Distinct gene-set burden patterns underlie common generalized and focal epilepsies
Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved..
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).
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:72 |
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| Enthalten in: |
EBioMedicine - 72(2021) vom: 30. Okt., Seite 103588 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Koko, Mahmoud [VerfasserIn] |
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| Links: |
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| Themen: |
Burden analysis |
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| Anmerkungen: |
Date Completed 07.02.2022 Date Revised 07.12.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ebiom.2021.103588 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Distinct gene-set burden patterns underlie common generalized and focal epilepsies |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Revised 07.12.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a FUNDING: DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany) | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Burden analysis | |
| 650 | 4 | |a Epilepsy | |
| 650 | 4 | |a Exome sequencing | |
| 650 | 4 | |a Gene-sets | |
| 650 | 4 | |a Ultra-rare variants | |
| 700 | 1 | |a Krause, Roland |e verfasserin |4 aut | |
| 700 | 1 | |a Sander, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Bobbili, Dheeraj Reddy |e verfasserin |4 aut | |
| 700 | 1 | |a Nothnagel, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a May, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Lerche, Holger |e verfasserin |4 aut | |
| 700 | 0 | |a Epi25 Collaborative |e verfasserin |4 aut | |
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