Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes

Line Skotte, João Fadista, Jonas Bybjerg-Grauholm, Vivek Appadurai, Michael S. Hildebrand, Thomas F. Hansen, Karina Banasik, Jakob Grove, Clara Albiñana, Frank Geller, Carmen F. Bjurström, Bjarni J. Vilhjálmsson, Matthew Coleman, John A. Damiano, Rosemary Burgess, Ingrid E. Scheffer, Ole Birger Vesterager Pedersen, Christian Erikstrup, David Westergaard, Kaspar René NielsenErik Sørensen, Mie Topholm Bruun, Xueping Liu, Henrik Hjalgrim, Tune H. Pers, Preben Bo Mortensen, Ole Mors, Merete Nordentoft, Julie W. Dreier, Anders D. Børglum, Jakob Christensen, David M. Hougaard, Alfonso Buil, Anders Hviid, Mads Melbye, Henrik Ullum, Samuel F. Berkovic, Thomas Werge, Bjarke Feenstra*

*Corresponding author for this work

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Abstract

Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.

Original languageEnglish
JournalBrain
Volume145
Issue number2
Pages (from-to)555-568
ISSN0006-8950
DOIs
Publication statusPublished - 1. Feb 2022

Bibliographical note

Publisher Copyright:
© 2021 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.

Keywords

  • epilepsy
  • febrile seizures
  • fever response genes
  • genome-wide association study
  • neuronal excitability genes

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