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

Item Type:Article
Title:Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32
Creators Name:Steffens, M. and Leu, C. and Ruppert, A.K. and Zara, F. and Striano, P. and Robbiano, A. and Capovilla, G. and Tinuper, P. and Gambardella, A. and Bianchi, A. and La Neve, A. and Crichiutti, G. and de Kovel, C.G.F. and Kasteleijn-Nolst Trenite, D. and de Haan, G.J. and Lindhout, D. and Gaus, V. and Schmitz, B. and Janz, D. and Weber, Y.G. and Becker, F. and Lerche, H. and Steinhoff, B.J. and Kleefuss-Lie, A.A. and Kunz, W.S. and Surges, R. and Elger, C.E. and Muhle, H. and von Spiczak, S. and Ostertag, P. and Helbig, I. and Stephani, U. and Moller, R.S. and Hjalgrim, H. and Dibbens, L.M. and Bellows, S. and Oliver, K. and Mullen, S. and Scheffer, I.E. and Berkovic, S.F. and Everett, K.V. and Gardiner, M.R. and Marini, C. and Guerrini, R. and Lehesjoki, A.E. and Siren, A. and Guipponi, M. and Malafosse, A. and Thomas, P. and Nabbout, R. and Baulac, S. and Leguern, E. and Guerrero, R. and Serratosa, J.M. and Reif, P.S. and Rosenow, F. and Mörzinger, M. and Feucht, M. and Zimprich, F. and Kapser, C. and Schankin, C.J. and Suls, A. and Smets, K. and De Jonghe, P. and Jordanova, A. and Caglayan, H. and Yapici, Z. and Yalcin, D.A. and Baykan, B. and Bebek, N. and Ozbek, U. and Gieger, C. and Wichmann, H.E. and Balschun, T. and Ellinghaus, D. and Franke, A. and Meesters, C. and Becker, T and Wienker, T.F. and Hempelmann, A. and Schulz, H. and Rueschendorf, F. and Leber, M. and Pauck, S.M. and Trucks, H. and Toliat, M.R. and Nuernberg, P. and Avanzini, G. and Koeleman, B.P. and Sander, T.
Abstract: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.
Keywords:Absence Epilepsy, Alleles, Generalized Epilepsy, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeodomain Proteins, Juvenile Myoclonic Epilepsy, Muscarinic M3 Receptor, NAV1.1 Voltage-Gated Sodium Channel, Protein-Serine-Threonine Kinases, Repressor Proteins
Source:Human Molecular Genetics
Publisher:Oxford University Press
Page Range:5359-5372
Date:15 December 2012
Official Publication:https://doi.org/10.1093/hmg/dds373
PubMed:View item in PubMed

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