Genetic regulation of gene expression in the epileptic human hippocampus

Abstract

Epilepsy is a serious and common neurological disorder. Expression quantitative loci (eQTL) analysis is a vital aid for the identification and interpretation of disease-risk loci. Many eQTLs operate in a tissue- and condition-specific manner. We have performed the first genome-wide cis-eQTL analysis of human hippocampal tissue to include not only normal (n = 22) but also epileptic (n = 22) samples. We demonstrate that disease-associated variants from an epilepsy GWAS meta-analysis and a febrile seizures (FS) GWAS are significantly more enriched with epilepsy-eQTLs than with normal hippocampal eQTLs from two larger independent published studies. In contrast, GWAS meta-analyses of two other brain diseases associated with hippocampal pathology (Alzheimer's disease and schizophrenia) are more enriched with normal hippocampal eQTLs than with epilepsy-eQTLs. These observations suggest that an eQTL analysis that includes disease-affected brain tissue is advantageous for detecting additional risk SNPs for the afflicting and closely related disorders, but not for distinct diseases affecting the same brain regions. We also show that epilepsy eQTLs are enriched within epilepsy-causing genes: an epilepsy cis-gene is significantly more likely to be a causal gene for a Mendelian epilepsy syndrome than to be a causal gene for another Mendelian disorder. Epilepsy cis-genes, compared to normal hippocampal cis-genes, are more enriched within epilepsy-causing genes. Hence, we utilize the epilepsy eQTL data for the functional interpretation of epilepsy disease-risk variants and, thereby, highlight novel potential causal genes for sporadic epilepsy. In conclusion, an epilepsy-eQTL analysis is superior to normal hippocampal tissue eQTL analyses for identifying the variants and genes underlying epilepsy.

Figure 1

(A–C) Enrichment of significant SNPs from three eQTL studies (epilepsy-eQTL, GTEx and Braineac) within SNPs from three GWAS meta-analyses: epilepsy (A), Alzheimer’s disease (B) and schizophrenia (C). (D) Enrichment of significant SNPs from the epilepsy-eQTL within SNPs from the three GWAS meta-analyses. Epi-eQTL = epilepsy-eQTL; AD = Alzheimer’s disease; p-value notations as in the following example: 1e⁻⁶ = 1 x 10⁻⁶.

Figure 2

Relative enrichment of epilepsy GWAS meta-analysis SNPs within epilepsy-eQTL SNPs.