Association of ultra-rare coding variants with genetic generalized epilepsy: A case–control whole exome sequencing study

Canadian Epilepsy Network, Epi4K Consortium, Epilepsy Phenome/Genome Project, EpiPGX Consortium, EuroEPINOMICS-CoGIE Consortium

Research output: Contribution to journalArticlepeer-review

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Abstract

Objective: We aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE. Methods: We performed a case–control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants (URVs; in 18 834 protein-coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19 genes encoding γ-aminobutyric acid type A [GABAA] receptors, 113 genes representing the GABAergic pathway). Results: GABRG2 was associated with GGE (p = 1.8 × 10−5), approaching study-wide significance in familial GGE (p = 3.0 × 10−6), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABAA receptors were associated with familial GGE (odds ratio [OR] = 3.9, 95% confidence interval [CI] = 1.9–7.8, false discovery rate [FDR]-adjusted p =.0024), whereas their association with sporadic GGE had marginally lower odds (OR = 3.1, 95% CI = 1.3–6.7, FDR-adjusted p =.022). URVs in GABAergic pathway genes were associated with familial GGE (OR = 1.8, 95% CI = 1.3–2.5, FDR-adjusted p =.0024) but not with sporadic GGE (OR = 1.3, 95% CI =.9–1.9, FDR-adjusted p =.19). Significance: URVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.

Original languageEnglish (US)
Pages (from-to)723-735
Number of pages13
JournalEpilepsia
Volume63
Issue number3
DOIs
StatePublished - Mar 2022

Bibliographical note

Funding Information:
We thank the individuals who participated in the Canadian Epilepsy Network (CENet), Epi4K, Epilepsy Phenome/Genome Project (EP/GP), EpiPGX, and EuroEPINOMICS-CoGIE studies. This work was supported by Research Unit FOR-2715 of the German Research Foundation, the National Research Fund of Luxembourg (DFG/FNR grants INTER/DFG/17/11583046 and Le1030/16-1), and ?Stiftung no epilep? (to Holger Lerche). M.K. was support by the German Academic Exchange Service (DAAD program number 57214224; doctoral grant to M.K.). J.E.M. is supported by the National Institutes of Health (TL1TR001875). P.M. obtained FNR funding as part of the National Centre of Excellence in Research on Parkinson?s Disease (NCER-PD, FNR11264123). CENet received joint funding from Genome Canada and Genome Quebec. The Epi4K consortium and EP/GP were supported by grants from the National Institute of Neurological Disorders and Stroke and Epilepsy-Research UK. The EpiPGX projects were supported by the European Commission Sixth and Seventh Framework Programs. The EuroEPINOMICS project was supported by the European Science Foundation through contributing national funding agencies. We are thankful to the Epi25 Collaborative for providing access to their control cohort of Italian individuals, which was of great help to match the southern European samples. This work used sequence data available through dbGaP under the accession numbers phs000806 and phs000572 or the European Nucleotide Archive under the accession number PRJEB20726. A full acknowledgment statement is provided in the Supplementary Material. Open access funding enabled and organized by ProjektDEAL.

Funding Information:
We thank the individuals who participated in the Canadian Epilepsy Network (CENet), Epi4K, Epilepsy Phenome/Genome Project (EP/GP), EpiPGX, and EuroEPINOMICS‐CoGIE studies. This work was supported by Research Unit FOR‐2715 of the German Research Foundation, the National Research Fund of Luxembourg (DFG/FNR grants INTER/DFG/17/11583046 and Le1030/16‐1), and ‘Stiftung no epilep’ (to Holger Lerche). M.K. was support by the German Academic Exchange Service (DAAD program number 57214224; doctoral grant to M.K.). J.E.M. is supported by the National Institutes of Health (TL1TR001875). P.M. obtained FNR funding as part of the National Centre of Excellence in Research on Parkinson’s Disease (NCER‐PD, FNR11264123). CENet received joint funding from Genome Canada and Genome Quebec. The Epi4K consortium and EP/GP were supported by grants from the National Institute of Neurological Disorders and Stroke and Epilepsy‐Research UK. The EpiPGX projects were supported by the European Commission Sixth and Seventh Framework Programs. The EuroEPINOMICS project was supported by the European Science Foundation through contributing national funding agencies. We are thankful to the Epi25 Collaborative for providing access to their control cohort of Italian individuals, which was of great help to match the southern European samples. This work used sequence data available through dbGaP under the accession numbers phs000806 and phs000572 or the European Nucleotide Archive under the accession number PRJEB20726. A full acknowledgment statement is provided in the Supplementary Material. Open access funding enabled and organized by ProjektDEAL.

Publisher Copyright:
© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Keywords

  • GABA receptors
  • GABRG2
  • GGE
  • familial epilepsy
  • sporadic epilepsy

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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