Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes.
epilepsy
febrile seizures
fever response genes
genome-wide association study
neuronal excitability genes
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
18 04 2022
18 04 2022
Historique:
received:
08
02
2021
revised:
09
05
2021
accepted:
07
06
2021
pubmed:
14
1
2022
medline:
21
4
2022
entrez:
13
1
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35022648
pii: 6503584
doi: 10.1093/brain/awab260
pmc: PMC9128543
doi:
Substances chimiques
ANO3 protein, human
0
Anoctamins
0
NAV1.1 Voltage-Gated Sodium Channel
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
555-568Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.
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