Stefan Wolking1,2, Herbert Schulz3, Anne T Nies4,5, Mark McCormack6, Elke Schaeffeler4,5, Pauls Auce7, Andreja Avbersek8, Felicitas Becker1, Karl M Klein9, Martin Krenn10, Rikke S Møller11,12, Marina Nikanorova11, Sarah Weckhuysen13,14,15, EpiPGx Consortium, Gianpiero L Cavalleri6,16, Norman Delanty6,17,18, Chantal Depondt19, Michael R Johnson16, Bobby Pc Koeleman20, Wolfram S Kunz21, Anthony G Marson22, Josemir W Sander8,23, Graeme J Sills22, Pasquale Striano24,25, Federico Zara26, Fritz Zimprich10, Yvonne G Weber1, Roland Krause27, Sanjay Sisodiya8, Matthias Schwab4,28,29, Thomas Sander3, Holger Lerche1. 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.
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.
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.
Authors: Laith N Al-Eitan; Islam M Al-Dalala; Afrah K Elshammari; Wael H Khreisat; Aseel F Nimiri; Adan H Alnaamneh; Hanan A Aljamal; Mansour A Alghamdi Journal: Pharmgenomics Pers Med Date: 2020-10-16
Authors: Stefan Wolking; Claudia Moreau; Mark McCormack; Roland Krause; Martin Krenn; Samuel Berkovic; Gianpiero L Cavalleri; Norman Delanty; Chantal Depondt; Michael R Johnson; Bobby P C Koeleman; Wolfram S Kunz; Holger Lerche; Anthony G Marson; Terence J O'Brien; Slave Petrovski; Josemir W Sander; Graeme J Sills; Pasquale Striano; Federico Zara; Fritz Zimprich; Sanjay M Sisodiya; Simon L Girard; Patrick Cossette Journal: Ann Clin Transl Neurol Date: 2021-05-21 Impact factor: 4.511
Authors: Stefan Wolking; Ciarán Campbell; Caragh Stapleton; Mark McCormack; Norman Delanty; Chantal Depondt; Michael R Johnson; Bobby P C Koeleman; Roland Krause; Wolfram S Kunz; Anthony G Marson; Josemir W Sander; Graeme J Sills; Pasquale Striano; Federico Zara; Sanjay M Sisodiya; Gianpiero L Cavalleri; Holger Lerche Journal: Front Pharmacol Date: 2021-06-09 Impact factor: 5.810