Journal article
Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus
MR Johnson, J Behmoaras, L Bottolo, ML Krishnan, K Pernhorst, PLM Santoscoy, T Rossetti, D Speed, PK Srivastava, M Chadeau-Hyam, N Hajji, A Dabrowska, M Rotival, B Razzaghi, S Kovac, K Wanisch, FW Grillo, A Slaviero, SR Langley, K Shkura Show all
Nature Communications | Published : 2015
DOI: 10.1038/ncomms7031
Abstract
Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease. Here we employ systems genetics approaches to characterize the genetic regulation of pathophysiological pathways in human temporal lobe epilepsy (TLE). Using surgically acquired hippocampi from 129 TLE patients, we identify a gene-regulatory network genetically associated with epilepsy that contains a specialized, highly expressed transcriptional module encoding proconvulsive cytokines and Toll-like receptor signalling genes. RNA sequencing analysis in a mouse model of TLE using 100 epileptic and 100 control hippocampi shows the proconvulsive module is preserv..
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Awarded by European Commission
Funding Acknowledgements
We acknowledge funding from Imperial NIHR Biomedical Research Centre/Imperial Innovations (E.P., J.B., M.R.J.), National Genome Research Network (NGFNplus: EMINet, grant 01GS08122; S.S., A.J.B.), DFG (SFB1089; A.J.B.), DFG (KFO177/SFB-1089; A.J.B., S.S.), BMBF (01GQ0806, S.S.), GIF (A.J.B.), ESF EuroEpinomics (A.J.B.), Else-Kroner Fresenius Foundation (A.J.B.), Wellcome Trust (J.B.), Imperial College Junior research fellowship (J.B.) and BONFOR (S.S., A.J.B.), UCB Pharma (M.R.J., E.P., R.K.), Medical Research Council UK (E.P.), CONACYT, Mexico (P.L.M.S., V.T.C.), Imperial College/Imperial College Healthcare, who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres (BRC) funding scheme (M.R.J., E.P.). DNA collection for GWAS was part funded by the Wellcome Trust (M.R.J., Grant Reference WT066056). The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602102 (EPITARGET; M.R.J., S.S., M.S., A.J.B., E.P.). The research was supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (M.R.J., E.P.). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We thank Mario Falchi and Philippe Froguel for providing critical comments on the first version of the manuscript.