Transcriptomic and genetic analyses reveal potential causal drivers for intractable partial epilepsy

TY - JOUR

T1 - Transcriptomic and genetic analyses reveal potential causal drivers for intractable partial epilepsy

AU - Guelfi, Sebastian

AU - Botia, Juan A.

AU - Thom, Maria

AU - Ramasamy, Adaikalavan

AU - Perona, Marina

AU - Stanyer, Lee

AU - Martinian, Lillian

AU - Trabzuni, Daniah

AU - Smith, Colin

AU - Walker, Robert

AU - Ryten, Mina

AU - Reimers, Mark

AU - Weale, Michael E.

AU - Hardy, John

AU - Matarin, Mar

PY - 2019/6

Y1 - 2019/6

N2 - Mesial temporal lobe epilepsy with hippocampal sclerosis represents the most common epilepsy syndrome in adult patients with medically intractable partial epilepsy. Mesial temporal lobe epilepsy is usually regarded as a polygenic and complex disorder, still poorly understood but probably caused and perpetuated by dysregulation of numerous biological networks and cellular functions. The study of gene expression changes by single nucleotide polymorphisms in regulatory elements (expression quantitative trait loci, eQTLs) has been shown to be a powerful complementary approach to the detection and understanding of risk loci by genome-wide association studies. We performed a whole (gene and exon-level) transcriptome analysis on cortical tissue samples (Brodmann areas 20 and 21) from 86 patients with mesial temporal lobe epilepsy with hippocampal sclerosis and 75 neurologically healthy controls. Genome-wide genotyping data from the same individuals (patients and controls) were analysed and paired with the transcriptome data. We report potential epilepsy-risk eQTLs, some of which are specific to tissue from patients with mesial temporal lobe epilepsy with hippocampal sclerosis. We also found large transcriptional and splicing deregulation in mesial temporal lobe epilepsy with hippocampal sclerosis tissue as well as gene networks involving neuronal and glial mechanisms that provide new insights into the cause and maintenance of the seizures. These data (available via the 'Seizubraineac' web-tool resource, www.seizubraineac.org) will facilitate the identification of new therapeutic targets and biomarkers as well as genetic risk variants that could influence epilepsy and pharmacoresistance.

AB - Mesial temporal lobe epilepsy with hippocampal sclerosis represents the most common epilepsy syndrome in adult patients with medically intractable partial epilepsy. Mesial temporal lobe epilepsy is usually regarded as a polygenic and complex disorder, still poorly understood but probably caused and perpetuated by dysregulation of numerous biological networks and cellular functions. The study of gene expression changes by single nucleotide polymorphisms in regulatory elements (expression quantitative trait loci, eQTLs) has been shown to be a powerful complementary approach to the detection and understanding of risk loci by genome-wide association studies. We performed a whole (gene and exon-level) transcriptome analysis on cortical tissue samples (Brodmann areas 20 and 21) from 86 patients with mesial temporal lobe epilepsy with hippocampal sclerosis and 75 neurologically healthy controls. Genome-wide genotyping data from the same individuals (patients and controls) were analysed and paired with the transcriptome data. We report potential epilepsy-risk eQTLs, some of which are specific to tissue from patients with mesial temporal lobe epilepsy with hippocampal sclerosis. We also found large transcriptional and splicing deregulation in mesial temporal lobe epilepsy with hippocampal sclerosis tissue as well as gene networks involving neuronal and glial mechanisms that provide new insights into the cause and maintenance of the seizures. These data (available via the 'Seizubraineac' web-tool resource, www.seizubraineac.org) will facilitate the identification of new therapeutic targets and biomarkers as well as genetic risk variants that could influence epilepsy and pharmacoresistance.

KW - co-expression regulatory network

KW - hippocampal sclerosis

KW - human brain eQTLs

KW - mesial temporal epilepsy

KW - splicing

UR - http://www.scopus.com/inward/record.url?scp=85066966549&partnerID=8YFLogxK

U2 - 10.1093/brain/awz074

DO - 10.1093/brain/awz074

M3 - Article

C2 - 30932156

AN - SCOPUS:85066966549

SN - 0006-8950

VL - 142

SP - 1616

EP - 1630

JO - Brain : a journal of neurology

JF - Brain : a journal of neurology

IS - 6

ER -