Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32
Tarih
2012Yazar
CAPOVILLA, Giuseppe
ROSENOW, Felix
MOERZINGER, Martina
FEUCHT, Martha
ZIMPRICH, Fritz
KAPSER, Claudia
SCHANKIN, Christoph J.
SULS, Arvid
SMETS, Katrin
DE JONGHE, Peter
JORDANOVA, Albena
Caglayan, Hande
YALCIN, Destina A.
GIEGER, Christian
WICHMANN, Heinz-Erich
BALSCHUN, Tobias
ELLINGHAUS, David
FRANKE, Andre
MEESTERS, Christian
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.
SANDER, Thomas
Baykan, BETÜL
Yapici, Zühal
Bebek, Nerses
Ozbek, Ugur
TINUPER, Paolo
GAMBARDELLA, Antonio
BIANCHI, Amedeo
LA NEVE, Angela
CRICHIUTTI, Giovanni
de Kovel, Carolien G. F.
Trenite, Dorothee Kasteleijn-Nolst
DE HAAN, Gerrit-Jan
Lindhout, Dick
GAUS, Verena
SCHMITZ, Bettina
JANZ, Dieter
WEBER, Yvonne G.
BECKER, Felicitas
LERCHE, Holger
STEINHOFF, Bernhard J.
KLEEFUSS-LIE, Ailing A.
KUNZ, Wolfram S.
STEFFENS, Michael
LEU, Costin
RUPPERT, Ann-Kathrin
ZARA, Federico
STRIANO, Pasquale
ROBBIANO, Angela
SURGES, Rainer
ELGER, Christian E.
MUHLE, Hiltrud
VON SPICZAK, Sarah
OSTERTAG, Philipp
HELBIG, Ingo
STEPHANI, Ulrich
MOLLER, Rikke S.
HJALGRIM, Helle
DIBBENS, Leanne M.
BELLOWS, Susannah
OLIVER, Karen
MULLEN, Saul
SCHEFFER, Ingrid E.
BERKOVIC, Samuel F.
EVERETT, Kate V.
Gardiner, Mark R.
MARINI, Carla
GUERRINI, Renzo
Lehesjoki, Anna-Elina
Siren, Auli
GUIPPONI, Michel
MALAFOSSE, Alain
THOMAS, Pierre
NABBOUT, Rima
BAULAC, Stephanie
LEGUERN, Eric
GUERRERO, Rosa
SERRATOSA, Jose M.
REIF, Philipp S.
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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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