Rare coding variants in genes encoding GABA A receptors in genetic generalised epilepsies: an exome-based case-control study

Item Type:	Article
Title:	Rare coding variants in genes encoding GABA A receptors in genetic generalised epilepsies: an exome-based case-control study
Creators Name:	May, P. and Girard, S. and Harrer, M. and Bobbili, D.R. and Schubert, J. and Wolking, S. and Becker, F. and Lachance-Touchette, P. and Meloche, C. and Gravel, M. and Niturad, C.E. and Knaus, J. and De Kovel, C. and Toliat, M. and Polvi, A. and Iacomino, M. and Guerrero-López, R. and Baulac, S. and Marini, C. and Thiele, H. and Altmüller, J. and Jabbari, K. and Ruppert, A.K. and Jurkowski, W. and Lal, D. and Rusconi, R. and Cestèle, S. and Terragni, B. and Coombs, I.D. and Reid, C.A. and Striano, P. and Caglayan, H. and Siren, A. and Everett, K. and Møller, R.S. and Hjalgrim, H. and Muhle, H. and Helbig, I. and Kunz, W.S. and Weber, Y.G. and Weckhuysen, S. and Jonghe, P.D. and Sisodiya, S.M. and Nabbout, R. and Franceschetti, S. and Coppola, A. and Vari, M.S. and Kasteleijn-Nolst Trenité, D. and Baykan, B. and Ozbek, U. and Bebek, N. and Klein, K.M. and Rosenow, F. and Nguyen, D.K. and Dubeau, F. and Carmant, L. and Lortie, A. and Desbiens, R. and Clément, J.F. and Cieuta-Walti, C. and Sills, G.J. and Auce, P. and Francis, B. and Johnson, M.R. and Marson, A.G. and Berghuis, B. and Sander, J.W. and Avbersek, A. and McCormack, M. and Cavalleri, G.L. and Delanty, N. and Depondt, C. and Krenn, M. and Zimprich, F. and Peter, S. and Nikanorova, M. and Kraaij, R. and van Rooij, J. and Balling, R. and Ikram, M.A. and Uitterlinden, A.G. and Avanzini, G. and Schorge, S. and Petrou, S. and Mantegazza, M. and Sander, T. and LeGuern, E. and Serratosa, J.M. and Koeleman, B.P.C. and Palotie, A. and Lehesjoki, A.E. and Nothnagel, M. and Nürnberg, P. and Maljevic, S. and Zara, F. and Cossette, P. and Krause, R. and Lerche, H.
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 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]; 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.
Keywords:	Case-Control Studies, Cohort Studies, Generalized Epilepsy, Europe, Exome Sequencing, Family Health, Genetic Predisposition to Disease, Genetic Variation, International Cooperation, Molecular Models, GABA-A Receptors
Source:	Lancet Neurology
ISSN:	1474-4422
Publisher:	Elsevier / Lancet
Volume:	17
Number:	8
Page Range:	699-708
Date:	August 2018
Additional Information:	Copyright © 2018 Elsevier Ltd. All rights reserved.
Official Publication:	https://doi.org/10.1016/S1474-4422(18)30215-1
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