@article{0a4dd83b472b4b97b3655189119ac693,
title = "Distinct gene-set burden patterns underlie common generalized and focal epilepsies",
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. Funding: DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany).",
keywords = "Burden analysis, Epilepsy, Exome sequencing, Gene-sets, Ultra-rare variants",
author = "{Epi25 Collaborative} and Mahmoud Koko and Roland Krause and Thomas Sander and Bobbili, {Dheeraj Reddy} and Michael Nothnagel and Patrick May and Holger Lerche and Feng, {Yen Chen Anne} and Howrigan, {Daniel P.} and Abbott, {Liam E.} and Katherine Tashman and Felecia Cerrato and Tarjinder Singh and Henrike Heyne and Byrnes, {Andrea E.} and Claire Churchhouse and Nick Watts and Matthew Solomonson and Dennis Lal and Namrata Gupta and Gabriel, {Stacey B.} and Daly, {Mark J.} and Lander, {Eric S.} and Neale, {Benjamin M.} and Berkovic, {Samuel F.} and Goldstein, {David B.} and Lowenstein, {Daniel H.} and Cavalleri, {Gianpiero L.} and Patrick Cossette and Chris Cotsapas and {De Jonghe}, Peter and Tracy Dixon-Salazar and Renzo Guerrini and Hakon Hakonarson and Heinzen, {Erin L.} and Dhindsa, {Ryan S.} and Stanley, {Kate E.} and Ingo Helbig and Patrick Kwan and Marson, {Anthony G.} and Slav{\'e} Petrovski and Sitharthan Kamalakaran and Sisodiya, {Sanjay M.} and Randy Stewart and Sarah Weckhuysen and Chantal Depondt and Dlugos, {Dennis J.} and Scheffer, {Ingrid E.} and Korczyn, {Amos D.} and Cherny, {Stacey S.}",
note = "Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = oct,
doi = "10.1016/j.ebiom.2021.103588",
language = "אנגלית",
volume = "72",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
}