Article (Scientific journals)
Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study
May, Patrick; Girard, Simon; Harrer, Merle et al.
2018In Lancet Neurology, 17 (8), p. 699-708
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Keywords :
Epilepsy; GABA; Exome; GGE
Abstract :
[en] Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. Methods For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes. Findings Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41–4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05–2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02–2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors. Interpretation Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group)
ULHPC - University of Luxembourg: High Performance Computing
Disciplines :
Genetics & genetic processes
Author, co-author :
May, Patrick  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Girard, Simon
Harrer, Merle
Bobbili, Dheeraj Reddy ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Schubert, Julian
Wolking, Stefan
Becker, Felicitas
Lachance-Touchette, Pamela
Meloche, Caroline
Gravel, Micheline
Niturad, Christina E.
Knaus, Julia
De Kovel, Carolien
Toliat, Mohamad
Polvi, Anne
Iacomino, Michele
Guerrero-López, Rosa
Baulac, Stéphanie
Marini, Carla
Thiele, Holger
Altmüller, Janine
Jabbari, Kamel
Ruppert, Ann-Kathrin
Jurkowski, Wiktor
Lal, Dennis
Rusconi, Raffaella
Cestèle, Sandrine
Terragni, Benedetta
Coombs, Ian D.
Reid, Christopher A.
Striano, Pasquale
Caglayan, Hande
Siren, Auli
Everett, Kate
Møller, Rikke S.
Hjalgrim, Hille
Muhle, Hiltrud
Helbig, Ingo
Kunz, Wolfram S.
Weber, Yvonne G.
De Jonghe, Peter
Sisodiya, Sanjay M.
Nabbout, Rima
Franceschetti, Silvana
Coppola, Antonietta
Vari, Maria S.
Kasteleijn-Nolst Trenité, Dorothée
Baykan, Betul
Ozbek, Ugur
Bebek, Nerses
Klein, Karl M.
Rosenow, Felix
Nguyen, Dang K.
Dubeau, Francis
Carmant, Lionel
Lortie, Anne
Desbiens, Richard
Clément, Jean-François
Sills, Graeme J.
Auce, Pauls
Francin, Ben
Johnson, Michael R.
Berghuis, Bianca
Sander, Josemir W.
Avbersek, Andreja
McCormack, Mark
Cavalleri, Gianpiero L.
Delanty, Norman
Depondt, Chantal
Krenn, Martin
Zimprich, Fritz
Peter, Sarah;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Nikanorova, Marina
Kraaij, Robert
van Rooij, Jeroen
Balling, Rudi ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Ikram, M. Arfan
Uitterlinden, André G.
Avanzini, Giuliano
Schorge, Stephanie
Petrou, Steven
Mantegazza, Massimo
Sander, Thomas
LeGuern, Eric
Serratosa Jose M.
Koeleman, Bobby P.C.
Palotie, Aarno
Lehesjoki, Anna-Elina
Nothnagel, Michael
Nürnberg, Peter
Maljevic, Snezana
Zara, Federico
Cossette, Patrick
Krause, Roland  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Lerche, Holger
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Title :
Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study
Publication date :
18 August 2018
Journal title :
Lancet Neurology
Publisher :
Elsevier, London, United Kingdom
Volume :
Issue :
Pages :
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
European Projects :
FP7 - 279062 - EPIPGX - Epilepsy Pharmacogenomics: delivering biomarkers for clinical use
Name of the research project :
Funders :
CE - Commission Européenne [BE]
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since 18 July 2018


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