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

Nature Genetics (2014) doi:10.1038/ng.3129 Received 20 May 2014 Accepted 03 October 2014 Published online 26 October 2014

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

Bjarke Feenstra,1,* Björn Pasternak,1 Frank Geller,1 Lisbeth Carstensen,1 Tongfei Wang,2,3,4 Fen Huang,2,3,4 Jennifer L. Eitson,5 Mads V. Hollegaard,6 Henrik Svanström,1 Mogens Vestergaard,7 David M. Hougaard,6 John W. Schoggins,5 Lily Yeh Jan,2,3,4 Mads Melbye,1,8 and Anders Hviid1

1Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
2Department of Physiology, University of California, San Francisco, California, USA
3Department of Biochemistry and Biophysics, University of California, San Francisco, California, USA
4Howard Hughes Medical Institute, San Francisco, California, USA
5Department of Microbiology, University of Texas Southwestern Medical School, Dallas, Texas, USA
6Danish Centre for Neonatal Screening, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark
7Research Unit and Section for General Practice, Department of Public Health, Aarhus University, Aarhus, Denmark
8Department of Medicine, Stanford University School of Medicine, Stanford, California, USA

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.