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

Research output: Contribution to journalJournal articlepeer-review

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

In: Brain, Vol. 145, No. 2, 2022, p. 555–568.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Skotte, L, Fadista, J, Bybjerg-Grauholm, J, Appadurai, V, Hildebrand, MS, Hansen, TF, Banasik, K, Grove, J, Albiñana, C, Geller, F, Bjurström, CF, Vilhjálmsson, BJ, Coleman, M, Damiano, JA, Burgess, R, Scheffer, IE, Pedersen, OBV, Erikstrup, C, Westergaard, D, Nielsen, KR, Sørensen, E, Bruun, MT, Liu, X, Hjalgrim, H, Pers, TH, Mortensen, PB, Mors, O, Nordentoft, M, Dreier, JW, Børglum, AD, Christensen, J, Hougaard, DM, Buil, A, Hviid, A, Melbye, M, Ullum, H, Berkovic, SF, Werge, T & Feenstra, B 2022, 'Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes', Brain, vol. 145, no. 2, pp. 555–568. https://doi.org/10.1093/brain/awab260

APA

Skotte, L., Fadista, J., Bybjerg-Grauholm, J., Appadurai, V., Hildebrand, M. S., Hansen, T. F., Banasik, K., Grove, J., Albiñana, C., Geller, F., Bjurström, C. F., Vilhjálmsson, B. J., Coleman, M., Damiano, J. A., Burgess, R., Scheffer, I. E., Pedersen, O. B. V., Erikstrup, C., Westergaard, D., ... Feenstra, B. (2022). Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes. Brain, 145(2), 555–568. https://doi.org/10.1093/brain/awab260

Vancouver

Skotte L, Fadista J, Bybjerg-Grauholm J, Appadurai V, Hildebrand MS, Hansen TF et al. Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes. Brain. 2022;145(2):555–568. https://doi.org/10.1093/brain/awab260

Author

Skotte, Line ; Fadista, João ; Bybjerg-Grauholm, Jonas ; Appadurai, Vivek ; Hildebrand, Michael S ; Hansen, Thomas F ; Banasik, Karina ; Grove, Jakob ; Albiñana, Clara ; Geller, Frank ; Bjurström, Carmen F ; Vilhjálmsson, Bjarni J ; Coleman, Matthew ; Damiano, John A ; Burgess, Rosemary ; Scheffer, Ingrid E ; Pedersen, Ole Birger Vesterager ; Erikstrup, Christian ; Westergaard, David ; Nielsen, Kaspar René ; Sørensen, Erik ; Bruun, Mie Topholm ; Liu, Xueping ; Hjalgrim, Henrik ; Pers, Tune H ; Mortensen, Preben Bo ; Mors, Ole ; Nordentoft, Merete ; Dreier, Julie W ; Børglum, Anders D ; Christensen, Jakob ; Hougaard, David M ; Buil, Alfonso ; Hviid, Anders ; Melbye, Mads ; Ullum, Henrik ; Berkovic, Samuel F ; Werge, Thomas ; Feenstra, Bjarke. / Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes. In: Brain. 2022 ; Vol. 145, No. 2. pp. 555–568.

Bibtex

@article{160f8a3708034ba686587ac156f5b24e,
title = "Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes",
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.",
author = "Line Skotte and Jo{\~a}o Fadista and Jonas Bybjerg-Grauholm and Vivek Appadurai and Hildebrand, {Michael S} and Hansen, {Thomas F} and Karina Banasik and Jakob Grove and Clara Albi{\~n}ana and Frank Geller and Bjurstr{\"o}m, {Carmen F} and Vilhj{\'a}lmsson, {Bjarni J} and Matthew Coleman and Damiano, {John A} and Rosemary Burgess and Scheffer, {Ingrid E} and Pedersen, {Ole Birger Vesterager} and Christian Erikstrup and David Westergaard and Nielsen, {Kaspar Ren{\'e}} and Erik S{\o}rensen and Bruun, {Mie Topholm} and Xueping Liu and Henrik Hjalgrim and Pers, {Tune H} and Mortensen, {Preben Bo} and Ole Mors and Merete Nordentoft and Dreier, {Julie W} and B{\o}rglum, {Anders D} and Jakob Christensen and Hougaard, {David M} and Alfonso Buil and Anders Hviid and Mads Melbye and Henrik Ullum and Berkovic, {Samuel F} and Thomas Werge and Bjarke Feenstra",
note = "{\textcopyright} The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.",
year = "2022",
doi = "10.1093/brain/awab260",
language = "English",
volume = "145",
pages = "555–568",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "2",

}

RIS

TY - JOUR

T1 - Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes

AU - Skotte, Line

AU - Fadista, João

AU - Bybjerg-Grauholm, Jonas

AU - Appadurai, Vivek

AU - Hildebrand, Michael S

AU - Hansen, Thomas F

AU - Banasik, Karina

AU - Grove, Jakob

AU - Albiñana, Clara

AU - Geller, Frank

AU - Bjurström, Carmen F

AU - Vilhjálmsson, Bjarni J

AU - Coleman, Matthew

AU - Damiano, John A

AU - Burgess, Rosemary

AU - Scheffer, Ingrid E

AU - Pedersen, Ole Birger Vesterager

AU - Erikstrup, Christian

AU - Westergaard, David

AU - Nielsen, Kaspar René

AU - Sørensen, Erik

AU - Bruun, Mie Topholm

AU - Liu, Xueping

AU - Hjalgrim, Henrik

AU - Pers, Tune H

AU - Mortensen, Preben Bo

AU - Mors, Ole

AU - Nordentoft, Merete

AU - Dreier, Julie W

AU - Børglum, Anders D

AU - Christensen, Jakob

AU - Hougaard, David M

AU - Buil, Alfonso

AU - Hviid, Anders

AU - Melbye, Mads

AU - Ullum, Henrik

AU - Berkovic, Samuel F

AU - Werge, Thomas

AU - Feenstra, Bjarke

N1 - © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

U2 - 10.1093/brain/awab260

DO - 10.1093/brain/awab260

M3 - Journal article

C2 - 35022648

VL - 145

SP - 555

EP - 568

JO - Brain

JF - Brain

SN - 0006-8950

IS - 2

ER -

ID: 301705778