期刊
BRAIN
卷 136, 期 -, 页码 3140-3150出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awt233
关键词
mesial temporal lobe epilepsy; mesial temporal sclerosis; SCN1A; association; complex genetics
资金
- Wellcome Trust [084730, 076467, 076113, 085475]
- UK Medical Research Council (MRC) [G0400126, G1100616, G0901254, G0802462]
- King Faisal Specialist Hospital and Research Centre (KFSH RC)
- University College London Hospitals Charities and the Clinical Research and Development Committee (UCLH/CRDC) [F136]
- National Institute for Health Research (NIHR) [08-08-SCC]
- National Society for Epilepsy
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- Marie Curie International Re-integration Grant
- European Commission [279062, LSHM-CT-2006-037315]
- Robert Bosch Foundation, Stuttgart
- University of Tubingen (IZEPHA project) [18-0-0]
- German Federal Ministry of Education and Research, National Genome Research Network (NGFNplus: EMINet) [01GS08123]
- BONFOR
- German Federal Ministry of Education and Research
- German Research Foundation [RO3396/2-1, DFG Bl421/3-1]
- Austrian Science Fund [FWF I643]
- National Health and Medical Research Council (NHMRC) [628952]
- Royal Melbourne Hospital Neuroscience Foundation
- Foundation of Science and Technology, Lisbon (FCT) [PIC/IC/83297/2007]
- National Institutes of Health, USA (NIH) [R01-NS-49306-01, R01-NS-064154-01]
- Irish Higher Education Authority Programme for Research in Third Level Institutions (PRTLI3) through a Science Foundation Ireland Research Frontiers Programme award [08/RFP/GEN1538]
- Medical Research Charities Group of Ireland/Health Research Board award from Brainwave-the Irish Epilepsy Association [2009/001]
- GlaxoSmithKline
- Fonds National de la Recherche Scientifique [FC 63574/3.4.620.06 F]
- Fonds Erasme, Universite Libre de Bruxelles
- Walloon Region
- French-Speaking Community of Belgium
- Belgian Science Policy
- University of Liege
- Swiss National Science Foundation
- SICPA Foundation, Prilly, Switzerland
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London
- UK Medical Research Council [74882]
- University of Bristol
- Muscular Dystrophy Association, USA
- Irish Institute of Clinical Neurosciences Travel Award
- National Institutes of Health, USA
- Fundação para a Ciência e a Tecnologia [PIC/IC/83297/2007] Funding Source: FCT
- Epilepsy Research UK [F1206] Funding Source: researchfish
- Medical Research Council [G0901254, MR/L016400/1, G9815508, MR/J006742/1, G0802462, G0400126, G1100616] Funding Source: researchfish
- MRC [G0901254, MR/L016400/1, G0400126, G0802462, G1100616] Funding Source: UKRI
Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 x 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.
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