| Title: |
Distinct gene-set burden patterns underlie common generalized and focal epilepsies |
| Authors: |
Koko M.; Krause R.; Sander T.; Bobbili D. R.; Nothnagel M.; May P.; Lerche H.; Epi25 Collaborative; Bisulli F.; Tinuper P.; Pippucci T. |
| Contributors: |
Koko M.; Krause R.; Sander T.; Bobbili D.R.; Nothnagel M.; May P.; Lerche H.; Epi25 Collaborative; Bisulli F.; Tinuper P.; Pippucci T. |
| Publication Year: |
2021 |
| Collection: |
IRIS Università degli Studi di Bologna (CRIS - Current Research Information System) |
| Subject Terms: |
Burden analysi; Epilepsy; Exome sequencing; Gene-set; Ultra-rare variant; Case-Control Studie; Epilepsies; Partial; Generalized; Exome; Female; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Human; Male; Whole Exome Sequencing |
| Description: |
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. Funding: DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany). |
| Document Type: |
article in journal/newspaper |
| File Description: |
ELETTRONICO |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/34571366; info:eu-repo/semantics/altIdentifier/wos/WOS:000703696900002; volume:72; firstpage:103588; lastpage:103588; numberofpages:13; journal:EBIOMEDICINE; http://hdl.handle.net/11585/854161; https://www.sciencedirect.com/science/article/pii/S2352396421003819?via=ihub |
| DOI: |
10.1016/j.ebiom.2021.103588 |
| Availability: |
http://hdl.handle.net/11585/854161; https://doi.org/10.1016/j.ebiom.2021.103588; https://www.sciencedirect.com/science/article/pii/S2352396421003819?via=ihub |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.3649CBC1 |
| Database: |
BASE |