Reference : Distinct gene-set burden patterns underlie common generalized and focal epilepsies
Scientific journals : Article
Life sciences : Genetics & genetic processes
Human health sciences : Neurology
Systems Biomedicine
http://hdl.handle.net/10993/48457
Distinct gene-set burden patterns underlie common generalized and focal epilepsies
English
Koko, Mahmoud []
Krause, Roland mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core >]
Sander, Thomas []
Bobbili, Dheeraj Reddy mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core >]
Nothnagel, Michael []
May, Patrick mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core >]
Lerche, Holger []
Epi25 Collaborative []
24-Sep-2021
EBioMedicine
Elsevier
72
103588
Yes (verified by ORBilu)
International
2352-3964
Amsterdam
Netherlands
[en] Burden analysis ; Ultra-rare variants ; Gene-sets ; epilepsy ; Exome sequencing
[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.
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany).
Researchers ; Professionals ; General public
http://hdl.handle.net/10993/48457
10.1016/j.ebiom.2021.103588
https://www.sciencedirect.com/science/article/pii/S2352396421003819?via%3Dihub
FnR ; FNR11583046 > Roland Krause > MechEPI > Epileptogenesis Of Genetic Epilepsies > 01/04/2018 > 30/06/2021 > 2017

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