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

Lancet Neurol
Authors
Keywords
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 receptors and was compared to the respective GABA 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 receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; p=0·0014, adjusted p=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=0·0081, adjusted p=0·016). Comparison of genes encoding GABA 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 receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; p=0·013, adjusted p=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 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).

Year of Publication
2018
Journal
Lancet Neurol
Volume
17
Issue
8
Pages
699-708
Date Published
2018 08
ISSN
1474-4465
DOI
10.1016/S1474-4422(18)30215-1
PubMed ID
30033060
Links
Grant list
G0800637 / Medical Research Council / United Kingdom
086185/Z/08/Z / Wellcome Trust / United Kingdom
MR/J002976/1 / Medical Research Council / United Kingdom
Department of Health / United Kingdom