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.
| Original language | English |
|---|---|
| Pages (from-to) | 723-735 |
| Number of pages | 13 |
| Journal | Epilepsia |
| Volume | 63 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 2022 |
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In: Epilepsia, Vol. 63, No. 3, 03.2022, p. 723-735.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Association of ultra-rare coding variants with genetic generalized epilepsy
T2 - A case–control whole exome sequencing study
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 - Glauser, Tracy
AU - Glynn, Simon
AU - Goldstein, David B.
AU - Gravel, Micheline
AU - Haas, Kevin
AU - Haut, Sheryl R.
AU - Heinzen, Erin L.
AU - Helbig, Ingo
AU - Hildebrand, Michael S.
AU - Johnson, Michael R.
AU - Jorgensen, Andrea
AU - Joshi, Sucheta
AU - Kanner, Andres
AU - Kirsch, Heidi E.
AU - Klein, Karl M.
AU - Knowlton, Robert C.
AU - Koeleman, Bobby P.C.
AU - Kossoff, Eric H.
AU - Krause, Roland
AU - Krenn, Martin
AU - Kunz, Wolfram S.
AU - Kuzniecky, Ruben
AU - Langley, Sarah R.
AU - LeGuern, Eric
AU - Lehesjoki, Anna Elina
AU - Lerche, Holger
AU - Leu, Costin
AU - Lortie, Anne
AU - Lowenstein, Daniel H.
AU - Marson, Anthony G.
AU - Mebane, Caroline
AU - Mefford, Heather C.
AU - Meloche, Caroline
AU - Moreau, Claudia
AU - Motika, Paul V.
AU - Muhle, Hiltrud
AU - Møller, Rikke S.
AU - Nabbout, Rima
AU - Nguyen, Dang K.
AU - Nikanorova, Marina
AU - Novotny, Edward J.
AU - Nürnberg, Peter
AU - Ottman, Ruth
AU - O’Brien, Terence J.
AU - Paolicchi, Juliann M.
AU - Parent, Jack M.
AU - Park, Kristen
AU - Peter, Sarah
AU - Petrou, Steven
AU - Petrovski, Slavé
AU - Pickrell, William O.
AU - Poduri, Annapurna
AU - Radtke, Rodney A.
AU - Rees, Mark I.
AU - Regan, Brigid M.
AU - Ren, Zhong
AU - Sadleir, Lynette G.
AU - Sander, Josemir W.
AU - Sander, Thomas
AU - Scheffer, Ingrid E.
AU - Schubert, Julian
AU - Shellhaas, Renée A.
AU - Sherr, Elliott H.
AU - Shih, Jerry J.
AU - Shinnar, Shlomo
AU - Sills, Graeme J.
AU - Singh, Rani K.
AU - Siren, Auli
AU - Sirven, Joseph
AU - Sisodiya, Sanjay M.
AU - Smith, Michael C.
AU - Sonsma, Anja C.M.
AU - Striano, Pasquale
AU - Sullivan, Joseph
AU - Thio, Liu Lin
AU - Thomas, Rhys H.
AU - Venkat, Anu
AU - Vining, Eileen P.G.
AU - Von Allmen, Gretchen K.
AU - Wang, Quanli
AU - Weber, Yvonne G.
AU - Weckhuysen, Sarah
AU - Weisenberg, Judith L.
AU - Widdess-Walsh, Peter
AU - Winawer, Melodie R.
AU - Wolking, Stefan
AU - Zara, Federico
AU - Zimprich, Fritz
AU - Canadian Epilepsy Network
AU - Epi4K Consortium
AU - Epilepsy Phenome/Genome Project
AU - EpiPGX Consortium
AU - EuroEPINOMICS-CoGIE Consortium
N1 - Funding Information: We thank the individuals who participated in the Canadian Epilepsy Network (CENet), Epi4K, Epilepsy Phenome/Genome Project (EP/GP), EpiPGX, and EuroEPINOMICS‐CoGIE studies. This work was supported by Research Unit FOR‐2715 of the German Research Foundation, the National Research Fund of Luxembourg (DFG/FNR grants INTER/DFG/17/11583046 and Le1030/16‐1), and ‘Stiftung no epilep’ (to Holger Lerche). M.K. was support by the German Academic Exchange Service (DAAD program number 57214224; doctoral grant to M.K.). J.E.M. is supported by the National Institutes of Health (TL1TR001875). P.M. obtained FNR funding as part of the National Centre of Excellence in Research on Parkinson’s Disease (NCER‐PD, FNR11264123). CENet received joint funding from Genome Canada and Genome Quebec. The Epi4K consortium and EP/GP were supported by grants from the National Institute of Neurological Disorders and Stroke and Epilepsy‐Research UK. The EpiPGX projects were supported by the European Commission Sixth and Seventh Framework Programs. The EuroEPINOMICS project was supported by the European Science Foundation through contributing national funding agencies. We are thankful to the Epi25 Collaborative for providing access to their control cohort of Italian individuals, which was of great help to match the southern European samples. This work used sequence data available through dbGaP under the accession numbers phs000806 and phs000572 or the European Nucleotide Archive under the accession number PRJEB20726. A full acknowledgment statement is provided in the Supplementary Material. Open access funding enabled and organized by ProjektDEAL. 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.
UR - http://www.scopus.com/inward/record.url?scp=85122822705&partnerID=8YFLogxK
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 -