Ultra-Rare Genetic Variation in the Epilepsies : A Whole-Exome Sequencing Study of 17,606 Individuals

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Epi25 Collaborative , Genomic Psychiat Cohort GPC Consor , Feng , Y-C A , Howrigan , D P , Heyne , H , Linnankivi , T , Lehesjoki , A-E , Palotie , A , Daly , M J & Neale , B M 2019 , ' Ultra-Rare Genetic Variation in the Epilepsies : A Whole-Exome Sequencing Study of 17,606 Individuals ' , American Journal of Human Genetics , vol. 105 , no. 2 , pp. 267-282 . https://doi.org/10.1016/j.ajhg.2019.05.020

Title: Ultra-Rare Genetic Variation in the Epilepsies : A Whole-Exome Sequencing Study of 17,606 Individuals
Author: Epi25 Collaborative; Genomic Psychiat Cohort GPC Consor; Feng, Yen-Chen Anne; Howrigan, Daniel P.; Heyne, Henrike; Linnankivi, Tarja; Lehesjoki, Anna-Elina; Palotie, Aarno; Daly, Mark J.; Neale, Benjamin M.
Contributor organization: Institute for Molecular Medicine Finland
Children's Hospital
HUS Children and Adolescents
Department of Medical and Clinical Genetics
University Management
Centre of Excellence in Complex Disease Genetics
Aarno Palotie / Principal Investigator
Genomics of Neurological and Neuropsychiatric Disorders
Date: 2019-08
Language: eng
Number of pages: 16
Belongs to series: American Journal of Human Genetics
ISSN: 0002-9297
DOI: https://doi.org/10.1016/j.ajhg.2019.05.020
URI: http://hdl.handle.net/10138/312995
Abstract: 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 GABA(A) 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 CACNAIG, 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.
3111 Biomedicine
1184 Genetics, developmental biology, physiology
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: draft

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