Universität zu Köln

Koko, Mahmoud ORCID: 0000-0001-9512-0184, Krause, Roland ORCID: 0000-0001-9938-7126, Sander, Thomas, Bobbili, Dheeraj Reddy, Nothnagel, Michael, May, Patrick ORCID: 0000-0001-8698-3770 and Lerche, Holger (2021). Distinct gene-set burden patterns underlie common generalized and focal epilepsies. EBioMedicine, 72. AMSTERDAM: ELSEVIER. ISSN 2352-3964

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Abstract

Background: 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. Methods: 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. Findings: 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. Interpretation: 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. (C) 2021 The Authors. Published by Elsevier B.V.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Koko, Mahmoud UNSPECIFIED orcid.org/0000-0001-9512-0184 UNSPECIFIED Krause, Roland UNSPECIFIED orcid.org/0000-0001-9938-7126 UNSPECIFIED Sander, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Bobbili, Dheeraj Reddy UNSPECIFIED UNSPECIFIED UNSPECIFIED Nothnagel, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED May, Patrick UNSPECIFIED orcid.org/0000-0001-8698-3770 UNSPECIFIED Lerche, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-585491
DOI:	10.1016/j.ebiom.2021.103588
Journal or Publication Title:	EBioMedicine
Volume:	72
Date:	2021
Publisher:	ELSEVIER
Place of Publication:	AMSTERDAM
ISSN:	2352-3964
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RARE CODING VARIANTS; DE-NOVO MUTATIONS; ION CHANNELS; GENOME; LOCALIZATION; INDIVIDUALS; MECHANISMS; SIGNATURES; RECEPTORS; FRAMEWORK Multiple languages Medicine, General & Internal; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58549