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

	Document type :	Scientific journals : Article
	Discipline(s) :	Life sciences : Genetics & genetic processes Human health sciences : Neurology
	Focus Areas :	Systems Biomedicine
	To cite this reference:	http://hdl.handle.net/10993/48457

Title :	Distinct gene-set burden patterns underlie common generalized and focal epilepsies
Language :	English
Author, co-author :	Koko, Mahmoud []
	Krause, Roland [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core >]
	Sander, Thomas []
	Bobbili, Dheeraj Reddy [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core >]
	Nothnagel, Michael []
	May, Patrick [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core >]
	Lerche, Holger []
	Epi25 Collaborative []
Publication date :	24-Sep-2021
Journal title :	EBioMedicine
Publisher :	Elsevier
Volume :	72
Pages :	103588
Peer reviewed :	Yes (verified by ORBilu)
Audience :	International
e-ISSN :	2352-3964
City :	Amsterdam
Country :	Netherlands
Keywords :	[en] Burden analysis ; Ultra-rare variants ; Gene-sets ; epilepsy ; Exome sequencing
Abstract :	[en] 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.
Research centres :	Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Funders :	DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany).
Target :	Researchers ; Professionals ; General public
Permalink :	http://hdl.handle.net/10993/48457
DOI :	10.1016/j.ebiom.2021.103588
Other URL :	https://www.sciencedirect.com/science/article/pii/S2352396421003819?via%3Dihub
FnR project :	FnR ; FNR11583046 > Roland Krause > MechEPI > Epileptogenesis Of Genetic Epilepsies > 01/04/2018 > 30/06/2021 > 2017

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