Genetic regulation of gene expression in the epileptic human hippocampus.

Nasir Mirza,Richard Appleton,Roderick Duncan,Anders Hviid,Vivek Josan,Rajiv Mohanraj,Arif Shukralla,Anthony G Marson,Sasha Burn,Bjarke Feenstra,Daniel Du Plessis,Graeme J Sills,Jibril Osman Farah,Munir Pirmohamed

doi:10.1093/hmg/ddx061

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.

Highlights

Epilepsy is amongst the most common neurological disorders, affecting up to 1% of the population [1]
We show that epilepsy Expression quantitative loci (eQTL) 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
Three individuals were excluded from the eQTL analysis on the basis of genotyping quality control (QC) filters, and one further individual was excluded from the eQTL analysis having failed the microarray QC criteria

Summary

Introduction

Epilepsy is amongst the most common neurological disorders, affecting up to 1% of the population [1]. A number of genome-wide association studies (GWAS) and a GWAS metaanalysis have been conducted in order to identify genetic variants associated with common epilepsies, but have identified less than ten distinct loci [3]. This lack of success is most readily explained by the limited statistical power of GWAS [4]: many of the missing variants are likely to be hidden amongst the signals discarded for failing to meet the stringent threshold of statistical significance required to tackle the multiple testing burden. The discovery of disease-associated variants can be enhanced as association of a variant with gene expression lends credibility to its association with disease status. eQTL-based selection for validation has been shown to be a useful approach for identifying disease-risk loci from GWAS in a number of disorders, for example Crohn’s disease [6]

Methods

Results

Conclusion