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.

Keywords: epilepsy; febrile seizures; fever response genes; genome-wide association study; neuronal excitability genes.

Figure 1

Overall study design.

Figure 2

Febrile seizures genome-wide association analysis. Manhattan plot of −log₁₀ P-values across the chromosomes (left) and corresponding quantile–quantile plot of observed versus expected −log₁₀ P-values (right). Robustly associated loci are named; previously known loci are indicated in black; novel loci in red. The names above each locus represent the nearest protein coding gene at the locus or the chromosome band if the locus is in an intergenic region.

Figure 3

MAFs and effect sizes (OR in discovery stage) for 11 robustly associated febrile seizure loci. Previously known loci are indicated in blue; novel loci in red. The red dotted lines represent ORs corresponding to 80% statistical power based on simulations with the sample size of the current study. The blue lines represent ORs needed for 80% power in simulations with the sample size of the previous febrile seizures GWAS.

Figure 4

Multiple regression of PRS for febrile seizures on iPSYCH group and febrile seizure diagnosis. (A) Effect estimates of adjusted mean PRS for 14 factors defined by iPSYCH group and febrile seizure diagnosis with 95% CI. P-values are from tests of difference from overall mean adjusted PRS. (B) P-values from Wald tests of the equal group effect in pairwise comparisons of the 14 groups. ADHD = attention deficit hyperactivity disorder; ASD = autism spectrum disorders; Schizo = schizophrenia.

Figure 5

Association between PRS for febrile seizures and history of hospital admissions with a febrile seizure diagnosis among 2511 febrile seizure cases in the iPSYCH cohort. (A) Number of separate admissions to hospital with a febrile seizure diagnosis among the 2511 cases. (B) Box plots of PRS for febrile seizures based on 11 genome-wide significant loci by number of febrile seizures hospital admissions. The boxes define the first and third quartiles, with a black line representing the median. Whiskers extend to the smallest and largest values no further than 1.5 times the interquartile range from the first and third quartiles, respectively. The mean PRS is marked with an ‘x’. (C) Kaplan–Meier curves of time-to-event analysis for first febrile seizures hospital admission by groupings of PRS. A log-rank test was used to test for difference between the three curves.