Genome-wide association study of MMR-related febrile seizures

Posted by & filed under Part 28: NEUROGENETICS.

Feenstra B et al. Common variants associated with general and MMR vaccine-related febrile seizures. Nat Genet. 2014 Dec;46(12):1274-82. Epub 2014 Oct 26.

Febrile seizures are a well-known side-effect of MMR (measles-mumps-rubella) vaccination. Polymorphisms associated with an increased risk of febrile seizures in general have been identified previously (particularly in genes encoding ion channels); this study addresses the question of whether distinct variants influence the risk of febrile seizures specifically as a reaction to MMR vaccination. The authors performed a series of genome-wide association scans comparing children with MMR-related febrile seizures, children with febrile seizures unrelated to vaccination, and healthy controls.

Polymorphisms in two genes were associated distinctly with MMR-associated seizures: the interferon-stimulated gene IFI44L, and CD46, encoding the measles virus receptor. Four loci were associated with febrile seizures in general, implicating: two sodium channel genes (SCN1A and SCN2A), a region associated with magnesium levels, and ANO3, a TMEM16 family gene. To explore the functional significance of the latter gene, the authors performed electrophysiological recording in brain slices from wild-type and Ano3-null rats, and found that in the latter hypothalamic neurons were less responsive to heat, whereas hippocampal neurons became hyperexcitable with rises in temperature.

This study suggests that MMR-associated febrile seizures involve an interplay between neurological and immunological genetic risk factors, and opens a promising avenue for further study.


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