0RJ, UK.
⁹ Epilepsy Center Frankfurt Rhine-Main, University Hospital Frankfurt, Goethe University Frankfurt, 60590 Frankfurt, Germany.
¹⁰ Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria.
¹¹ Danish Epilepsy Centre - Filadelfia, 4293 Dianalund, Denmark.
¹² Department of Regional Health Research, University of Southern Denmark, 5000 Odense, Denmark.
¹³ Neurogenetics Group, Center for Molecular Neurology, VIB-University of Antwerp, 2650 Edegem, Belgium.
¹⁴ Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2650 Edegem, Belgium.
¹⁵ Department of Neurology, Antwerp University Hospital, 2650 Edegem, Belgium.
¹⁶ Division of Brain Sciences, Imperial College Faculty of Medicine, London, SW2 2AZ, UK.
¹⁷ Division of Neurology, Beaumont Hospital, Dublin 9, Ireland.
¹⁸ The FutureNeuro Research Centre, Royal College of Surgeons in Ireland, Dublin, D02 YN77, Ireland.
¹⁹ Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium.
²⁰ Department of Genetics, University Medical Center Utrecht, 3584 Utrecht, The Netherlands.
²¹ Institute of Experimental Epileptology & Cognition Research & Department of Epileptology, University of Bonn, 53127 Bonn, Germany.
²² Department of Molecular & Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 7ZB, UK.
²³ Stichting Epilepsie Instellingen Nederland (SEIN), 2103 Heemstede, The Netherlands.
²⁴ Pediatric Neurology & Muscular Diseases Unit, IRCCS 'G. Gaslini' Institute, 16147 Genova, Italy.
²⁵ Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal & Child Health, University of Genova, 16147 Genova, Italy.
²⁶ Laboratory of Neurogenetics and Neuroscience, IRCCS 'G. Gaslini' Institute, 16147 Genova, Italy.
²⁷ Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg.
²⁸ Department of Clinical Pharmacology, University Hospital Tübingen, 72076 Tübingen, Germany.
²⁹ Department of Pharmacy & Biochemistry, University Tübingen, 72076 Tübingen, Germany.

PMID: 32308125
DOI: 10.2217/pgs-2019-0179

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.

Keywords: GWAS; antiepileptic drugs; genetic generalized epilepsy; lamotrigine; levetiracetam; pharmacoresistance; valproic acid.

PubMed Disclaimer

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources