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Steffens, M.* ; Leu, C.* ; Ruppert, A.K.* ; Zara, F.* ; Striano, P.* ; Robbiano, A.* ; Capovilla, G.* ; Tinuper, P.* ; Gambardella, A.* ; Bianchi, A.* ; La Neve, A.* ; Crichiutti, G.* ; de Kovel, C.G.F.* ; Trenite, D.K.N.* ; de Haan, G.J.* ; Lindhout, D.* ; Gaus, V.* ; Schmitz, B.* ; Janz, D.* ; Weber, Y.G.* ; Becker, F.* ; Lerche, H.* ; Steinhoff, B.J.* ; Kleefuss-Lie, A.A.* ; Kunz, W.S.* ; Surges, R.* ; Elger, C.E.* ; Muhle, H.* ; von Spiczak, S.* ; Ostertag, P.* ; Helbig, I.* ; Stephani, U.* ; Moller, R.S.* ; Hjalgrim, H.* ; Dibbens, L.M.* ; Bellows, S.* ; Oliver, K.* ; Mullen, S.* ; Scheffer, I.E.* ; Berkovic, S.F.* ; Everett, K.V.* ; Gardiner, M.R.* ; Marini, C.* ; Guerrini, R.* ; Lehesjoki, A.E.* ; Siren, A.* ; Guipponi, M.* ; Malafosse, A.* ; Thomas, P.* ; Nabbout, R.* ; Baulac, S.* ; Leguern, E.* ; Guerrero, R.* ; Serratosa, J.M.* ; Reif, P.S.* ; Rosenow, F.* ; Morzinger, M.* ; Feucht, M.* ; Zimprich, F.* ; Kapser, C.* ; Schankin, C.J.* ; Suls, A.* ; Smets, K.* ; de Jonghe, P.* ; Jordanova, A.* ; Caglayan, H.* ; Yapici, Z.* ; Yalcin, D.A.* ; Baykan, B.* ; Bebek, N.* ; Ozbek, U.* ; Gieger, C. ; Wichmann, H.-E. ; Balschun, T.* ; Ellinghaus, D.* ; Franke, A.* ; Meesters, C.* ; Becker, T.* ; Wienker, T.F.* ; Hempelmann, A.* ; Schulz, S.* ; Ruschendorf, F.* ; Leber, M.* ; Pauck, S.M.* ; Trucks, H.* ; Toliat, M.R.* ; Nürnberg, P.* ; Avanzini, G.* ; Koeleman, B.P.C.* ; Sander, T.* ; EPICURE Consortium (*) ; EMINet Consortium (*)

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

Hum. Mol. Genet. 21, 5359-5372 (2012)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Juvenile Myoclonic Epilepsy ; Independent Tests ; Seizure Types ; Risk ; Mechanisms ; Mutations ; Microdeletions ; Visualization ; Architecture ; Replication
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Quellenangaben Volume: 21, Issue: 24, Pages: 5359-5372 Article Number: , Supplement: ,
Publisher Oxford University Press
Reviewing status Peer reviewed