title: 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.
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Bjarke
authors.initials: B
authors.lastname: Feenstra
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Björn
authors.identifier: 0000000220978466
authors.initials: B
authors.lastname: Pasternak
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Frank
authors.initials: F
authors.lastname: Geller
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Carstensen
authors.affiliation: 1] Department of Physiology, University of California, San Francisco, San Francisco, California, USA. [2] Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, USA. [3] Howard Hughes Medical Institute, San Francisco, California, USA.
authors.forename: Tongfei
authors.initials: T
authors.lastname: Wang
authors.affiliation: 1] Department of Physiology, University of California, San Francisco, San Francisco, California, USA. [2] Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, USA. [3] Howard Hughes Medical Institute, San Francisco, California, USA.
authors.forename: Fen
authors.initials: F
authors.lastname: Huang
authors.affiliation: Department of Microbiology, University of Texas Southwestern Medical School, Dallas, Texas, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Eitson
authors.affiliation: Danish Centre for Neonatal Screening, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Mads V
authors.initials: MV
authors.lastname: Hollegaard
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Svanström
authors.affiliation: Research Unit and Section for General Practice, Department of Public Health, Aarhus University, Aarhus, Denmark.
authors.forename: Mogens
authors.initials: M
authors.lastname: Vestergaard
authors.affiliation: Danish Centre for Neonatal Screening, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: David M
authors.initials: DM
authors.lastname: Hougaard
authors.affiliation: Department of Microbiology, University of Texas Southwestern Medical School, Dallas, Texas, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Schoggins
authors.affiliation: 1] Department of Physiology, University of California, San Francisco, San Francisco, California, USA. [2] Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, USA. [3] Howard Hughes Medical Institute, San Francisco, California, USA.
authors.forename: Lily Yeh
authors.initials: LY
authors.lastname: Jan
authors.affiliation: 1] Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. [2] Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. [3] Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Mads
authors.initials: M
authors.lastname: Melbye
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Hviid
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000075368:Anoctamins; D000941:Antigens / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008274:Magnesium / Q000097:blood; D008297:Male; D022542:Measles-Mumps-Rubella Vaccine / Q000009:adverse effects*; D051916:Membrane Cofactor Protein / Q000235:genetics; D009474:Neurons / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D055647:Rats, Transgenic; D003294:Seizures, Febrile / Q000209:etiology* / Q000235:genetics*; D013696:Temperature; D055815:Young Adult
chemical_list: C577591:ANO3 protein, human; D000075368:Anoctamins; D000941:Antigens; C497857:CD46 protein, human; D018118:Chloride Channels; D003598:Cytoskeletal Proteins; C065888:IFI44 protein, human; D022542:Measles-Mumps-Rubella Vaccine; D051916:Membrane Cofactor Protein; D008274:Magnesium