Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/30004
Title: Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes.
Austin Authors: 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
Affiliation: The Florey Institute of Neuroscience and Mental Health
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark..
Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden..
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland..
Danish Centre for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark..
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark..
Mental Health Center Sct. Hans, Mental Health Services, Capital Region Denmark, Roskilde, Denmark..
Epilepsy Research Centre
Medicine (University of Melbourne)
Murdoch Children's Research Institute, Parkville, Victoria, Australia..
Danish Headache Center, Department of Neurology, Rigshospitalet-Glostrup, Denmark..
Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark..
Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark..
Department of Biomedicine-Human Genetics, Aarhus University, Aarhus, Denmark..
Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark..
National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark..
Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, Flemington, Victoria, Australia..
Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark..
Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark..
Department of Clinical Immunology, Aalborg University Hospital North, Aalborg, Denmark..
Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark..
Department of Clinical Immunology, Odense University Hospital, Odense, Denmark..
Department of Haematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark..
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark..
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark..
Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark..
Mental Health Center Copenhagen, Mental Health Services in the Capital Region of Denmark, Copenhagen, Denmark..
Department of Neurology, Aarhus University Hospital, Aarhus, Denmark..
Department of Drug Design and Pharmacology, Pharmacovigilance Research Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark..
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA..
Statens Serum Institut, Copenhagen, Denmark..
Issue Date: 18-Apr-2022
Publication information: Brain : A Journal of Neurology 2022; 145(2): 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 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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/30004
DOI: 10.1093/brain/awab260
ORCID: 0000-0001-6703-7762
0000-0003-2489-2499
0000-0002-2311-2174
0000-0001-6551-6647
0000-0003-0128-8432
0000-0002-9339-4170
0000-0002-9385-6435
0000-0002-7509-9127
0000-0003-4580-841X
0000-0003-1478-649X
0000-0003-2739-0515
Journal: Brain : A Journal of Neurology
PubMed URL: 35022648
PubMed URL: https://pubmed.ncbi.nlm.nih.gov/35022648/
Type: Journal Article
Subjects: epilepsy
febrile seizures
fever response genes
genome-wide association study
neuronal excitability genes
Appears in Collections:Journal articles

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