Steffens, Michael ORCID: 0000-0002-6445-8593, Leu, Costin ORCID: 0000-0003-0598-3301, Ruppert, Ann-Kathrin, Zara, Federico ORCID: 0000-0001-9744-5222, Striano, Pasquale ORCID: 0000-0002-6065-1476, Robbiano, Angela, Capovilla, Giuseppe, Tinuper, Paolo, Gambardella, Antonio ORCID: 0000-0001-7384-3074, Bianchi, Amedeo, La Neve, Angela, Crichiutti, Giovanni, de Kovel, Carolien G. F., Trenite, Dorothee Kasteleijn-Nolst, de Haan, Gerrit-Jan ORCID: 0000-0003-2373-9863, Lindhout, Dick ORCID: 0000-0001-9580-624X, Gaus, Verena, Schmitz, Bettina, Janz, Dieter, Weber, Yvonne G., Becker, Felicitas, Lerche, Holger, Steinhoff, Bernhard J., Kleefuss-Lie, Ailing A., Kunz, Wolfram S. ORCID: 0000-0003-1113-3493, Surges, Rainer ORCID: 0000-0002-3177-8582, Elger, Christian E., Muhle, Hiltrud, von Spiczak, Sarah, Ostertag, Philipp, Helbig, Ingo ORCID: 0000-0001-8486-0558, Stephani, Ulrich, Moller, Rikke S., Hjalgrim, Helle, Dibbens, Leanne M., Bellows, Susannah ORCID: 0000-0003-1949-8489, Oliver, Karen, Mullen, Saul, Scheffer, Ingrid E., Berkovic, Samuel F., Everett, Kate V., Gardiner, Mark R., Marini, Carla, Guerrini, Renzo ORCID: 0000-0002-7272-7079, Lehesjoki, Anna-Elina, Siren, Auli, Guipponi, Michel, Malafosse, Alain, Thomas, Pierre, Nabbout, Rima, Baulac, Stephanie ORCID: 0000-0001-6430-4693, Leguern, Eric, Guerrero, Rosa ORCID: 0000-0002-4138-4667, Serratosa, Jose M., Reif, Philipp S., Rosenow, Felix, Moerzinger, Martina, Feucht, Martha, Zimprich, Fritz ORCID: 0000-0002-6998-5480, Kapser, Claudia, Schankin, Christoph J., Suls, Arvid ORCID: 0000-0003-0328-198X, Smets, Katrin, De Jonghe, Peter, Jordanova, Albena ORCID: 0000-0002-3833-3754, Caglayan, Hande, Yapici, Zuhal, Yalcin, Destina A., Baykan, Betul, Bebek, Nerses, Ozbek, Ugur ORCID: 0000-0001-5319-0547, Gieger, Christian ORCID: 0000-0001-6986-9554, Wichmann, Heinz-Erich, Balschun, Tobias, Ellinghaus, David ORCID: 0000-0002-4332-6110, Franke, Andre ORCID: 0000-0003-1530-5811, Meesters, Christian ORCID: 0000-0003-2408-7588, Becker, Tim, Wienker, Thomas F., Hempelmann, Anne, Schulz, Herbert, Rueschendorf, Franz, Leber, Markus, Pauck, Steffen M., Trucks, Holger, Toliat, Mohammad R., Nuernberg, Peter, Avanzini, Giuliano, Koeleman, Bobby P. C. and Sander, Thomas (2012). Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32. Hum. Mol. Genet., 21 (24). S. 5359 - 5373. OXFORD: OXFORD UNIV PRESS. ISSN 0964-6906

