Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A

Abstract

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.

Keywords: SCN1A; association; complex genetics; mesial temporal lobe epilepsy; mesial temporal sclerosis.

Figure 1

The results of genome-wide association analysis in MTLEHS+FS in discovery stage. (A) Manhattan plot, −log₁₀ (P-values) of the logistic regression test are plotted against single nucleotide polymorphism positions on each chromosome. (B) Quantile-quantile plot, the grey shaded area represents the 95% confidence interval of expected −log₁₀ (P-values). Black dots represent the observed P-values; λ = 1.022. (C) Regional association results for the chromosome 2q24.3 locus. The left y-axis represents −log₁₀ (P-values) for association with MTLEHS, the right y-axis represents the recombination rate, and the x-axis represents base-pair positions along the chromosome (human genome Build 37). The top single nucleotide polymorphism, rs7587026, is shown in purple, the rest of the single nucleotide polymorphisms are coloured according to their linkage disequilibrium r² value with rs7587026.

Figure 2

Forest plot for association of rs7587026 with MTLEHS+FS. The confidence interval for each study population is given by a horizontal line, and the point estimate is given by a square whose area is inversely proportional to the standard error of the estimate. The combined odds ratio is drawn as a diamond with horizontal limits at the confidence limits and width inversely proportional to its standard error. The study populations are ordered in descending order by the number of MTLEHS+FS cases.