Genetic regulation of gene expression in the epileptic human hippocampus

Mirza, N. et al. (2017) Genetic regulation of gene expression in the epileptic human hippocampus. Human Molecular Genetics, 26(9), pp. 1759-1769. (doi: 10.1093/hmg/ddx061) (PMID:28334860) (PMCID:PMC5411756)

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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.

Item Type:Articles
Additional Information:NM was funded by a Medical Research Council Research Training Fellowship. MP is an NIHR Senior Investigator, and acknowledges support from the NHS Chair of Pharmacogenetics and the MRC Centre for Drug Safety Science. The FS GWAS analysis was supported by National Institutes of Health (NIH)/National Institute of Allergy And Infectious Diseases grant R01AI093697 (AH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. BF is supported by an Oak Foundation fellowship and AH is supported by a HallasMøller stipend from the Novo Nordisk Foundation. Funding to pay the Open Access publication charges for this article was provided by the Medical Research Council through a block grant administered by the University of Liverpool.
Glasgow Author(s) Enlighten ID:Sills, Dr Graeme
Authors: Mirza, N., Appleton, R., Burn, S., du Plessis, D., Duncan, R., Farah, J. O., Feenstra, B., Hviid, A., Josan, V., Mohanraj, R., Shukralla, A., Sills, G. J., Marson, A. G., and Pirmohamed, M.
College/School:College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Human Molecular Genetics
Publisher:Oxford University Press
ISSN (Online):1460-2083
Published Online:03 March 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Human Molecular Genetics 26(9):1759-1769
Publisher Policy:Reproduced under a Creative Commons License

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