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

Skotte, Line ; Fadista, João LU ; Bybjerg-Grauholm, Jonas ; Appadurai, Vivek ; Hildebrand, Michael S. ; Hansen, Thomas F. ; Banasik, Karina ; Grove, Jakob ; Albiñana, Clara and Geller, Frank , et al. (2022) In Brain 145(2). p.555-568
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
epilepsy, febrile seizures, fever response genes, genome-wide association study, neuronal excitability genes
in
Brain
volume
145
issue
2
pages
14 pages
publisher
Oxford University Press
external identifiers
  • scopus:85128437215
  • pmid:35022648
ISSN
0006-8950
DOI
10.1093/brain/awab260
language
English
LU publication?
yes
id
781b7c00-bd3b-48cb-a379-b3a4d725c9d7
date added to LUP
2022-12-29 09:39:45
date last changed
2024-06-27 23:51:36
@article{781b7c00-bd3b-48cb-a379-b3a4d725c9d7,
  abstract     = {{<p>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 &lt; 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.</p>}},
  author       = {{Skotte, Line and Fadista, João and Bybjerg-Grauholm, Jonas and Appadurai, Vivek and Hildebrand, Michael S. and Hansen, Thomas F. and Banasik, Karina and Grove, Jakob and Albiñana, Clara and Geller, Frank and Bjurström, Carmen F. and Vilhjálmsson, Bjarni J. and Coleman, Matthew and Damiano, John A. and Burgess, Rosemary and Scheffer, Ingrid E. and Pedersen, Ole Birger Vesterager and Erikstrup, Christian and Westergaard, David and Nielsen, Kaspar René and Sørensen, Erik and Bruun, Mie Topholm and Liu, Xueping and Hjalgrim, Henrik and Pers, Tune H. and Mortensen, Preben Bo and Mors, Ole and Nordentoft, Merete and Dreier, Julie W. and Børglum, Anders D. and Christensen, Jakob and Hougaard, David M. and Buil, Alfonso and Hviid, Anders and Melbye, Mads and Ullum, Henrik and Berkovic, Samuel F. and Werge, Thomas and Feenstra, Bjarke}},
  issn         = {{0006-8950}},
  keywords     = {{epilepsy; febrile seizures; fever response genes; genome-wide association study; neuronal excitability genes}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{555--568}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain}},
  title        = {{Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes}},
  url          = {{http://dx.doi.org/10.1093/brain/awab260}},
  doi          = {{10.1093/brain/awab260}},
  volume       = {{145}},
  year         = {{2022}},
}