Genome-wide association study identifies common variants associated with general and MMR vaccine-related febrile seizures. B. Feenstra1, B. Pasternak1, F. Geller1, L. Carstensen1, T. Wang2, F. Huang2, J. L. Eitson3, M. V. Hollegaard4, H. Svanström1, M. Vestergaard5, D. M. Hougaard4, J. W. Schoggins3, L. Y. Jan2, M. Melbye1, A. Hviid1,6 1) Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; 2) Departments of Physiology, Biochemistry and Biophysics, University of California, San Francisco, Howard Hughes Medical Institute, San Fransisco, CA; 3) Department of Microbiology, University of Texas Southwestern Medical School, Dallas, TX; 4) Danish Centre for Neonatal Screening, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark; 5) Research Unit and Section for General Practice, Department of Public Health, Aarhus University, Aarhus, Denmark; 6) Department of Medicine, Stanford University School of Medicine, Stanford, CA.

   Fever is a common reaction to immunization, and febrile seizures (FS) occasionally occur after vaccination, especially with live-virus vaccines such as the measles, mumps, and rubella (MMR) vaccine. Overall, FS occur in 2-5% of children before 5 years of age, and it has been estimated that 3 to 16 FS cases per 10,000 children can be attributed to MMR vaccination. To identify genetic risk factors associated with MMR-related FS and with FS in general, we conducted a series of genome-wide association scans based on samples in the Danish National Biobank comparing 929 children with MMR-related FS, 1,070 children with FS unrelated to vaccination, and 4,118 controls with no history of FS. After replication genotyping in an additional set of 408 children with MMR-related FS, 1,035 children with MMR-unrelated FS, and 1,647 controls, six independent genetic loci were associated with P < 5×10-8 in one or more of the analyses. Two loci were distinctly associated with MMR-related FS, harbouring the interferon-stimulated gene IFI44L (odds ratio (OR) = 1.41, P = 5.9×10-12 vs. controls; OR = 1.42, P = 1.2×10-9 vs. MMR-unrelated FS) and the measles virus receptor CD46 (OR = 1.43, P = 9.6×10-11 vs. controls; OR = 1.48, P = 1.6×10-9 vs. MMR-unrelated FS). As compared with controls, four loci were associated with FS in general implicating two sodium channel genes (SCN1A, OR = 1.34, P = 2.2×10-16 and SCN2A, OR = 1.22, P = 3.1×10-10), a TMEM16 family gene (TMEM16C, OR = 2.09, P = 3.7×10-20), and a region associated with serum magnesium levels (12q21.33, OR = 1.25, P = 3.4×10-11). To further investigate the functional relevance of TMEM16, we conducted a follow-up study in an animal knockout model. Electrophysiological recordings in brain slices from wild-type and knockout rats revealed that in the absence of Tmem16C, hypothalamic neurons were less responsive to heat, which could lead to impaired homeostatic control when body temperature rises, and hippocampal neurons became hyperexcitable, which could possibly contribute to FS genesis. In conclusion, these findings provide new insights into genetic mechanisms and biological pathways associated with FS occurring as an adverse event following MMR vaccination and in general.

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