TY - JOUR
T1 - Association of ultra-rare coding variants with genetic generalized epilepsy
T2 - A case–control whole exome sequencing study
AU - Canadian Epilepsy Network
AU - Epi4K Consortium
AU - Epilepsy Phenome/Genome Project
AU - EpiPGX Consortium
AU - EuroEPINOMICS-CoGIE Consortium
AU - Koko, Mahmoud
AU - Motelow, Joshua E.
AU - Stanley, Kate E.
AU - Bobbili, Dheeraj R.
AU - Dhindsa, Ryan S.
AU - May, Patrick
AU - Alldredge, Brian K.
AU - Allen, Andrew S.
AU - Altmüller, Janine
AU - Amrom, Dina
AU - Andermann, Eva
AU - Auce, Pauls
AU - Avbersek, Andreja
AU - Baulac, Stéphanie
AU - Bautista, Jocelyn F.
AU - Becker, Felicitas
AU - Bellows, Susannah T.
AU - Berghuis, Bianca
AU - Berkovic, Samuel F.
AU - Bluvstein, Judith
AU - Boro, Alex
AU - Bridgers, Joshua
AU - Burgess, Rosemary
AU - Caglayan, Hande
AU - Cascino, Gregory D.
AU - Cavalleri, Gianpiero L.
AU - Chung, Seo Kyung
AU - Cieuta-Walti, Cécile
AU - Cloutier, Véronique
AU - Consalvo, Damian
AU - Cossette, Patrick
AU - Crumrine, Patricia
AU - Delanty, Norman
AU - Depondt, Chantal
AU - Desbiens, Richard
AU - Devinsky, Orrin
AU - Dlugos, Dennis
AU - Epstein, Michael P.
AU - Everett, Kate
AU - Fiol, Miguel
AU - Fountain, Nathan B.
AU - Francis, Ben
AU - French, Jacqueline
AU - Freyer, Catharine
AU - Friedman, Daniel
AU - Gambardella, Antonio
AU - Geller, Eric B.
AU - Girard, Simon
AU - Haut, Sheryl R.
AU - Shinnar, Shlomo
N1 - Publisher Copyright:
© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
KW - GABA receptors
KW - GABRG2
KW - GGE
KW - familial epilepsy
KW - sporadic epilepsy
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U2 - 10.1111/epi.17166
DO - 10.1111/epi.17166
M3 - Article
C2 - 35032048
AN - SCOPUS:85122822705
SN - 0013-9580
VL - 63
SP - 723
EP - 735
JO - Epilepsia
JF - Epilepsia
IS - 3
ER -