Evidence map›Paper›PMID 40240269›Full record

SynthesisEBioMedicine2025

Genome-wide association meta-analyses of drug-resistant epilepsy.

Costin Leu, Andreja Avbersek, Remi Stevelink, Helena Martins Custodio, Siwei Chen, Doug Speed, Caitlin A Bennett, Lina Jonsson, Unnur Unnsteinsdóttir, Andrea L Jorgensen and 25 more

Abstract readMeta-Analysis
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in EBioMedicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Article
  3. Article
  4. Article
  5. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

35 authors.

Costin LeuDepartment of Neurology, McGovern Medical School, UTHealth Houston, Houston, TX, USA; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address: Costin.Leu@uth.tmc.edu.
Andreja AvbersekDepartment of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; Chalfont Centre for Epilepsy, Chalfont-St-Peter, Buckinghamshire, UK.
Remi StevelinkDepartment 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.
Helena Martins CustodioDepartment of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; Chalfont Centre for Epilepsy, Chalfont-St-Peter, Buckinghamshire, UK.
Siwei ChenProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Doug SpeedCenter for Quantitative Genetics and Genomics, Aarhus University, Aarhus, Denmark.
Caitlin A BennettDepartment of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Melbourne, Australia.
Lina JonssonDepartment of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Unnur UnnsteinsdóttirdeCODE Genetics/Amgen Inc., Reykjavik, Iceland.
Andrea L JorgensenDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
Gianpiero L CavalleriDepartment of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland; FutureNeuro Research Centre, Science Foundation Ireland, Dublin, Ireland.
Norman DelantyFutureNeuro Research Centre, Science Foundation Ireland, Dublin, Ireland; Department of Neurology, Beaumont Hospital, Dublin, Ireland.
John J CraigDepartment of Neurology, Belfast Health and Social Care Trust, Belfast, UK.
Chantal DepondtDepartment of Neurology, CUB Erasmus Hospital, Free University of Brussels, University Hospital Brussels, Brussels, Belgium.
Michael R JohnsonDepartment of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK.
Bobby P C KoelemanDepartment of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Emadeldin HassaninLuxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg.
Maryam Erfanian OmidvarDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Roland KrauseLuxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg.
Holger LercheDepartment of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Anthony G MarsonDepartment 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.
Terence J O'BrienDepartments of Medicine and Neurology, Royal Melbourne Hospital, University of Melbourne, Parkville, Australia; Departments of Neuroscience and Neurology, The School of Translational Medicine, Monash University and the Alfred Hospital, Melbourne, Australia.
Josemir W SanderDepartment of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; Chalfont Centre for Epilepsy, Chalfont-St-Peter, Buckinghamshire, UK; Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands; Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.
Graeme J SillsSchool of Life Sciences, University of Glasgow, Glasgow, UK.
Pasquale StrianoPaediatric Neurology and Muscular Diseases Unit, IRCCS "G. Gaslini" Institute, Genova, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova, Italy.
Federico ZaraDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova, Italy; Laboratory of Neurogenetics and Neuroscience, IRCCS "G. Gaslini" Institute, Genova, Italy.
Hreinn StefanssondeCODE Genetics/Amgen Inc., Reykjavik, Iceland.
Kari StefanssondeCODE Genetics/Amgen Inc., Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Patrick MayLuxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg.
Benjamin M NealeProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Dennis LalDepartment of Neurology, McGovern Medical School, UTHealth Houston, Houston, TX, USA; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA; Center of Neurogenetics, UTHealth Houston, TX, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T, Cambridge, MA, USA.
Samuel F BerkovicDepartment of Medicine, Epilepsy Research Centre, Austin Health, University of Melbourne, Melbourne, Australia; Department of Neurology, Austin Health, Heidelberg, Australia.
Epi25 Collaborative
EpiPGX Consortium
Sanjay M SisodiyaDepartment of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; Chalfont Centre for Epilepsy, Chalfont-St-Peter, Buckinghamshire, UK. Electronic address: s.sisodiya@ucl.ac.uk.

Funding

Center for Common Disease GeneticsUM1HG008895 · NHGRI · BROAD INSTITUTE, INC. · PI DALY, MARK JOSEPH, GABRIEL, STACEY · 2016 to 2020
$111.2M
Powering whole genome sequence-based genetic discovery for common human diseases- Extended 2021-2022.U01HG009088 · NHGRI · HARVARD SCHOOL OF PUBLIC HEALTH · PI LIN, XIHONG, NEALE, BENJAMIN MICHAEL · 2016 to 2021
$5.1M
Polygenic risk in familial epilepsyK23NS121520 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI ELLIS, COLIN · 2021 to 2025
$1.1M
Epi25 Clinical Phenotyping R03R03NS108145 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI LOWENSTEIN, DANIEL H · 2018 to 2019
$137k
NHGRI NIH HHS U01 HG009088NHGRI NIH HHS UM1 HG008895NINDS NIH HHS K23 NS121520NINDS NIH HHS R03 NS108145
6 · The paper itself

Abstract

backgroundEpilepsy 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.

methodsWe 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.

findingsOur 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

interpretationWe 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.

fundingThis work is part of the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 279062 (EpiPGX) and the Centers for Common Disease Genomics (CCDG) program, funded by the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI).

Indexed as

Drug Resistant EpilepsyGenome-Wide Association StudyFemaleGenetic Predisposition to DiseaseHumansMalePolymorphism, Single NucleotideAntiseizure medicationAssociationGeneticsPharmacogenomicsTreatment

Identifiers

PMID40240269
PMCPMC12143209

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.