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; Gianpiero L Cavalleri; Norman Delanty; John J Craig; Chantal Depondt; Michael R Johnson; Bobby P C Koeleman; Emadeldin Hassanin; Maryam Erfanian Omidvar; Roland Krause; Holger Lerche; Anthony G Marson; Terence J O'Brien; Josemir W Sander; Graeme J Sills; Pasquale Striano; Federico Zara; Hreinn Stefansson; Kari Stefansson; Patrick May; Benjamin M Neale; Dennis Lal; Samuel F Berkovic; Sanjay M Sisodiya

doi:10.1016/j.ebiom.2025.105675

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, Gianpiero L Cavalleri, Norman Delanty, John J Craig, Chantal Depondt, Michael R Johnson, Bobby P C Koeleman, Emadeldin Hassanin, Maryam Erfanian Omidvar, Roland Krause, Holger LercheAnthony G Marson, Terence J O'Brien, Josemir W Sander, Graeme J Sills, Pasquale Striano, Federico Zara, Hreinn Stefansson, Kari Stefansson, Patrick May, Benjamin M Neale, Dennis Lal, Samuel F Berkovic, Sanjay M Sisodiya,

^*Corresponding author for this work

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

Abstract

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.

FUNDING: This 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).

Original language	English
Article number	105675
Journal	EBioMedicine
Volume	115
Early online date	15 Apr 2025
DOIs	https://doi.org/10.1016/j.ebiom.2025.105675
Publication status	Published - May 2025

Keywords

Antiseizure medication
Association
Genetics
Pharmacogenomics
Treatment

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10.1016/j.ebiom.2025.105675Licence: CC BY-NC-ND

PIIS2352396425001197Final published version, 1.35 MBLicence: CC BY-NC-ND

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Leu, C., Avbersek, A., Stevelink, R., Custodio, H. M., Chen, S., Speed, D., Bennett, C. A., Jonsson, L., Unnsteinsdóttir, U., Jorgensen, A. L., Cavalleri, G. L., Delanty, N., Craig, J. J., Depondt, C., Johnson, M. R., Koeleman, B. P. C., Hassanin, E., Omidvar, M. E., Krause, R. (2025). Genome-wide association meta-analyses of drug-resistant epilepsy. EBioMedicine, 115, Article 105675. https://doi.org/10.1016/j.ebiom.2025.105675

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title = "Genome-wide association meta-analyses of drug-resistant epilepsy",

abstract = "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.FUNDING: This 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).",

keywords = "Antiseizure medication, Association, Genetics, Pharmacogenomics, Treatment",

author = "Costin Leu and Andreja Avbersek and Remi Stevelink and Custodio, {Helena Martins} and Siwei Chen and Doug Speed and Bennett, {Caitlin A} and Lina Jonsson and Unnur Unnsteinsd{\'o}ttir and Jorgensen, {Andrea L} and Cavalleri, {Gianpiero L} and Norman Delanty and Craig, {John J} and Chantal Depondt and Johnson, {Michael R} and Koeleman, {Bobby P C} and Emadeldin Hassanin and Omidvar, {Maryam Erfanian} and Roland Krause and Holger Lerche and Marson, {Anthony G} and O'Brien, {Terence J} and Sander, {Josemir W} and Sills, {Graeme J} and Pasquale Striano and Federico Zara and Hreinn Stefansson and Kari Stefansson and Patrick May and Neale, {Benjamin M} and Dennis Lal and Berkovic, {Samuel F} and Sisodiya, {Sanjay M}",

note = "Publisher Copyright: {\textcopyright} 2025",

year = "2025",

month = may,

doi = "10.1016/j.ebiom.2025.105675",

language = "English",

volume = "115",

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Leu, C, Avbersek, A, Stevelink, R, Custodio, HM, Chen, S, Speed, D, Bennett, CA, Jonsson, L, Unnsteinsdóttir, U, Jorgensen, AL, Cavalleri, GL, Delanty, N, Craig, JJ, Depondt, C, Johnson, MR, Koeleman, BPC, Hassanin, E, Omidvar, ME, Krause, R, Lerche, H, Marson, AG, O'Brien, TJ, Sander, JW, Sills, GJ, Striano, P, Zara, F, Stefansson, H, Stefansson, K, May, P, Neale, BM, Lal, D, Berkovic, SF, Sisodiya, SM 2025, 'Genome-wide association meta-analyses of drug-resistant epilepsy', EBioMedicine, vol. 115, 105675. https://doi.org/10.1016/j.ebiom.2025.105675

TY - JOUR

T1 - Genome-wide association meta-analyses of drug-resistant epilepsy

AU - Leu, Costin

AU - Avbersek, Andreja

AU - Stevelink, Remi

AU - Custodio, Helena Martins

AU - Chen, Siwei

AU - Speed, Doug

AU - Bennett, Caitlin A

AU - Jonsson, Lina

AU - Unnsteinsdóttir, Unnur

AU - Jorgensen, Andrea L

AU - Cavalleri, Gianpiero L

AU - Delanty, Norman

AU - Craig, John J

AU - Depondt, Chantal

AU - Johnson, Michael R

AU - Koeleman, Bobby P C

AU - Hassanin, Emadeldin

AU - Omidvar, Maryam Erfanian

AU - Krause, Roland

AU - Lerche, Holger

AU - Marson, Anthony G

AU - O'Brien, Terence J

AU - Sander, Josemir W

AU - Sills, Graeme J

AU - Striano, Pasquale

AU - Zara, Federico

AU - Stefansson, Hreinn

AU - Stefansson, Kari

AU - May, Patrick

AU - Neale, Benjamin M

AU - Lal, Dennis

AU - Berkovic, Samuel F

AU - Sisodiya, Sanjay M

PY - 2025/5

Y1 - 2025/5

N2 - 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.FUNDING: This 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).

AB - 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.FUNDING: This 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).

KW - Antiseizure medication

KW - Association

KW - Genetics

KW - Pharmacogenomics

KW - Treatment

UR - http://www.scopus.com/inward/record.url?scp=105002773318&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2025.105675

DO - 10.1016/j.ebiom.2025.105675

M3 - Article

C2 - 40240269

SN - 2352-3964

VL - 115

JO - EBioMedicine

JF - EBioMedicine

M1 - 105675

ER -

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

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Keywords

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