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Title: Epilepsy in Families: Age at onset is a familial trait, independent of syndrome.
Austin Authors: Ellis, Colin A;Churilov, Leonid ;Epstein, Michael P;Xie, Sharon X;Bellows, Susannah T;Ottman, Ruth;Berkovic, Samuel F 
Affiliation: Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Department of Human Genetics, Emory University, Atlanta, GA, USA
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
Departments of Epidemiology and Neurology, and the G. H. Sergievsky Center, Columbia University, New York, NY, USA
Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, USA
Division of Translational Epidemiology, New York State Psychiatric Institute, New York, NY, USA
Issue Date: Jul-2019 2019-05-02
Publication information: Annals of Neurology 2019; 86(1): 91-98
Abstract: We tested two hypotheses regarding age at onset within familial epilepsies: (1) family members with epilepsy tend to have similar ages at onset, independent of epilepsy syndrome; (2) age at onset is younger in successive generations after controlling for sampling bias. We analyzed clinical data collected by the Epi4K Consortium (303 multiplex families, 1,120 individuals). To test hypothesis 1, we used both linear mixed models commonly used for heritability analysis and Cox regression models with frailty terms to assess clustering of onset within families after controlling for other predictors. To test hypothesis 2, we used mixed effects models, pair-wise analyses, and survival analysis to address sampling-related bias that may mimic anticipation. (1) Age at seizure onset was significantly heritable (ICC 0.17, p < 0.001) after adjusting for epilepsy type, sex, site, history of febrile seizure, and age at last observation. This finding remained significant after adjusting for epilepsy syndromes, and was robust across statistical methods in all families and in generalized families. (2) The mean age at onset decreased in successive generations (p < 0.001). After adjusting for age at last observation, this effect was not significant in mixed-effects models (p=0.14), but remained significant in pair-wise (p=0.0003) and survival analyses (p=0.02). Age at seizure onset is an independent familial trait, and may have genetic determinants distinct from the determinants of particular epilepsy syndromes. Younger onsets in successive generations can be explained in part by sampling bias, but the presence of genetic anticipation cannot be excluded. This article is protected by copyright. All rights reserved.
DOI: 10.1002/ana.25499
ORCID: 0000-0003-4580-841X
PubMed URL: 31050039
Type: Journal Article
Subjects: Anticipation
Epilepsy onset
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