TY - JOUR
T1 - Distinct gene-set burden patterns underlie common generalized and focal epilepsies
AU - Epi25 Collaborative
AU - Koko, Mahmoud
AU - Krause, Roland
AU - Sander, Thomas
AU - Bobbili, Dheeraj Reddy
AU - Nothnagel, Michael
AU - May, Patrick
AU - Lerche, Holger
AU - Feng, Yen Chen Anne
AU - Howrigan, Daniel P.
AU - Abbott, Liam E.
AU - Tashman, Katherine
AU - Cerrato, Felecia
AU - Singh, Tarjinder
AU - Heyne, Henrike
AU - Byrnes, Andrea E.
AU - Churchhouse, Claire
AU - Watts, Nick
AU - Solomonson, Matthew
AU - Lal, Dennis
AU - Gupta, Namrata
AU - Gabriel, Stacey B.
AU - Daly, Mark J.
AU - Lander, Eric S.
AU - Neale, Benjamin M.
AU - Berkovic, Samuel F.
AU - Goldstein, David B.
AU - Lowenstein, Daniel H.
AU - Cavalleri, Gianpiero L.
AU - Cossette, Patrick
AU - Cotsapas, Chris
AU - De Jonghe, Peter
AU - Dixon-Salazar, Tracy
AU - Guerrini, Renzo
AU - Hakonarson, Hakon
AU - Heinzen, Erin L.
AU - Dhindsa, Ryan S.
AU - Stanley, Kate E.
AU - Helbig, Ingo
AU - Kwan, Patrick
AU - Marson, Anthony G.
AU - Petrovski, Slavé
AU - Kamalakaran, Sitharthan
AU - Sisodiya, Sanjay M.
AU - Stewart, Randy
AU - Weckhuysen, Sarah
AU - Depondt, Chantal
AU - Dlugos, Dennis J.
AU - Scheffer, Ingrid E.
AU - Buono, Russell J.
AU - Ferraro, Thomas N.
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/10
Y1 - 2021/10
N2 - 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).
AB - 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).
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U2 - 10.1016/j.ebiom.2021.103588
DO - 10.1016/j.ebiom.2021.103588
M3 - Article
C2 - 34571366
AN - SCOPUS:85115643859
SN - 2352-3964
VL - 72
JO - EBioMedicine
JF - EBioMedicine
M1 - 103588
ER -