Genetic regulation of gene expression in the epileptic human hippocampus.
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.
Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool L69 3GL, UK.
Nasir
N
Mirza
The Roald Dahl EEG Unit, Paediatric Neurosciences Foundation, Alder Hey Children's NHS Foundation Trust, Liverpool L12 2AP, UK.
Richard
R
Appleton
Department of Neurosurgery, Alder Hey Children's NHS Foundation Trust, Liverpool L12 2AP, UK.
Sasha
S
Burn
Department of Cellular Pathology, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK.
Daniel
D
du Plessis
Department of Neurology, Christchurch Hospital, Christchurch 8140, New Zealand.
Roderick
R
Duncan
Department of Neurosurgery, The Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK.
Jibril Osman
JO
Farah
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Bjarke
B
Feenstra
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Anders
A
Hviid
Department of Neurosurgery, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK.
Vivek
V
Josan
Department of Neurology, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK.
Rajiv
R
Mohanraj
Department of Neurology, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK.
Arif
A
Shukralla
Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool L69 3GL, UK.
Graeme J
GJ
Sills
Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool L69 3GL, UK.
Anthony G
AG
Marson
Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool L69 3GL, UK.
Munir
M
Pirmohamed
D001921:Brain / Q000378:metabolism / Q000502:physiology; D004827:Epilepsy / Q000235:genetics*; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics; D012307:Risk Factors; D003294:Seizures, Febrile / Q000235:genetics*