Association of ultra‐rare coding variants with genetic generalized epilepsy: A case–control whole exome sequencing study. Issue 3 (15th January 2022)

• Record Type: Journal Article
• Authors: Koko, Mahmoud; Motelow, Joshua E.; Stanley, Kate E.; Bobbili, Dheeraj R.; Dhindsa, Ryan S.; May, Patrick
• Other Names: Alldredge Brian K. investigator.; Allen Andrew S. investigator.; Altmüller Janine investigator.; Amrom Dina investigator.; Andermann Eva investigator.; Auce Pauls investigator.; Avbersek Andreja investigator.; Baulac Stéphanie investigator.; Bautista Jocelyn F. investigator.; Becker Felicitas investigator.; Bellows Susannah T. investigator.; Berghuis Bianca investigator.; Berkovic Samuel F. investigator.; Bluvstein Judith investigator.; Boro Alex investigator.; Bridgers Joshua investigator.; Burgess Rosemary investigator.; Caglayan Hande investigator.; Cascino Gregory D. investigator.; Cavalleri Gianpiero L. investigator.; Chung Seo‐Kyung investigator.; Cieuta‐Walti Cécile investigator.; Cloutier Véronique investigator.; Consalvo Damian investigator.; Cossette Patrick investigator.; Crumrine Patricia investigator.; Delanty Norman investigator.; Depondt Chantal investigator.; Desbiens Richard investigator.; Devinsky Orrin investigator.; Dlugos Dennis investigator.; Epstein Michael P. investigator.; Everett Kate investigator.; Fiol Miguel investigator.; Fountain Nathan B. investigator.; Francis Ben investigator.; French Jacqueline investigator.; Freyer Catharine investigator.; Friedman Daniel investigator.; Gambardella Antonio investigator.; Geller Eric B. investigator.; Girard Simon investigator.; Glauser Tracy investigator.; Glynn Simon investigator.; Goldstein David B. investigator.; Gravel Micheline investigator.; Haas Kevin investigator.; Haut Sheryl R. investigator.; Heinzen Erin L. investigator.; Helbig Ingo investigator.; Hildebrand Michael S. investigator.; Johnson Michael R. investigator.; Jorgensen Andrea investigator.; Joshi Sucheta investigator.; Kanner Andres investigator.; Kirsch Heidi E. investigator.; Klein Karl M. investigator.; Knowlton Robert C. investigator.; Koeleman Bobby P. C. investigator.; Kossoff Eric H. investigator.; Krause Roland investigator.; Krenn Martin investigator.; Kunz Wolfram S. investigator.; Kuzniecky Ruben investigator.; Langley Sarah R. investigator.; LeGuern Eric investigator.; Lehesjoki Anna‐Elina investigator.; Lerche Holger investigator.; Leu Costin investigator.; Lortie Anne investigator.; Lowenstein Daniel H. investigator.; Marson Anthony G. investigator.; Mebane Caroline investigator.; Mefford Heather C. investigator.; Meloche Caroline investigator.; Moreau Claudia investigator.; Motika Paul V. investigator.; Muhle Hiltrud investigator.; Møller Rikke S. investigator.; Nabbout Rima investigator.; Nguyen Dang K. investigator.; Nikanorova Marina investigator.; Novotny Edward J. investigator.; Nürnberg Peter investigator.; Ottman Ruth investigator.; O'Brien Terence J. investigator.; Paolicchi Juliann M. investigator.; Parent Jack M. investigator.; Park Kristen investigator.; Peter Sarah investigator.; Petrou Steven investigator.; Petrovski Slavé investigator.; Pickrell William O. investigator.; Poduri Annapurna investigator.; Radtke Rodney A. investigator.; Rees Mark I. investigator.; Regan Brigid M. investigator.; Ren Zhong investigator.; Sadleir Lynette G. investigator.; Sander Josemir W. investigator.; Sander Thomas investigator.; Scheffer Ingrid E. investigator.; Schubert Julian investigator.; Shellhaas Renée A. investigator.; Sherr Elliott H. investigator.; Shih Jerry J. investigator.; Shinnar Shlomo investigator.; Sills Graeme J. investigator.; Singh Rani K. investigator.; Siren Auli investigator.; Sirven Joseph investigator.; Sisodiya Sanjay M. investigator.; Smith Michael C. investigator.; Sonsma Anja C. M. investigator.; Striano Pasquale investigator.; Sullivan Joseph investigator.; Thio Liu Lin investigator.; Thomas Rhys H. investigator.; Venkat Anu investigator.; Vining Eileen P. G. investigator.; Von Allmen Gretchen K. investigator.; Wang Quanli investigator.; Weber Yvonne G. investigator.; Weckhuysen Sarah investigator.; Weisenberg Judith L. investigator.; Widdess‐Walsh Peter investigator.; Winawer Melodie R. investigator.; Wolking Stefan investigator.; Zara Federico investigator.; Zimprich Fritz investigator.;
• Is Part Of: Epilepsia. Volume 63:Issue 3(2022)
• Page Start: 723
• Page End: 735
• Publication Date: 2022-01-15
• Subjects: familial epilepsy -- GABAA receptors -- GABRG2 -- GGE -- sporadic epilepsy; Epilepsy -- Periodicals; 616.853
• DOI: 10.1111/epi.17166
• Languages: English
• ISSNs: 0013-9580

Abstract

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.