@article{2cca53c0671a4e20b29f3491b265aa18,
title = "Association of ultra-rare coding variants with genetic generalized epilepsy: A case–control whole exome sequencing study",
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.",
keywords = "GABA receptors, GABRG2, GGE, familial epilepsy, sporadic epilepsy",
author = "{Canadian Epilepsy Network} and {Epi4K Consortium} and {Epilepsy Phenome/Genome Project} and {EpiPGX Consortium} and {EuroEPINOMICS-CoGIE Consortium} and Mahmoud Koko and Motelow, {Joshua E.} and Stanley, {Kate E.} and Bobbili, {Dheeraj R.} and Dhindsa, {Ryan S.} and Patrick May and Alldredge, {Brian K.} and Allen, {Andrew S.} and Janine Altm{\"u}ller and Dina Amrom and Eva Andermann and Pauls Auce and Andreja Avbersek and St{\'e}phanie Baulac and Bautista, {Jocelyn F.} and Felicitas Becker and Bellows, {Susannah T.} and Bianca Berghuis and Berkovic, {Samuel F.} and Judith Bluvstein and Alex Boro and Joshua Bridgers and Rosemary Burgess and Hande Caglayan and Cascino, {Gregory D.} and Cavalleri, {Gianpiero L.} and Chung, {Seo Kyung} and C{\'e}cile Cieuta-Walti and V{\'e}ronique Cloutier and Damian Consalvo and Patrick Cossette and Patricia Crumrine and Norman Delanty and Chantal Depondt and Richard Desbiens and Orrin Devinsky and Dennis Dlugos and Epstein, {Michael P.} and Kate Everett and Miguel Fiol and Fountain, {Nathan B.} and Ben Francis and Jacqueline French and Catharine Freyer and Daniel Friedman and Antonio Gambardella and Geller, {Eric B.} and Simon Girard and Tracy Glauser and Simon Glynn and Goldstein, {David B.} and Micheline Gravel and Kevin Haas and Haut, {Sheryl R.} and Heinzen, {Erin L.} and Ingo Helbig and Hildebrand, {Michael S.} and Johnson, {Michael R.} and Andrea Jorgensen and Sucheta Joshi and Andres Kanner and Kirsch, {Heidi E.} and Klein, {Karl M.} and Knowlton, {Robert C.} and Koeleman, {Bobby P.C.} and Kossoff, {Eric H.} and Roland Krause and Martin Krenn and Kunz, {Wolfram S.} and Ruben Kuzniecky and Langley, {Sarah R.} and Eric LeGuern and Lehesjoki, {Anna Elina} and Holger Lerche and Costin Leu and Anne Lortie and Lowenstein, {Daniel H.} and Marson, {Anthony G.} and Caroline Mebane and Mefford, {Heather C.} and Caroline Meloche and Claudia Moreau and Motika, {Paul V.} and Hiltrud Muhle and M{\o}ller, {Rikke S.} and Rima Nabbout and Nguyen, {Dang K.} and Marina Nikanorova and Novotny, {Edward J.} and Peter N{\"u}rnberg and Ruth Ottman and O{\textquoteright}Brien, {Terence J.} and Paolicchi, {Juliann M.} and Parent, {Jack M.} and Kristen Park and Sarah Peter and Steven Petrou and Slav{\'e} Petrovski and Pickrell, {William O.} and Annapurna Poduri and Radtke, {Rodney A.} and Rees, {Mark I.} and Regan, {Brigid M.} and Zhong Ren and Sadleir, {Lynette G.} and Sander, {Josemir W.} and Thomas Sander and Scheffer, {Ingrid E.} and Julian Schubert and Shellhaas, {Ren{\'e}e A.} and Sherr, {Elliott H.} and Shih, {Jerry J.} and Shlomo Shinnar and Sills, {Graeme J.} and Singh, {Rani K.} and Auli Siren and Joseph Sirven and Sisodiya, {Sanjay M.} and Smith, {Michael C.} and Sonsma, {Anja C.M.} and Pasquale Striano and Joseph Sullivan and Thio, {Liu Lin} and Thomas, {Rhys H.} and Anu Venkat and Vining, {Eileen P.G.} and {Von Allmen}, {Gretchen K.} and Quanli Wang and Weber, {Yvonne G.} and Sarah Weckhuysen and Weisenberg, {Judith L.} and Peter Widdess-Walsh and Winawer, {Melodie R.} and Stefan Wolking and Federico Zara and Fritz Zimprich",
note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.",
year = "2022",
month = mar,
doi = "10.1111/epi.17166",
language = "English",
volume = "63",
pages = "723--735",
journal = "Epilepsia",
issn = "0013-9580",
number = "3",
}