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

Febrile seizures represent a recognized 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) vs. controls; P =1.2×10(−9) vs. MMR-unrelated febrile seizures) and the measles virus receptor CD46 (rs1318653; P = 9.6×10(−11) vs. controls; P = 1.6×10(−9) vs. 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 (TMEM16C; rs114444506; P = 3.7×10(−20)), and a region associated with magnesium levels (12q21.33; rs11105468; P = 3.4×10(−11)). Finally, functional relevance of TMEM16C was demonstrated with electrophysiological experiments in wild-type and knockout rats.