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

Nat Genet. 2014 Dec;46(12):1274-82. doi: 10.1038/ng.3129. Epub 2014 Oct 26.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Anoctamins
  • Antigens / genetics
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Chloride Channels / genetics
  • Cytoskeletal Proteins / genetics
  • Female
  • Fibroblasts / metabolism
  • Genome-Wide Association Study
  • Hippocampus / pathology
  • Humans
  • Magnesium / blood
  • Male
  • Measles-Mumps-Rubella Vaccine / adverse effects*
  • Membrane Cofactor Protein / genetics
  • Neurons / pathology
  • Polymorphism, Single Nucleotide*
  • Rats
  • Rats, Transgenic
  • Seizures, Febrile / etiology*
  • Seizures, Febrile / genetics*
  • Temperature
  • Young Adult

Substances

  • ANO3 protein, human
  • Anoctamins
  • Antigens
  • CD46 protein, human
  • Chloride Channels
  • Cytoskeletal Proteins
  • IFI44 protein, human
  • Measles-Mumps-Rubella Vaccine
  • Membrane Cofactor Protein
  • Magnesium