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

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

Research output: Contribution to journalArticlepeer-review


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, Pmeta = 2.5 × 10-9, OR[T] = 0.81) and 17q21.32 (rs72823592, Pmeta = 9.3 × 10-9, OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, Pmeta = 9.1 × 10-9, OR[T] = 0.68) and at 1q43 for JME (rs12059546, Pmeta = 4.1 × 10-8, OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, Pmeta = 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.

Original languageEnglish
Article numberdds373
Pages (from-to)5359-5372
Number of pages14
JournalHuman Molecular Genetics
Issue number24
Publication statusPublished - Dec 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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