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Common variants associated with general and MMR vaccine–related febrile seizures

Abstract

Febrile seizures represent a serious adverse event following measles, mumps and rubella (MMR) vaccination. We conducted a series of genome-wide association scans comparing children with MMR-related febrile seizures, children with febrile seizures unrelated to vaccination and controls with no history of febrile seizures. Two loci were distinctly associated with MMR-related febrile seizures, harboring the interferon-stimulated gene IFI44L (rs273259: P = 5.9 × 10−12 versus controls, P = 1.2 × 10−9 versus MMR-unrelated febrile seizures) and the measles virus receptor CD46 (rs1318653: P = 9.6 × 10−11 versus controls, P = 1.6 × 10−9 versus MMR-unrelated febrile seizures). Furthermore, four loci were associated with febrile seizures in general, implicating the sodium channel genes SCN1A (rs6432860: P = 2.2 × 10−16) and SCN2A (rs3769955: P = 3.1 × 10−10), a TMEM16 family gene (ANO3; rs114444506: P = 3.7 × 10−20) and a region associated with magnesium levels (12q21.33; rs11105468: P = 3.4 × 10−11). Finally, we show the functional relevance of ANO3 (TMEM16C) with electrophysiological experiments in wild-type and knockout rats.

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Figure 1: Discovery-stage results from the MMR-related febrile seizures versus controls scan.
Figure 2: Discovery-stage results from the febrile seizures overall versus controls scan.
Figure 3: ANO3 is involved in the temperature response of hypothalamic neurons.
Figure 4: Hippocampal CA1 pyramidal neurons exhibit hyperexcitability in the absence of ANO3.

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Acknowledgements

The study was partially supported by a grant from the Danish Medical Research Council (0602-01818B). Research reported in this publication was supported by US National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases grant R01AI093697 (A.H.), by NIH/National Institute of Diabetes and Digestive and Kidney Diseases grant K01DK095031 (J.W.S.) and by NIH/National Institute of Neurological Disorders and Stroke grant R01NS069229 (L.Y.J.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The Danish National Biobank was established with the support of major grants from the Novo Nordisk Foundation, the Danish Medical Research Council and the Lundbeck Foundation. L.Y.J. is an investigator of the Howard Hughes Medical Institute. B.F. is supported by an Oak Foundation fellowship.

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B.F., B.P., F.G., M.M. and A.H. designed the project and drafted the manuscript. B.P., H.S., M.V. and A.H. planned and performed register data acquisition, informatics and phenotypic characterization. B.F., F.G. and L.C. carried out the statistical genetics and bioinformatics analyses. M.V.H. and D.M.H. performed sampling, whole-genome amplification and genotyping. J.L.E. and J.W.S. designed and performed the cell-based overexpression experiments and analyzed the data. T.W., F.H. and L.Y.J. designed and performed the electrophysiology experiments and analyzed the data. All authors contributed to the final manuscript.

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Correspondence to Bjarke Feenstra.

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Feenstra, B., Pasternak, B., Geller, F. et al. Common variants associated with general and MMR vaccine–related febrile seizures. Nat Genet 46, 1274–1282 (2014). https://doi.org/10.1038/ng.3129

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