Genome-wide association study of febrile seizures identifies seven new loci implicating fever response and neuronal excitability genes

Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental, and developmental factors. While usually benign, in a minority of cases, febrile seizures precede later development of epilepsy. Here, we conducted a genome-wide association study of febrile seizures with 7,635 cases and 93,966 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 harbored genes ( BSN, ERC2, GABRG2, HERC1 ) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. GABRG2 is a well-established epilepsy gene comprising variants associated with febrile seizures, and overall we found positive genetic correlations with epilepsies ( r g = 0.39, P = 1.68 × 10−4). Finally, a polygenic risk score based on all genome-wide significant loci was associated within patients with number of hospital admissions with febrile seizures and age at first admission, suggesting potential clinical utility of improved genetic understanding of febrile seizure genesis. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study was supported by grants from the Danish Medical Research Council (0602-01818B), the Oak Foundation (OCAY-18-598), the US National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (R01AI093697), the Novo Nordisk Foundation Challenge programme (NNF17OC0027594), a Lundbeck Foundation Ascending Investigator grant (R313-2019-554) to B.F., and National Health and Medical Research Council (NHMRC) Program Grant (1091593) to S.F.B. and I.E.S, Practitioner Fellowship (1006110) to I.E.S., and R.D Wright Career Development Fellowship (1063799) to M.S.H., and a Novo Nordisk Foundation Hallas-Moeller grant to A.H. The Danish National Biobank was established with the support of major grants from the Novo Nordisk Foundation, the Danish Medical Research Council and the Lundbeck Foundation. L.S. received support from a Carlsberg Foundation postdoctoral fellowship (CF15-0899); X.L. reports funding from the Nordic Center of Excellence in Health-Related e-Sciences; K.B. received support from the Novo Nordisk Foundation (NNF14CC0001, NNF17OC0027594); D.W. reports funding from the Novo Nordisk Foundation (NNF18SA0034956, NNF14CC0001, NNF17OC0027594); T.H.P. acknowledges the Novo Nordisk Foundation (NNF18CC0034900) and the Lundbeck Foundation (R190-2014-3904); J.C. and J.W.D. report funding from the Novo Nordisk Foundation (NNF16OC0019126), The Danish Epilepsy Association, and the Central Denmark Region; C.A. is supported by The Danish National Research Foundation (Niels Bohr Professorship to John McGrath). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The SSI study was approved by the Scientific Ethics Committee for the Capital City Region (Copenhagen) and the Danish Data Protection Agency. The Scientific Ethics Committee also granted exemption from obtaining informed consent from participants (H-3-2010-003) as the study was based on biobank material. The Danish Scientific Ethics Committee, the Danish Data Protection Agency and the Danish Neonatal Screening Biobank Steering Committee approved the iPSYCH study. DBDS was approved by the Central Denmark Regional Committee on Health Research Ethics (M-20090237) and the Danish Data Protection Agency, Copenhagen (2012-58-0004, RH-30-0444 / I-suite no.: 00922). For the Australian replication cohort, all experimental protocols were approved by the Human Research Ethics Committee of Austin Health, Melbourne, Australia. All methods were carried out in accordance with the approved guidelines of the Human Research Ethics Committee of Austin Health, Melbourne, Australia. Informed consent was obtained from all human subjects. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes GWAS summary statistics from this study will be made available via the Danish National Biobank website (https://www.danishnationalbiobank.com/gwas) upon publication of the study in a peer-reviewed journal.