May, Patrick ORCID: 0000-0001-8698-3770, Girard, Simon ORCID: 0000-0002-4089-2280, Harrer, Merle, Bobbili, Dheeraj R., Schubert, Julian, Wolking, Stefan ORCID: 0000-0002-1460-6623, Becker, Felicitas, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E., Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-Lopez, Rosa, Baulac, Stephanie ORCID: 0000-0001-6430-4693, Marini, Carla, Thiele, Holger, Altmueller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Dennis, Rusconi, Raffaella, Cestele, Sandrine ORCID: 0000-0002-5982-1562, Terragni, Benedetta, Coombs, Ian D., Reid, Christopher A., Striano, Pasquale ORCID: 0000-0002-6065-1476, Caglayan, Hande, Siren, Auli, Everett, Kate ORCID: 0000-0001-6700-1698, Moller, Rikke S., Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S. ORCID: 0000-0003-1113-3493, Weber, Yvonne G., Weckhuysen, Sarah ORCID: 0000-0003-2878-1147, De Jonghe, Peter, Sisodiya, Sanjay M., Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S., Trenite, Dorothee Kasteleijn-Nolst, Baykan, Betul, Ozbek, Ugur ORCID: 0000-0001-5319-0547, Bebek, Nerses, Klein, Karl M., Rosenow, Felix, Nguyen, Dang K., Dubeau, Francois, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clement, Jean-Francois, Cieuta-Walti, Cecile, Sills, Graeme J., Auce, Pauls, Francis, Ben, Johnson, Michael R., Marson, Anthony G., Berghuis, Bianca, Sander, Josemir W., Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin ORCID: 0000-0003-3026-3082, Zimprich, Fritz ORCID: 0000-0002-6998-5480, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi ORCID: 0000-0003-2902-5650, Ikram, M. Arfan, Uitterlinden, Andre G., Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven ORCID: 0000-0002-4960-6375, Mantegazza, Massimo ORCID: 0000-0002-1070-7929, Sander, Thomas, LeGuern, Eric, Serratosa, Jose M., Koeleman, Bobby P. C., Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael ORCID: 0000-0001-8305-7114, Nuernberg, Peter, Maljevic, Snezana ORCID: 0000-0003-1876-5872, Zara, Federico, Cossette, Patrick, Krause, Roland ORCID: 0000-0001-9938-7126 and Lerche, Holger (2018). Rare coding variants in genes encoding GABA(A) receptors in genetic generalised epilepsies: an exome-based case-control study. Lancet Neurol., 17 (8). S. 699 - 709. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1474-4465

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Abstract

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 GABA(A) receptors and was compared to the respective GABA(A) 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 GABA(A) receptors in cases (odds ratio [OR] 2.40 [95% CI 1.41-4.10]; p(Nonsyn)=0.0014, adjusted p(Nonsyn)=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]; p(Nonsyn)=0.0081, adjusted p(Nonsyn)=0.016). Comparison of genes encoding GABA(A) 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 GABA(A) receptor genes in cases compared with controls (OR 1.46 [95% CI 1.02-2.08]; p(Nonsyn)=0.013, adjusted p(Nonsyn)=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 GABA(A) 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. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
May, PatrickUNSPECIFIEDorcid.org/0000-0001-8698-3770UNSPECIFIED
Girard, SimonUNSPECIFIEDorcid.org/0000-0002-4089-2280UNSPECIFIED
Harrer, MerleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bobbili, Dheeraj R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schubert, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolking, StefanUNSPECIFIEDorcid.org/0000-0002-1460-6623UNSPECIFIED
Becker, FelicitasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lachance-Touchette, PamelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meloche, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gravel, MichelineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niturad, Cristina E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knaus, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Kovel, CarolienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toliat, MohamadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Polvi, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iacomino, MicheleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guerrero-Lopez, RosaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baulac, StephanieUNSPECIFIEDorcid.org/0000-0001-6430-4693UNSPECIFIED
Marini, CarlaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jabbari, KamelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruppert, Ann-KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jurkowski, WiktorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lal, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rusconi, RaffaellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cestele, SandrineUNSPECIFIEDorcid.org/0000-0002-5982-1562UNSPECIFIED
Terragni, BenedettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coombs, Ian D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reid, Christopher A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Striano, PasqualeUNSPECIFIEDorcid.org/0000-0002-6065-1476UNSPECIFIED
Caglayan, HandeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siren, AuliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Everett, KateUNSPECIFIEDorcid.org/0000-0001-6700-1698UNSPECIFIED
Moller, Rikke S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hjalgrim, HelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muhle, HiltrudUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helbig, IngoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kunz, Wolfram S.UNSPECIFIEDorcid.org/0000-0003-1113-3493UNSPECIFIED
Weber, Yvonne G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weckhuysen, SarahUNSPECIFIEDorcid.org/0000-0003-2878-1147UNSPECIFIED
De Jonghe, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sisodiya, Sanjay M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nabbout, RimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Franceschetti, SilvanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coppola, AntoniettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vari, Maria S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trenite, Dorothee Kasteleijn-NolstUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baykan, BetulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ozbek, UgurUNSPECIFIEDorcid.org/0000-0001-5319-0547UNSPECIFIED
Bebek, NersesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, Karl M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenow, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nguyen, Dang K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dubeau, FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carmant, LionelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lortie, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Desbiens, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clement, Jean-FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cieuta-Walti, CecileUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sills, Graeme J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Auce, PaulsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Francis, BenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Johnson, Michael R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marson, Anthony G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berghuis, BiancaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sander, Josemir W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Avbersek, AndrejaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McCormack, MarkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cavalleri, Gianpiero L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Delanty, NormanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Depondt, ChantalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krenn, MartinUNSPECIFIEDorcid.org/0000-0003-3026-3082UNSPECIFIED
Zimprich, FritzUNSPECIFIEDorcid.org/0000-0002-6998-5480UNSPECIFIED
Peter, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nikanorova, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kraaij, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Rooij, JeroenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balling, RudiUNSPECIFIEDorcid.org/0000-0003-2902-5650UNSPECIFIED
Ikram, M. ArfanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uitterlinden, Andre G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Avanzini, GiulianoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schorge, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Petrou, StevenUNSPECIFIEDorcid.org/0000-0002-4960-6375UNSPECIFIED
Mantegazza, MassimoUNSPECIFIEDorcid.org/0000-0002-1070-7929UNSPECIFIED
Sander, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
LeGuern, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Serratosa, Jose M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koeleman, Bobby P. C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palotie, AarnoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lehesjoki, Anna-ElinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nothnagel, MichaelUNSPECIFIEDorcid.org/0000-0001-8305-7114UNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maljevic, SnezanaUNSPECIFIEDorcid.org/0000-0003-1876-5872UNSPECIFIED
Zara, FedericoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cossette, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krause, RolandUNSPECIFIEDorcid.org/0000-0001-9938-7126UNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-177354
DOI: 10.1016/S1474-4422(18)30215-1
Journal or Publication Title: Lancet Neurol.
Volume: 17
Number: 8
Page Range: S. 699 - 709
Date: 2018
Publisher: ELSEVIER SCIENCE INC
Place of Publication: NEW YORK
ISSN: 1474-4465
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DE-NOVO MUTATIONS; EPILEPTIC ENCEPHALOPATHIES; ABSENCE EPILEPSY; 15Q13.3 MICRODELETIONS; ASSOCIATION ANALYSIS; FEBRILE SEIZURES; SEQUENCE DATA; MOUSE MODEL; RISK; GAMMA-2-SUBUNITMultiple languages
Clinical NeurologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17735

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