Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32.

Human molecular genetics ·第 21 卷 ·第 24 期 ·2013-05-31

, , Steffens Michael, Leu Costin, Ruppert Ann-Kathrin, Zara Federico, Striano Pasquale, Robbiano Angela, Capovilla Giuseppe, Tinuper Paolo, Gambardella Antonio, Bianchi Amedeo, La Neve Angela, Crichiutti Giovanni, de Kovel Carolien G F, Kasteleijn-Nolst Trenité Dorothée, de Haan Gerrit-Jan, Lindhout Dick, Gaus Verena, Schmitz Bettina, Janz Dieter, Weber Yvonne G, Becker Felicitas, Lerche Holger, Steinhoff Bernhard J, Kleefuß-Lie Ailing A, Kunz Wolfram S, Surges Rainer, Elger Christian E, Muhle Hiltrud, von Spiczak Sarah, Ostertag Philipp, Helbig Ingo, Stephani Ulrich, Møller Rikke S, Hjalgrim Helle, Dibbens Leanne M, Bellows Susannah, Oliver Karen, Mullen Saul, Scheffer Ingrid E, Berkovic Samuel F, Everett Kate V, Gardiner Mark R, Marini Carla, Guerrini Renzo, Lehesjoki Anna-Elina, Siren Auli, Guipponi Michel, Malafosse Alain, Thomas Pierre, Nabbout Rima, Baulac Stephanie, Leguern Eric, Guerrero Rosa, Serratosa Jose M, Reif Philipp S, Rosenow Felix, Mörzinger Martina, Feucht Martha, Zimprich Fritz, Kapser Claudia, Schankin Christoph J, Suls Arvid, Smets Katrin, De Jonghe Peter, Jordanova Albena, Caglayan Hande, Yapici Zuhal, Yalcin Destina A, Baykan Betul, Bebek Nerses, Ozbek Ugur, Gieger Christian, Wichmann Heinz-Erich, Balschun Tobias, Ellinghaus David, Franke Andre, Meesters Christian, Becker Tim, Wienker Thomas F, Hempelmann Anne, Schulz Herbert, Rüschendorf Franz, Leber Markus, Pauck Steffen M, Trucks Holger, Toliat Mohammad R, Nürnberg Peter, Avanzini Giuliano, Koeleman Bobby P C, Sander Thomas

摘要

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

文献信息

期刊

Human molecular genetics

期刊简称

Hum Mol Genet

ISSN

0964-6906

DOI

10.1093/hmg/dds373

发表日期

2013-05-31

收录日期

2012-12-03

更新日期

2012-12-03

语言

英语

国家/地区

England

NLM ID

9208958

外部链接

PubMed 原文 DOI: 10.1093/hmg/dds373 查看期刊详情

分析服务

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32.

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