TY - JOUR
T1 - Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies
T2 - an exome-based case-control study
AU - May, Patrick
AU - Girard, Simon
AU - Harrer, Merle
AU - Bobbili, Dheeraj R.
AU - Schubert, Julian
AU - Wolking, Stefan
AU - Becker, Felicitas
AU - Lachance-Touchette, Pamela
AU - Meloche, Caroline
AU - Gravel, Micheline
AU - Niturad, Cristina E.
AU - Knaus, Julia
AU - De Kovel, Carolien
AU - Toliat, Mohamad
AU - Polvi, Anne
AU - Iacomino, Michele
AU - Guerrero-López, Rosa
AU - Baulac, Stéphanie
AU - Marini, Carla
AU - Thiele, Holger
AU - Altmüller, Janine
AU - Jabbari, Kamel
AU - Ruppert, Ann Kathrin
AU - Jurkowski, Wiktor
AU - Lal, Dennis
AU - Rusconi, Raffaella
AU - Cestèle, Sandrine
AU - Terragni, Benedetta
AU - Coombs, Ian D.
AU - Reid, Christopher A.
AU - Striano, Pasquale
AU - Caglayan, Hande
AU - Siren, Auli
AU - Everett, Kate
AU - Møller, Rikke S.
AU - Hjalgrim, Helle
AU - Muhle, Hiltrud
AU - Helbig, Ingo
AU - Kunz, Wolfram S.
AU - Weber, Yvonne G.
AU - Weckhuysen, Sarah
AU - De Jonghe, Peter
AU - Sisodiya, Sanjay M.
AU - Nabbout, Rima
AU - Franceschetti, Silvana
AU - Kasteleijn-Nolst Trenité, Dorothée
AU - Koeleman, Bobby P.C.
AU - Kasteleijn-Nolst Trenité, Dorothée
AU - Koeleman, Bobby P.C.
AU - Sonsma, Anja C.M.
N1 - Funding Information:
We thank all individuals who participated in this study. The study was supported by the European Commission (Sixth Framework Programme project Epicure, LSHM-CT-2006-037315 to HL, FZ, PN, AEL, BPCK, JMS, ELG, CM, TS, MM, SS, GA, FR, SF, RN, and WSK, and Seventh Framework Programme Grant 279062 EpiPGX to SMS, HL, GLC, GJS, MRJ, AGM, CD, FZ, WSK, JWS, and BPCK), by the European Science Foundation (EuroEPINOMICS project, grants from national funding agencies: DFG [Le1030/11-1/2 to HL, Nu50/8-1 to PN, Sa434/5-1 to TS, He5415/3-1 to IH], FNR [INTER/ESF/10/02/CoGIE to RB], Academy of Finland 141549 to AEL, Spanish Ministry of Science (EUI-EURC-2011-4325 SAF2010-18586 to JMS), TUBITAK 110S518 to HC; associated partners without funding were FZ, AP, BPCK, MM, SP, and SS), by Research Unit FOR2715 of the DFG and the FNR (grants Le1030/16-1, Nu50/11-1, Kr5093/2-1, No755/6-1, Sa434/6-1, We4896/4-1, and He5415/7-1), by the German Society for Epileptology (to HL, YGW, IH, and HM), by the foundation no-epilep (to HL), by the Epilepsy Society UK (to JWS and SMS), by the Wellcome Trust (086185/Z/08/Z to IDC), by the Medical Research Council (MR/J002976/1 to IDC), by the Royal Society (to SS), by the International Coordination Action grant G0E8614N (to SW), by the JPND Courage-PD research grant (to PM and DRB), and by the FNR NCER-PD grant (to RB and PM). MMc and GLC are supported by Science Foundation Ireland, grant 13/CDA/2223. MMc is supported by a Marie-Curie Individual Fellowship (number 751761) from the European Commission. This work was partly done at University College London (UCL) Hospital and UCL, which received a proportion of funding from the UK Department of Health's NIHR Biomedical Research Centre funding scheme (JWS and SMS) and Imperial College NIHR Biomedical Research Centre Scheme (MRJ). Generation and management of genomics data for the Rotterdam Study were supported by the Netherlands Organisation of Scientific Research NOW Investments (numbers 175.010.2005.011 and 911-03-012) and the Netherlands Genomics Initiative (NGI)/NOW project number 050-060-810 (Netherlands Consortium for Healthy Ageing). We thank the members of the Genomics Lab and the ERGO support team for their help in sampling the data and in creating the database. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development, the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff of the Rotterdam Study, and the participating general practitioners and pharmacists. Parts of the computational analysis were done on the high-performance computer system of the University of Luxembourg ( [email protected] ).