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Abstract

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3 and account for 2030 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Steffens, MichaelUNSPECIFIEDorcid.org/0000-0002-6445-8593UNSPECIFIED
Leu, CostinUNSPECIFIEDorcid.org/0000-0003-0598-3301UNSPECIFIED
Ruppert, Ann-KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zara, FedericoUNSPECIFIEDorcid.org/0000-0001-9744-5222UNSPECIFIED
Striano, PasqualeUNSPECIFIEDorcid.org/0000-0002-6065-1476UNSPECIFIED
Robbiano, AngelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Capovilla, GiuseppeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tinuper, PaoloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gambardella, AntonioUNSPECIFIEDorcid.org/0000-0001-7384-3074UNSPECIFIED
Bianchi, AmedeoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
La Neve, AngelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Crichiutti, GiovanniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Kovel, Carolien G. F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trenite, Dorothee Kasteleijn-NolstUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Haan, Gerrit-JanUNSPECIFIEDorcid.org/0000-0003-2373-9863UNSPECIFIED
Lindhout, DickUNSPECIFIEDorcid.org/0000-0001-9580-624XUNSPECIFIED
Gaus, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitz, BettinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Janz, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, Yvonne G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, FelicitasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinhoff, Bernhard J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kleefuss-Lie, Ailing A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kunz, Wolfram S.UNSPECIFIEDorcid.org/0000-0003-1113-3493UNSPECIFIED
Surges, RainerUNSPECIFIEDorcid.org/0000-0002-3177-8582UNSPECIFIED
Elger, Christian E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muhle, HiltrudUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Spiczak, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ostertag, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helbig, IngoUNSPECIFIEDorcid.org/0000-0001-8486-0558UNSPECIFIED
Stephani, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moller, Rikke S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hjalgrim, HelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dibbens, Leanne M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bellows, SusannahUNSPECIFIEDorcid.org/0000-0003-1949-8489UNSPECIFIED
Oliver, KarenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mullen, SaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheffer, Ingrid E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berkovic, Samuel F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Everett, Kate V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gardiner, Mark R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marini, CarlaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guerrini, RenzoUNSPECIFIEDorcid.org/0000-0002-7272-7079UNSPECIFIED
Lehesjoki, Anna-ElinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siren, AuliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guipponi, MichelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Malafosse, AlainUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, PierreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nabbout, RimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baulac, StephanieUNSPECIFIEDorcid.org/0000-0001-6430-4693UNSPECIFIED
Leguern, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guerrero, RosaUNSPECIFIEDorcid.org/0000-0002-4138-4667UNSPECIFIED
Serratosa, Jose M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reif, Philipp S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenow, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moerzinger, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Feucht, MarthaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zimprich, FritzUNSPECIFIEDorcid.org/0000-0002-6998-5480UNSPECIFIED
Kapser, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schankin, Christoph J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suls, ArvidUNSPECIFIEDorcid.org/0000-0003-0328-198XUNSPECIFIED
Smets, KatrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Jonghe, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jordanova, AlbenaUNSPECIFIEDorcid.org/0000-0002-3833-3754UNSPECIFIED
Caglayan, HandeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yapici, ZuhalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yalcin, Destina A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baykan, BetulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bebek, NersesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ozbek, UgurUNSPECIFIEDorcid.org/0000-0001-5319-0547UNSPECIFIED
Gieger, ChristianUNSPECIFIEDorcid.org/0000-0001-6986-9554UNSPECIFIED
Wichmann, Heinz-ErichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balschun, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ellinghaus, DavidUNSPECIFIEDorcid.org/0000-0002-4332-6110UNSPECIFIED
Franke, AndreUNSPECIFIEDorcid.org/0000-0003-1530-5811UNSPECIFIED
Meesters, ChristianUNSPECIFIEDorcid.org/0000-0003-2408-7588UNSPECIFIED
Becker, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wienker, Thomas F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hempelmann, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulz, HerbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rueschendorf, FranzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leber, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pauck, Steffen M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trucks, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toliat, Mohammad R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Avanzini, GiulianoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koeleman, Bobby P. C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sander, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-476648
DOI: 10.1093/hmg/dds373
Journal or Publication Title: Hum. Mol. Genet.
Volume: 21
Number: 24
Page Range: S. 5359 - 5373
Date: 2012
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 0964-6906
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
JUVENILE MYOCLONIC EPILEPSY; INDEPENDENT TESTS; SEIZURE TYPES; RISK; MECHANISMS; MUTATIONS; MICRODELETIONS; VISUALIZATION; ARCHITECTURE; REPLICATIONMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/47664

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