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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
Institution:1. EPICURE Consortium, Participating Groups are Listed in the Appendix;2. Cologne Center for Genomics, University of Cologne, Cologne, Germany;3. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands;4. Muscular and Neurodegenerative Disease Unit, G. Gaslini Institute, University of Genoa, Genoa, Italy;5. Epilepsy Center, Unit of Neurology, Hospital “San Donato,” Arezzo, Italy;6. Department of Neurological Sciences, University of Bologna, Bologna, Italy;7. Epilepsy Center, Federico II University, Napoli, Italy;8. Department of Neurological Sciences, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy;9. Department of Child Neuropsychiatry, Ospedale C. Poma, Mantua, Italy;10. SEIN Epilepsy Institute in the Netherlands, Hoofddorp, The Netherlands;11. Department of Neurology, Charité University Medicine, Campus Virchow Clinic, Humboldt University of Berlin, Berlin, Germany;12. Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany;13. Department of Epileptology, University Clinics Bonn, Bonn, Germany;14. Department of Neuropediatrics, University Medical Center Schleswig‐Holstein (Kiel Campus), Kiel, Germany;15. Department of Neurology, Danish Epilepsy Center, Dianalund, Denmark;16. Wilhelm Johannsen Center for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark;17. Institute for Regional Health Services Research, University of Southern Denmark, Odense, Denmark;18. Epilepsy Research Centre and Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia;19. Human Genetics Research Centre, St George′s University of London, London, United Kingdom;20. UCL Institute of Child Health, University College London, London, United Kingdom;21. Child Neurology Unit, Children’s Hospital A. Meyer, University of Florence, Florence, Italy;22. Neuroscience Center, University of Helsinki and Folkh?lsan Institute of Genetics, Helsinki, Finland;23. Department of Pediatrics, Tampere University Hospital, Tampere, Finland;24. Department of Neuropediatrics, H?pital Necker‐Enfants Malades, AP‐HP and INSERM U663, Paris‐Descartes University, Paris, France;25. CRICM, UPMC/Inserm UMR‐S 975, CNRS UMR 7225, Brain and Spine Institute, Pitie‐Salpetriere Hospital, Paris, France;26. Epilepsy Unit, Neurology Service and Institute for Medical Research, Fundación Jiménez Díaz, Madrid, Spain;27. Unit 744, Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain;28. Epilepsy‐Center Hessen, Department of Neurology, University Hospitals and Philipps‐University Marburg, Marburg, Germany;29. Department of Pediatrics and Neonatology, Medical University of Vienna, Vienna, Austria;30. Department of Neurology, Medical University Innsbruck, Innsbruck, Austria;31. Neurology Department, The Children Hospital “Agia Sophia,” Athens, Greece;32. Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium;33. Laboratory of Neurogenetics, Institute Born‐Bunge, University of Antwerp, Antwerp, Belgium;34. Epilepsy Center Kempenhaeghe, Hans Berger Kliniek, Oosterhout, The Netherlands;35. Department of Chemistry and Biochemistry, Molecular Medicine Center, Medical University‐Sofia, Sofia, Bulgaria;36. Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey;37. Institute of Neurological Sciences, Marmara University, Maltepe, Istanbul, Turkey;38. Department of Neurology, Epilepsy Center (EPIMER), Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey;39. Department of Genetics, Experimental Medicine Research Institute (DETAE), Istanbul University, Istanbul, Turkey;40. Max‐Delbrück‐Centrum for Molecular Medicine, Berlin, Germany;41. Fondazione IRRCS, Carlo Besta Neurological Institute, Milan, Italy
Abstract: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.
Keywords:Genetic generalized epilepsy  Complex inheritance  Absence seizure  Myoclonic seizure  Linkage analysis
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