Reference : Association of ultra-rare coding variants with genetic generalized epilepsy: A case–c...
Scientific journals : Article
Life sciences : Genetics & genetic processes
Human health sciences : Neurology
Systems Biomedicine
http://hdl.handle.net/10993/49673
Association of ultra-rare coding variants with genetic generalized epilepsy: A case–control whole exome sequencing study
English
Koko, Mahmoud [> >]
Motelow, Joshua E. [> >]
Stanley, Kate E. [> >]
Bobbili, Dheeraj Reddy mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core]
Dhindsa, Ryan S. [> >]
May, Patrick mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core]
Network, Canadian Epilepsy [> >]
Consortium, Epi K. [> >]
Project, Epilepsy Phenome Genome [> >]
Consortium, Epipgx [> >]
Consortium, Euroepinomics-Cogie [> >]
15-Jan-2022
Epilepsia
Blackwell
Yes (verified by ORBilu)
International
0013-9580
1528-1167
Oxford
United Kingdom
[en] familial epilepsy ; GABAA receptors ; GABRG2 ; GGE ; sporadic epilepsy
[en] Abstract Objective We aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE. Methods We performed a case–control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants (URVs; in 18 834 protein-coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19 genes encoding γ-aminobutyric acid type A [GABAA] receptors, 113 genes representing the GABAergic pathway). Results GABRG2 was associated with GGE (p = 1.8 × 10−5), approaching study-wide significance in familial GGE (p = 3.0 × 10−6), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABAA receptors were associated with familial GGE (odds ratio [OR] = 3.9, 95 confidence interval [CI] = 1.9–7.8, false discovery rate [FDR]-adjusted p = .0024), whereas their association with sporadic GGE had marginally lower odds (OR = 3.1, 95 CI = 1.3–6.7, FDR-adjusted p = .022). URVs in GABAergic pathway genes were associated with familial GGE (OR = 1.8, 95 CI = 1.3–2.5, FDR-adjusted p = .0024) but not with sporadic GGE (OR = 1.3, 95 CI = .9–1.9, FDR-adjusted p = .19). Significance URVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Fonds National de la Recherche - FnR
MechEPI
Researchers ; Professionals
http://hdl.handle.net/10993/49673
10.1111/epi.17166
https://onlinelibrary.wiley.com/doi/abs/10.1111/epi.17166
FnR ; FNR11583046 > Roland Krause > MechEPI > Epileptogenesis Of Genetic Epilepsies > 01/04/2018 > 30/06/2021 > 2017

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