Distinct gene-set burden patterns underlie common generalized and focal epilepsies.

Koko, Mahmoud ORCID: 0000-0001-9512-0184, Krause, Roland ORCID: 0000-0001-9938-7126, Sander, Thomas, Bobbili, Dheeraj Reddy ORCID: 0000-0002-1368-9623, Nothnagel, Michael, May, Patrick ORCID: 0000-0001-8698-3770, Lerche, Holger and Epi25 Collaborative,
(2021) Distinct gene-set burden patterns underlie common generalized and focal epilepsies. EBioMedicine, 72. 103588-.

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<h4>Background</h4>Analyses of few gene-sets in epilepsy showed a potential to unravel key disease associations. We set out to investigate the burden of ultra-rare variants (URVs) in a comprehensive range of biologically informed gene-sets presumed to be implicated in epileptogenesis.<h4>Methods</h4>The burden of 12 URV types in 92 gene-sets was compared between cases and controls using whole exome sequencing data from individuals of European descent with developmental and epileptic encephalopathies (DEE, n = 1,003), genetic generalized epilepsy (GGE, n = 3,064), or non-acquired focal epilepsy (NAFE, n = 3,522), collected by the Epi25 Collaborative, compared to 3,962 ancestry-matched controls.<h4>Findings</h4>Missense URVs in highly constrained regions were enriched in neuron-specific and developmental genes, whereas genes not expressed in brain were not affected. GGE featured a higher burden in gene-sets derived from inhibitory vs. excitatory neurons or associated receptors, whereas the opposite was found for NAFE, and DEE featured a burden in both. Top-ranked susceptibility genes from recent genome-wide association studies (GWAS) and gene-sets derived from generalized vs. focal epilepsies revealed specific enrichment patterns of URVs in GGE vs. NAFE.<h4>Interpretation</h4>Missense URVs affecting highly constrained sites differentially impact genes expressed in inhibitory vs. excitatory pathways in generalized vs. focal epilepsies. The excess of URVs in top-ranked GWAS risk-genes suggests a convergence of rare deleterious and common risk-variants in the pathogenesis of generalized and focal epilepsies.<h4>Funding</h4>DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany).

Item Type: Article
Uncontrolled Keywords: Epi25 Collaborative, Humans, Epilepsies, Partial, Epilepsy, Generalized, Genetic Predisposition to Disease, Case-Control Studies, Female, Male, Genetic Variation, Genome-Wide Association Study, Exome, Exome Sequencing
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 29 Sep 2023 09:18
Last Modified: 29 Sep 2023 09:18
DOI: 10.1016/j.ebiom.2021.103588
Open Access URL: https://doi.org/10.1016/j.ebiom.2021.103588
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3173193