Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1,2q22.3 and 17q21.32
| Autor: | Steffens, M., Leu, C., Ruppert, A., Zara, F., Striano, P., Robbiano, A., Capovilla, G., Tinuper, P., Gambardella, A., Bianchi, A., La neve, A., Crichiutti, G., de kovel, C. G., Trenité, D. K. -N., de haan, G., 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., Møller, 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, Chiara, Guerrini, R., Lehesjoki, A., Siren, A., Guipponi, M., Malafosse, A., Thomas, P., Nabbout, R., Baulac, S., Leguern, E., Guerrero, R., Serratosa, J. M., Reif, P. S., Rosenow, F., Mörzinger, 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., Balschun, T., Ellinghaus, D., Franke, A., Meesters, C., Becker, T., Wienker, T. F., Hempelmann, A., Schulz, H., Rüschendorf, F., Leber, M., Pauck, S. M., Trucks, H., Toliat, M. R., Nürnberg, P., Avanzini, G., Koeleman, B. P., Sander, T., Weckhuysen, S., Claes, L., Deprez, L., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Lehesjoki, A. -E., von Spiczak, S., Martin Klein, K., Oertel, W. H., Hamer, H. M., Marini, C., Mei, D., Norci, V., Pezzella, M., La Neve, A., Vigliano, P., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Egeo, G., Teresa Giallonardo, M., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., de Haan, G. -J., Giraldez, B. G., Ozbeck, U., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Ozkara, C., Yalcin, O., Turkdogan, D., Dizdarer, G., Agan, K. |
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| Přispěvatelé: | Steffens, Michael, Leu, Costin, Ruppert, Ann-Kathrin, Zara, Frederico, Dibbens, Leanne Michelle, Sander, Thomas, EPICURE Consortium, Epicure, Consortium, DEL GIUDICE, Ennio, Steffens, M, Leu, C, Ruppert, Ak, Zara, F, Striano, P, Robbiano, A., Coppola, Antonietta, E. P. I. C. U. R. E. Consortium, E. M. I.Net Consortium, M. Steffen, C. Leu, A. Ruppert, F. Zara, P. Striano, A. Robbiano, G. Capovilla, P. Tinuper, A. Gambardella, A. Bianchi, A. L. Neve, G. Crichiutti, C. G. F, D. K. Trenité, G. d. Haan, D. Lindhout, V. Gau, B. Schmitz, D. Janz, Y. G. Weber, F. Becker, H. Lerche, B. J. Steinhoff, A. A. Kleefuß-Lie, W. S. Kunz, R. Surge, C. E. Elger, H. Muhle, S. v. Spiczak, P. Ostertag, I. Helbig, U. Stephani, R. S. Møller, H. Hjalgrim, L. M. Dibben, S. Bellow, K. Oliver, S. Mullen, I. E. Scheffer, S. F. Berkovic, K. V. Everett, M. R. Gardiner, C. Marini, R. Guerrini, A. Lehesjoki, A. Siren, M. Guipponi, A. Malafosse, P. Thoma, R. Nabbout, S. Baulac, E. Leguern, R. Guerrero, J. M. Serratosa, P. S. Reif, F. Rosenow, M. Mörzinger, M. Feucht, F. Zimprich, C. Kapser, C. J. Schankin, A. Sul, K. Smet, P. D. Jonghe, A. Jordanova, H. Caglayan, Z. Yapici, D. A. Yalcin, B. Baykan, N. Bebek, U. Ozbek, C. Gieger, H. Wichmann, T. Balschun, D. Ellinghau, A. Franke, C. Meester, T. Becker, T. F. Wienker, A. Hempelmann, H. Schulz, F. Rüschendorf, M. Leber, S. M. Pauck, H. Truck, M. R. Toliat, P. Nürnberg, G. Avanzini, B. P. C, T. Sander |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Candidate gene
Juvenile Genome-wide association study Alleles Epilepsy ZEB2 protein human VRK2 protein human 0302 clinical medicine genetics [Genetic Predisposition to Disease] genetics Humans Myoclonic Epilepsy genetics [Epilepsy Generalized] SCN1A protein human Genetics (clinical) Genetics 0303 health sciences genetics [Epilepsy Absence] Myoclonic Epilepsy Juvenile genetics Genetic Predisposition to Disease General Medicine Protein-Serine-Threonine Kinases 3. Good health Chemistry Absence genetics Epilepsy genetics [Myoclonic Epilepsy Juvenile] Epilepsy Generalized genetics [Receptor Muscarinic M3] genetics NAV1.1 Voltage-Gated Sodium Channel genetics [Homeodomain Proteins] Single-nucleotide polymorphism genetics [NAV1.1 Voltage-Gated Sodium Channel] Protein Serine-Threonine Kinases Biology genetics [Protein-Serine-Threonine Kinases] 03 medical and health sciences ddc:570 Genetic variation medicine Humans Genetic Predisposition to Disease genetics Repressor Protein Allele Molecular Biology Alleles Zinc Finger E-box Binding Homeobox 2 030304 developmental biology Homeodomain Proteins Receptor Muscarinic M3 genetics Protein-Serine-Threonine Kinase genetics Receptor Generalized genetics Genome-Wide Association Study Homeodomain Protein Heritability medicine.disease NAV1.1 Voltage-Gated Sodium Channel Repressor Proteins genetics [Repressor Proteins] Muscarinic M3 Epilepsy Absence Myoclonic epilepsy Human medicine Juvenile myoclonic epilepsy 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | Hum. Mol. Genet. 21, 5359-5372 (2012) Human molecular genetics Human molecular genetics 21(24), 5359-5372 (2012). doi:10.1093/hmg/dds373 Human Molecular Genetics 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 K, 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, H, Ruschendorf, F, Leber, M, Pauck, S M, Trucks, H, Toliat, M R, Nurnberg, P, Avanzini, G, Koeleman, B P C, Sander, T, Consortium, E & Consortium, E 2012, ' Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32 ', Human Molecular Genetics, vol. 21, no. 24, pp. 5359-5372 . https://doi.org/10.1093/hmg/dds373 |
| ISSN: | 0964-6906 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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