title: Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32.
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.
authors.affiliation: Institute for Medical Biometry, Informatic and Epidemiology, University of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Steffens
authors.forename: Costin
authors.initials: C
authors.lastname: Leu
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Ruppert
authors.forename: Federico
authors.initials: F
authors.lastname: Zara
authors.forename: Pasquale
authors.initials: P
authors.lastname: Striano
authors.forename: Angela
authors.initials: A
authors.lastname: Robbiano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Capovilla
authors.forename: Paolo
authors.initials: P
authors.lastname: Tinuper
authors.forename: Antonio
authors.initials: A
authors.lastname: Gambardella
authors.forename: Amedeo
authors.initials: A
authors.lastname: Bianchi
authors.forename: Angela
authors.initials: A
authors.lastname: La Neve
authors.forename: Giovanni
authors.initials: G
authors.lastname: Crichiutti
authors.forename: Carolien G F
authors.initials: CG
authors.lastname: de Kovel
authors.forename: Dorothée
authors.initials: D
authors.lastname: Kasteleijn-Nolst Trenité
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: de Haan
authors.forename: Dick
authors.initials: D
authors.lastname: Lindhout
authors.forename: Verena
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authors.lastname: Gaus
authors.forename: Bettina
authors.initials: B
authors.lastname: Schmitz
authors.forename: Dieter
authors.initials: D
authors.lastname: Janz
authors.forename: Yvonne G
authors.initials: YG
authors.lastname: Weber
authors.forename: Felicitas
authors.initials: F
authors.lastname: Becker
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Steinhoff
authors.forename: Ailing A
authors.initials: AA
authors.lastname: Kleefuß-Lie
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.forename: Rainer
authors.initials: R
authors.lastname: Surges
authors.forename: Christian E
authors.initials: CE
authors.lastname: Elger
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Muhle
authors.forename: Sarah
authors.initials: S
authors.lastname: von Spiczak
authors.forename: Philipp
authors.initials: P
authors.lastname: Ostertag
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
authors.forename: Ulrich
authors.initials: U
authors.lastname: Stephani
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
authors.forename: Helle
authors.initials: H
authors.lastname: Hjalgrim
authors.forename: Leanne M
authors.initials: LM
authors.lastname: Dibbens
authors.forename: Susannah
authors.initials: S
authors.lastname: Bellows
authors.forename: Karen
authors.initials: K
authors.lastname: Oliver
authors.forename: Saul
authors.initials: S
authors.lastname: Mullen
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: Kate V
authors.initials: KV
authors.lastname: Everett
authors.forename: Mark R
authors.initials: MR
authors.lastname: Gardiner
authors.forename: Carla
authors.initials: C
authors.lastname: Marini
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.forename: Auli
authors.initials: A
authors.lastname: Siren
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.forename: Alain
authors.initials: A
authors.lastname: Malafosse
authors.forename: Pierre
authors.initials: P
authors.lastname: Thomas
authors.forename: Rima
authors.initials: R
authors.lastname: Nabbout
authors.forename: Stephanie
authors.initials: S
authors.lastname: Baulac
authors.forename: Eric
authors.initials: E
authors.lastname: Leguern
authors.forename: Rosa
authors.initials: R
authors.lastname: Guerrero
authors.forename: Jose M
authors.initials: JM
authors.lastname: Serratosa
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Reif
authors.forename: Felix
authors.initials: F
authors.lastname: Rosenow
authors.forename: Martina
authors.initials: M
authors.lastname: Mörzinger
authors.forename: Martha
authors.initials: M
authors.lastname: Feucht
authors.forename: Fritz
authors.initials: F
authors.lastname: Zimprich
authors.forename: Claudia
authors.initials: C
authors.lastname: Kapser
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Schankin
authors.forename: Arvid
authors.initials: A
authors.lastname: Suls
authors.forename: Katrin
authors.initials: K
authors.lastname: Smets
authors.forename: Peter
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authors.lastname: De Jonghe
authors.forename: Albena
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authors.lastname: Jordanova
authors.forename: Hande
authors.initials: H
authors.lastname: Caglayan
authors.forename: Zuhal
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authors.lastname: Yapici
authors.forename: Destina A
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authors.lastname: Yalcin
authors.forename: Betul
authors.initials: B
authors.lastname: Baykan
authors.forename: Nerses
authors.initials: N
authors.lastname: Bebek
authors.forename: Ugur
authors.initials: U
authors.lastname: Ozbek
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Heinz-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Tobias
authors.initials: T
authors.lastname: Balschun
authors.forename: David
authors.initials: D
authors.lastname: Ellinghaus
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Christian
authors.initials: C
authors.lastname: Meesters
authors.forename: Tim
authors.initials: T
authors.lastname: Becker
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wienker
authors.forename: Anne
authors.initials: A
authors.lastname: Hempelmann
authors.forename: Herbert
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authors.lastname: Schulz
authors.forename: Franz
authors.initials: F
authors.lastname: Rüschendorf
authors.forename: Markus
authors.initials: M
authors.lastname: Leber
authors.forename: Steffen M
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authors.lastname: Pauck
authors.forename: Holger
authors.initials: H
authors.lastname: Trucks
authors.forename: Mohammad R
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authors.lastname: Toliat
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Giuliano
authors.initials: G
authors.lastname: Avanzini
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
authors.forename: Thomas
authors.initials: T
authors.lastname: Sander
mesh_terms: D000483:Alleles; D004832:Epilepsy, Absence / Q000235:genetics; D004829:Epilepsy, Generalized / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D020190:Myoclonic Epilepsy, Juvenile / Q000235:genetics; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D043587:Receptor, Muscarinic M3 / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D018398:Homeodomain Proteins; D062550:NAV1.1 Voltage-Gated Sodium Channel; D043587:Receptor, Muscarinic M3; D012097:Repressor Proteins; C568242:SCN1A protein, human; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D017346:Protein Serine-Threonine Kinases; C109891:VRK2 protein, human