| Title: |
Distinct gene-set burden patterns underlie common generalized and focal epilepsies |
| Authors: |
Koko, M; Krause, R; Sander, T; Bobbili, DR; Nothnagel, M; May, P; Lerche, H; Feng, YCA; Howrigan, DP; Abbott, LE; Tashman, K; Cerrato, F; Singh, T; Heyne, H; Byrnes, AE; Churchhouse, C; Watts, N; Solomonson, M; Lal, D; Gupta, N; Gabriel, SB; Daly, MJ; Lander, ES; Neale, BM; Berkovic, SF; Goldstein, DB; Lowenstein, DH; Cavalleri, GL; Cossette, P; Cotsapas, C; De Jonghe, P; Dixon-Salazar, T; Guerrini, R; Hakonarson, H; Heinzen, EL; Dhindsa, RS; Stanley, KE; Helbig, I; Kwan, P; Marson, AG; Petrovski, S; Kamalakaran, S; Sisodiya, SM; Stewart, R; Weckhuysen, S; Depondt, C; Dlugos, DJ; Scheffer, IE; Striano, P; Freyer, C; McKenna, K; Regan, BM; Bellows, ST; Leu, C; Bennett, CA; Johns, EMC; MacDonald, A; Shilling, H; Burgess, R; Weckhuysen, D; Bahlo, M; O'Brien, TJ; Todaro, M; Stamberger, H; Andrade, DM; Sadoway, TR; Mo, K; Krestel, H; Gallati, S; Papacostas, SS; Kousiappa, I; Tanteles, GA; Štěrbová, K; Vlčková, M; Sedláčková, L; Laššuthová, P; Klein, KM; Rosenow, F; Reif, PS; Knake, S; Kunz, WS; Zsurka, G; Elger, CE; Bauer, J; Rademacher, M; Pendziwiat, M; Muhle, H; Rademacher, A; Van Baalen, A; Von Spiczak, S; Stephani, U; Afawi, Z; Korczyn, AD; Kanaan, M; Canavati, C; Kurlemann, G; Müller-Schlüter, K; Kluger, G; Häusler, M; Blatt, I |
| Publisher Information: |
ELSEVIER |
| Publication Year: |
2021 |
| Collection: |
The University of Melbourne: Digital Repository |
| 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 |
| Language: |
English |
| ISSN: |
2352-3964 |
| Relation: |
https://hdl.handle.net/11343/307075 |
| Availability: |
https://hdl.handle.net/11343/307075 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 ; CC BY |
| Accession Number: |
edsbas.7C08E1D |
| Database: |
BASE |