Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals

Epi25 Collaborative, (2019) Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals. American Journal of Human Genetics, 105(2), pp. 267-282. (doi: 10.1016/j.ajhg.2019.05.020) (PMID:31327507) (PMCID:PMC6698801)

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Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.

Item Type:Articles
Additional Information:This work is part of the Centers for Common Disease Genomics (CCDG) program, funded by the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI). CCDG research activities at the Broad Institute was supported by NHGRI grant UM1 HG008895. The Genome Sequencing Program efforts were also supported by NHGRI grant 5U01HG009088-02. Supplemental grant for Epi25 phenotyping was supported by “Epi25 Clinical Phenotyping R03”, National Institutes of Health (1R03NS108145-01), with D.H.L and S.F.B as the principal investigators.
Glasgow Author(s) Enlighten ID:Sills, Dr Graeme
Authors: Epi25 Collaborative,
College/School:College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:American Journal of Human Genetics
ISSN (Online):1537-6605
Published Online:18 July 2019
Copyright Holders:Copyright © 2019 American Society of Human Genetics
First Published:First published in American Journal of Human Genetics 105(2):267-282
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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