[en] Background Epilepsy is one of the most common neurological disorders, affecting over 50 million people worldwide. One-third of people with epilepsy do not respond to currently available anti-seizure medications, constituting one of the most important problems in epilepsy. Little is known about the molecular pathology of drug resistance in epilepsy, in particular, possible underlying genetic factors are largely unknown. Methods We performed a genome-wide association study (GWAS) in two epilepsy cohorts of European ancestry, comparing drug-resistant (N = 4208) to drug-responsive individuals (N = 2618) followed by meta-analyses across the studies. Next, we performed subanalyses split into two broad subtypes: acquired or non-acquired focal and genetic generalized epilepsy. Findings Our drug-resistant versus drug-responsive epilepsy GWAS meta-analysis showed no significant loci when combining all epilepsy types. Sub-analyses on individuals with focal epilepsy (FE) identified a significant locus on chromosome 1q42.11-q42.12 (lead SNP: rs35915186, P = 1⋅51 × 10 −8 , OR[C] = 0⋅74). This locus was not associated with any epilepsy subtype in the latest epilepsy GWAS (lowest uncorrected P = 0⋅009 for FE vs. healthy controls), and drug resistance in FE was not genetically correlated with susceptibility to FE itself. Seven genome-wide significant SNPs within this locus, encompassing the genes CNIH4, WDR26, and CNIH3, were identified to protect against drug-resistant FE. Further transcriptome-wide association studies (TWAS) imply significantly higher expression levels of CNIH3 and WDR26 in drug-resistant FE than in drug-responsive FE. CNIH3 is implicated in AMPA receptor assembly and function, while WDR26 haploinsufficiency is linked to intellectual disability and seizures. These findings suggest that CNIH3 and WDR26 may play a role in mediating drug response in focal epilepsy. Interpretation We identified a contribution of common genetic variation to drug-resistant focal epilepsy. These findings provide insights into possible mechanisms underlying drug response variability in epilepsy, offering potential targets for personalised treatment approaches.
Disciplines :
Neurology
Author, co-author :
Leu, Costin; Department of Neurology, McGovern Medical School, UTHealth Houston, Houston, USA ; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK ; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, USA ; Corresponding author. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Queen Square, London, UK
Avbersek, Andreja; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK ; Chalfont Centre for Epilepsy, Chalfont-St-Peter, Buckinghamshire, UK ; Corresponding author. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Queen Square, London, UK
Stevelink, Remi; Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands ; Department of Child Neurology, UMC Utrecht Brain Centers, University Medical Center Utrecht, Utrecht, the Netherlands
Martins Custodio, Helena; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK ; Chalfont Centre for Epilepsy, Chalfont-St-Peter, Buckinghamshire, UK
Chen, Siwei; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, USA ; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, USA
Speed, Doug; Center for Quantitative Genetics and Genomics, Aarhus University, Aarhus, Denmark
Bennett, Caitlin; Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, Australia
Jonsson, Lina; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Jorgensen, Andrea; Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
Cavalleri, Gianpiero; Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland ; FutureNeuro Research Centre, Science Foundation Ireland, Dublin, Ireland
Delanty, Norman; FutureNeuro Research Centre, Science Foundation Ireland, Dublin, Ireland ; Department of Neurology, Beaumont Hospital, Dublin, Ireland
Craig, John; Department of Neurology, Belfast Health and Social Care Trust, Belfast, UK
Depondt, Chantal; Department of Neurology, CUB Erasmus Hospital, Free University of Brussels, University Hospital Brussels, Brussels, Belgium
Johnson, Michael; Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK
Koeleman, Bobby; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
HASSANIN, Emadeldin ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Omidvar, Maryam; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
KRAUSE, Roland ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Lerche, Holger; Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
Marson, Anthony; Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK ; The Walton Centre NHS Foundation Trust, Liverpool, UK ; Liverpool Health Partners, Liverpool, UK
O'brien, Terence; Departments of Medicine and Neurology, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia ; Departments of Neuroscience and Neurology, ab Stichting Epilepsie Instellingen Nederland (SEIN), Department of Neurology, The School of Translational Medicine, Monash University and the Alfred Hospital, Melbourne, Heemstede, Australia, the Netherlands ac ; ad School of Life Sciences, West China Hospital, Sichuan University, Chengdu, China ; ae Paediatric Neurology and Muscular Diseases Unit, University of Glasgow, Glasgow, UK ; Department of Neurosciences, Genetics, Maternal and Child Health, IRCCS "G. Gaslini" Institute, Genova, Rehabilitation, Italy af ; ag Laboratory of Neurogenetics and Neuroscience, University of Genoa, Genova, Italy ; Faculty of Medicine, IRCCS "G. Gaslini" Institute, Genova, Italy ah ; ai Center of Neurogenetics, University of Iceland, Reykjavik, Iceland ; UTHealth Houston, USA ; Department of Neurology, aj Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T, Cambridge, USA ak ; Austin Health, Heidelberg, Australia
Sander, Josemir; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK ; Chalfont Centre for Epilepsy, Chalfont-St-Peter, Buckinghamshire, UK
MAY, Patrick ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core ; deCODE Genetics, Amgen Inc, Reykjavik, Iceland
Neale, Benjamin; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, USA ; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, USA
Lal, Dennis; Department of Neurology, McGovern Medical School, UTHealth Houston, Houston, USA ; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, USA
Berkovic, Samuel; Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, Australia
Collaborative, Epi25
Consortium, Epipgx
Sisodiya, Sanjay; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK ; Chalfont Centre for Epilepsy, Chalfont-St-Peter, Buckinghamshire, UK ; Corresponding author. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, Queen Square, London, UK
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