Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies

Costin Leu, Carolien G F De Kovel, Federico Zara, Pasquale Striano, Marianna Pezzella, Angela Robbiano, Amedeo Bianchi, Francesca Bisulli, Antonietta Coppola, Anna Teresa Giallonardo, Francesca Beccaria, Dorothée Kasteleijn Nolst Trenité, Dick Lindhout, Verena Gaus, Bettina Schmitz, Dieter Janz, Yvonne G. Weber, Felicitas Becker, Holger Lerche, Ailing A. Kleefuß-LieKerstin Hallman, Wolfram S. Kunz, Christian E. Elger, Hiltrud Muhle, Ulrich Stephani, Rikke S. Møller, Helle Hjalgrim, Saul Mullen, Ingrid E. Scheffer, Samuel F. Berkovic, Kate V. Everett, Mark R. Gardiner, Carla Marini, Renzo Guerrini, Anna Elina Lehesjoki, Auli Siren, Rima Nabbout, Stephanie Baulac, Eric Leguern, Jose M. Serratosa, Felix Rosenow, Martha Feucht, Iris Unterberger, Athanasios Covanis, Arvid Suls, Sarah Weckhuysen, Radka Kaneva, Hande Caglayan, Dilsad Turkdogan, Betul Baykan, Nerses Bebek, Ugur Ozbek, Anne Hempelmann, Herbert Schulz, Franz Rüschendorf, Holger Trucks, Peter Nürnberg, Giuliano Avanzini, Bobby P C Koeleman, Thomas Sander

Research output: Contribution to journalArticlepeer-review


Purpose: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. Methods: Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. Key Findings: For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). Significance: Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype- genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.

Original languageEnglish
Pages (from-to)308-318
Number of pages11
Issue number2
Publication statusPublished - Feb 2012


  • Absence seizure
  • Complex inheritance
  • Genetic generalized epilepsy
  • Linkage analysis
  • Myoclonic seizure

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology


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