Genome‐wide linkage meta‐analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies
Authors:   EPICURE Consortium, Leu Costin , de Kovel Carolien G.F. , Zara Federico , Striano Pasquale , Pezzella Marianna , Robbiano Angela , Bianchi Amedeo , Bisulli Francesca , Coppola Antonietta , Giallonardo Anna Teresa , Beccaria Francesca , Trenité Dorothée Kasteleijn‐Nolst , Lindhout Dick , Gaus Verena , Schmitz Bettina , Janz Dieter , Weber Yvonne G. , Becker Felicitas , Lerche Holger , Kleefuß‐Lie Ailing A. , Hallman Kerstin , Kunz Wolfram S. , Elger Christian E. , Muhle Hiltrud , Stephani Ulrich , Møller Rikke S. , Hjalgrim Helle , Mullen Saul , Scheffer Ingrid E. , Berkovic Samuel F. , Everett Kate V. , Gardiner Mark R. , Marini Carla , Guerrini Renzo , Lehesjoki Anna‐Elina , Siren Auli , Nabbout Rima , Baulac Stephanie , Leguern Eric , Serratosa Jose M. , Rosenow Felix , Feucht Martha , Unterberger Iris , Covanis Athanasios , Suls Arvid , Weckhuysen Sarah , Kaneva Radka , Caglayan Hande , Turkdogan Dilsad , Baykan Betul , Bebek Nerses , Ozbek Ugur , Hempelmann Anne , Schulz Herbert , Rüschendorf Franz , Trucks Holger , Nürnberg Peter , Avanzini Giuliano , Koeleman Bobby P.C. , Sander Thomas 
Published: January 2012

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.