Article (Scientific journals)
Distinct gene-set burden patterns underlie common generalized and focal epilepsies
Koko, Mahmoud; Krause, Roland; Sander, Thomas et al.
2021In EBioMedicine, 72, p. 103588
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Keywords :
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 center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Neurology
Genetics & genetic processes
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
External co-authors :
yes
Language :
English
Title :
Distinct gene-set burden patterns underlie common generalized and focal epilepsies
Publication date :
24 September 2021
Journal title :
EBioMedicine
ISSN :
2352-3964
Publisher :
Elsevier, Amsterdam, Netherlands
Volume :
72
Pages :
103588
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
FnR Project :
FNR11583046 - Epileptogenesis Of Genetic Epilepsies, 2017 (01/04/2018-30/06/2021) - Roland Krause
Funders :
DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany).
Available on ORBilu :
since 28 October 2021

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