Funding Information:
HL has received funding from Deutsche Forschungsgemeinschaft (DFG), BMBF, EU, Deutsche Gesellschaft für Epileptologie (DGfE) and the foundation no-epilep related in part to this work (see Acknowledgments); and personal fees for consulting, speaking, or travel support from Bial, Biomarin, Desitin, Eisai, and UCB Pharma, outside of the submitted work. KMK reports personal fees from UCB Pharma, Novartis Pharma AG, and Eisai, outside the submitted work. SP is a scientific co-founder and holds equity from Praxis Precision Medicine, is a scientific founder and holds equity from RogCone, and is an advisory board member and equity holder from Pairnomix. SP received grants from Praxis Precision Medicine, and grants and personal fees from RogCon, outside of the submitted work. SP also has a US Provisional Application 62/450,025 patent pending. FR reports personal fees and non-financial support from UCB Pharma, personal fees from Shire, Eisai, Desitin Arzneimittel, Bial, cerbomed, GW-Pharma, Bayer Vital, Sandoz, University of Munich, and Verband der forschenden Arzneimittelindustrie; non-financial support from Novartis Japan, grants from European Union, Seventh Framework Programme, grants from Hessisches Ministerium für Wissenschaft und Kunst (LOEWE-Programme), personal fees from the University of Munich, and grants from Detlev-Wrobel Fonds for Epilepsy Research, outside of the submitted work. AA reports grants from European Commission, during the conduct of the study; AA is currently employed by UCB Pharma, Belgium, as Associate Director, outside the submitted work. AGM was awarded grants from GlaxoSmithKline, Eisai, and UCB Pharma, which funded the National Audit of Seizure Management in Hospitals, and the European Union during the conduct of the study. JWS reports grants and personal fees from Eisai and UCB, grants from WHO, grants from NEF, and personal fees from Eisai, outside of the submitted work. JWS's current position is endowed by the Epilepsy Society, and JWS is a member of the Editorial Board of The Lancet Neurology, and receives research support from the Marvin Weil Epilepsy Research Fund. AC was awarded a grant from Eisai and personal fees for speaking from Eisai, outside of the submitted work. GJS reports grants from the European Commision (Seventh Framework Programme), during the conduct of the study, and personal fees from UCB Pharma and Eisai, outside of the submitted work. CD reports grants and personal fees from UCB Pharma, outside of the submitted work. AP reports grants and personal fees from serving the Pfizer Genetics Scientific Advisory Panel and the FinnGen Project, outside of the submitted work. RB is the Co-Founder of Theracule and Megeno. PA reports grants from the EU Seventh Framework Programme (EpiPGX), during the conduct of the study. PM is Co-Founder of Megeno, outside of the submitted work. JMS reports grants from Spanish Ministry of Science, Innovation and Universities, during the conduct of the study; and personal fess for consulting, speaking, or travel support from Bial, Eisai, Esteve and UCB Pharma, outside of the submitted work. All other authors declare no competing interests.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/8
Y1 - 2018/8
N2 - 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. Funding: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).
AB - 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. Funding: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).
UR - https://www.scopus.com/pages/publications/85049923895
U2 - 10.1016/S1474-4422(18)30215-1
DO - 10.1016/S1474-4422(18)30215-1
M3 - Article
AN - SCOPUS:85049923895
SN - 1474-4422
VL - 17
SP - 699
EP - 708
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 8
ER -