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

EPICURE Consortium, EuroEPINOMICS CoGIE Consortium, EpiPGX Consortium

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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Resumé

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).

OriginalsprogEngelsk
TidsskriftLancet Neurology
Vol/bind17
Udgave nummer8
Sider (fra-til)699-708
ISSN1474-4422
DOI
StatusUdgivet - aug. 2018

Fingeraftryk

Exome
GABA-A Receptors
Case-Control Studies
Odds Ratio
Luxembourg
Research
Monozygotic Twins
Xenopus laevis
Microelectrodes
Constriction
Oocytes
Organizations

Bibliografisk note

Copyright © 2018 Elsevier Ltd. All rights reserved.

Citer dette

EPICURE Consortium ; EuroEPINOMICS CoGIE Consortium ; EpiPGX Consortium. / Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies : an exome-based case-control study. I: Lancet Neurology. 2018 ; Bind 17, Nr. 8. s. 699-708.
@article{e7c5ab1c5e5642a48a6eaea795f4c024,
title = "Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study",
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 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).",
author = "Patrick May and Simon Girard and Merle Harrer and Bobbili, {Dheeraj R} and Julian Schubert and Stefan Wolking and Felicitas Becker and Pamela Lachance-Touchette and Caroline Meloche and Micheline Gravel and Niturad, {Cristina E} and Julia Knaus and {De Kovel}, Carolien and Mohamad Toliat and Anne Polvi and Michele Iacomino and Rosa Guerrero-L{\'o}pez and St{\'e}phanie Baulac and Carla Marini and Holger Thiele and Janine Altm{\"u}ller and Kamel Jabbari and Ann-Kathrin Ruppert and Wiktor Jurkowski and Dennis Lal and Raffaella Rusconi and Sandrine Cest{\`e}le and Benedetta Terragni and Coombs, {Ian D} and Reid, {Christopher A} and Pasquale Striano and Hande Caglayan and Auli Siren and Kate Everett and M{\o}ller, {Rikke S} and Helle Hjalgrim and Hiltrud Muhle and Ingo Helbig and Kunz, {Wolfram S} and Weber, {Yvonne G} and Sarah Weckhuysen and Jonghe, {Peter De} and Sisodiya, {Sanjay M} and Rima Nabbout and Silvana Franceschetti and Antonietta Coppola and Vari, {Maria S} and {Kasteleijn-Nolst Trenit{\'e}}, Doroth{\'e}e and Betul Baykan and Marina Nikanorova and {EPICURE Consortium} and {EuroEPINOMICS CoGIE Consortium} and {EpiPGX Consortium}",
note = "Copyright {\circledC} 2018 Elsevier Ltd. All rights reserved.",
year = "2018",
month = "8",
doi = "10.1016/S1474-4422(18)30215-1",
language = "English",
volume = "17",
pages = "699--708",
journal = "Lancet Neurology",
issn = "1474-4422",
publisher = "TheLancet Publishing Group",
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Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies : an exome-based case-control study. / EPICURE Consortium; EuroEPINOMICS CoGIE Consortium; EpiPGX Consortium.

I: Lancet Neurology, Bind 17, Nr. 8, 08.2018, s. 699-708.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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 - Jonghe, Peter De

AU - Sisodiya, Sanjay M

AU - Nabbout, Rima

AU - Franceschetti, Silvana

AU - Coppola, Antonietta

AU - Vari, Maria S

AU - Kasteleijn-Nolst Trenité, Dorothée

AU - Baykan, Betul

AU - Nikanorova, Marina

AU - EPICURE Consortium

AU - EuroEPINOMICS CoGIE Consortium

AU - EpiPGX Consortium

N1 - Copyright © 2018 Elsevier Ltd. All rights reserved.

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).

U2 - 10.1016/S1474-4422(18)30215-1

DO - 10.1016/S1474-4422(18)30215-1

M3 - Journal article

C2 - 30033060

VL - 17

SP - 699

EP - 708

JO - Lancet Neurology

JF - Lancet Neurology

SN - 1474-4422

IS - 8

ER -