Imperial College London

ProfessorMichaelJohnson

Faculty of MedicineDepartment of Medicine

Professor of Neurology and Genomic Medicine
 
 
 
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m.johnson Website

 
 
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E419Burlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
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91 results found

Laaniste L, Srivastava P, Stylianou T, Syed N, Cases-Cunillera S, Shkura K, Zeng Q, Rackham O, Langley S, Delahaye-Duriez A, O'Neill K, Williams M, Becker A, Roncaroli F, Petretto E, Johnson Met al., Integrated systems-genetic analyses reveal a network target for delaying glioma progression, Annals of Clinical and Translational Neurology, ISSN: 2328-9503

Journal article

Berghuis B, Stapleton C, Sonsma ACM, Hulst J, de Haan GJ, Lindhout D, Demurtas R, Krause R, Depondt C, Kunz WS, Zara F, Striano P, Craig J, Auce P, Marson AG, Stefansson H, O'Brien TJ, Johnson MR, Sills GJ, Wolking S, Lerche H, Sisodiya SM, Sander JW, Cavalleri GL, Koeleman BPC, McCormack Met al., 2019, A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine, Epilepsia Open, Vol: 4, Pages: 102-109, ISSN: 2470-9239

Epilepsia Open published by Wiley Periodicals Inc. on behalf of International League Against Epilepsy. Objective: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy. Methods: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum. Results: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found. Significance: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.

Journal article

Silvennoinen K, de Lange N, Zagaglia S, Balestrini S, Androsova G, Borghei M, Wassenaar M, Auce P, Avbersek, Becker F, Berghuis B, Campbell E, Coppola A, Francis B, Wolking S, Cavalleri GL, Craig J, Delanty N, Johnson MR, Koeleman BPC, Kunz WS, Lerche H, Marson AG, O'Brien TJ, Sander JW, Sills GJ, Striano P, Zara F, Krause R, Depondt C, Sisodiya SMet al., 2018, Retrospective Analysis Of Antiepileptic Drug Effectiveness And Tolerability In Juvenile Myoclonic Epilepsy, 13th European Congress on Epileptology, Publisher: WILEY, Pages: S219-S220, ISSN: 0013-9580

Conference paper

The International League Against Epilepsy Consortium on Complex Epilepsies, 2018, Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies, Nature Communications, Vol: 9, ISSN: 2041-1723

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.

Journal article

Srivastava P, van Eyll J, Godard P, Manuela M, Delahaye-Duriez A, Van Steenwinckel J, Gressens P, Danis B, Vandenplas C, Patrik F, Leclercq K, Mairet-Coello G, Cardenas A, Vanclef F, Laaniste L, Niespodziany I, Keaney J, Gasser J, Gillet G, Shkura K, Chong S-A, Behmoaras J, Kadiu I, Petretto EG, Kaminski R, Johnson Met al., 2018, A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target, Nature Communications, Vol: 9, ISSN: 2041-1723

The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery that combines gene regulatory information with causal reasoning (“Causal Reasoning Analytical Framework for Target discovery”—CRAFT). Using a systems genetics approach and starting from gene expression data from the target tissue, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof of concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in three pre-clinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. CRAFT is applicable to disease settings other than epilepsy.

Journal article

May P, Girard S, Harrer M, Bobbili DR, Schubert J, Wolking S, Becker F, Lachance-Touchette P, Meloche C, Gravel M, Niturad CE, Knaus J, De Kovel C, Toliat M, Polvi A, Iacomino M, Guerrero-Lopez R, Baulac S, Marini C, Thiele H, Altmueller J, Jabbari K, Ruppert A-K, Jurkowski W, Lal D, Rusconi R, Cestele S, Terragni B, Coombs ID, Reid CA, Striano P, Caglayan H, Siren A, Everett K, Moller RS, Hjalgrim H, Muhle H, Helbig I, Kunz WS, Weber YG, Weckhuysen S, De Jonghe P, Sisodiya SM, Nabbout R, Franceschetti S, Coppola A, Vari MS, Trenite DK-N, Baykan B, Ozbek U, Bebek N, Klein KM, Rosenow F, Nguyen DK, Dubeau F, Carmant L, Lortie A, Desbiens R, Clement J-F, Cieuta-Walti C, Sills GJ, Auce P, Francis B, Johnson MR, Marson AG, Berghuis B, Sander JW, Avbersek A, McCormack M, Cavalleri GL, Delanty N, Depondt C, Krenn M, Zimprich F, Peter S, Nikanorova M, Kraaij R, van Rooij J, Balling R, Ikram MA, Uitterlinden AG, Avanzini G, Schorge S, Petrou S, Mantegazza M, Sander T, LeGuern E, Serratosa JM, Koeleman BPC, Palotie A, Lehesjoki A-E, Nothnagel M, Nuernberg P, Maljevic S, Zara F, Cossette P, Krause R, Lerche Het al., 2018, Rare coding variants in genes encoding GABA(A) receptors in genetic generalised epilepsies: an exome-based case-control study, Lancet Neurology, Vol: 17, Pages: 699-708, ISSN: 1474-4422

BackgroundGenetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.MethodsFor this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.FindingsStatistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41–4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05–2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare mis

Journal article

McCormack M, Gui H, Ingason A, Speed D, Wright GEB, Zhang EJ, Secolin R, Yasuda C, Kwok M, Wolking S, Becker F, Rau S, Avbersek A, Heggeli K, Leu C, Depondt C, Sills GJ, Marson AG, Auce P, Brodie MJ, Francis B, Johnson MR, Koeleman BPC, Striano P, Coppola A, Zara F, Kunz WS, Sander JW, Lerche H, Klein KM, Weckhuysen S, Krenn M, Gudmundsson LJ, Stefansson K, Krause R, Shear N, Ross CJD, Delanty N, Pirmohamed M, Carleton BC, Cendes F, Lopes-Cendes I, Liao W-P, O'Brien TJ, Sisodiya SM, Cherny S, Kwan P, Baum L, Cavalleri GLet al., 2017, Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients, NEUROLOGY, Vol: 90, Pages: E332-E341, ISSN: 0028-3878

Objective To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs.Methods We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed.Results We report an association between a rare variant in the complement factor H–related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10–11; odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients.Conclusions The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.

Journal article

Srivastava PK, Roncon P, Lukasiuk K, Gorter JA, Aronica E, Pitkänen A, Petretto E, Johnson MR, Simonato Met al., 2017, Meta-Analysis of MicroRNAs Dysregulated in the Hippocampal Dentate Gyrus of Animal Models of Epilepsy., eNeuro, Vol: 4, ISSN: 2373-2822

The identification of mechanisms transforming normal to seizure-generating tissue after brain injury is key to developing new antiepileptogenic treatments. MicroRNAs (miRNAs) may act as regulators and potential treatment targets for epileptogenesis. Here, we undertook a meta-analysis of changes in miRNA expression in the hippocampal dentate gyrus (DG) following an epileptogenic insult in three epilepsy models. We identified 26 miRNAs significantly differentially expressed during epileptogenesis, and five differentially expressed in chronic epilepsy. Of these, 13 were not identified in any of the individual studies. To assess the role of these miRNAs, we predicted their mRNA targets and then filtered the list to include only target genes expressed in DG and negatively correlated with miRNA expression. Functional enrichment analysis of mRNA targets of miRNAs dysregulated during epileptogenesis suggested a role for molecular processes related to inflammation and synaptic function. Our results identify new miRNAs associated with epileptogenesis from existing data, highlighting the utility of meta-analysis in maximizing value from preclinical data.

Journal article

van Vliet EA, Puhakka N, Mills JD, Srivastava PK, Johnson MR, Roncon P, Das Gupta S, Karttunen J, Simonato M, Lukasiuk K, Gorter JA, Aronica E, Pitkänen Aet al., 2017, Standardization procedure for plasma biomarker analysis in rat models of epileptogenesis: Focus on circulating microRNAs., Epilepsia, Vol: 58, Pages: 2013-2024, ISSN: 0013-9580

The World Health Organization estimates that globally 2.4 million people are diagnosed with epilepsy each year. In nearly 30% of these cases, epilepsy cannot be properly controlled by antiepileptic drugs. More importantly, treatments to prevent or modify epileptogenesis do not exist. Therefore, novel therapies are urgently needed. In this respect, it is important to identify which patients will develop epilepsy and which individually tailored treatment is needed. However, currently, we have no tools to identify the patients at risk, and diagnosis of epileptogenesis remains as a major unmet medical need, which relates to lack of diagnostic biomarkers for epileptogenesis. As the epileptogenic process in humans is typically slow, the use of animal models is justified to speed up biomarker discovery. We aim to summarize recommendations for molecular biomarker research and propose a standardized procedure for biomarker discovery in rat models of epileptogenesis. The potential of many phylogenetically conserved circulating noncoding small RNAs, including microRNAs (miRNAs), as biomarkers has been explored in various brain diseases, including epilepsy. Recent studies show the feasibility of detecting miRNAs in blood in both experimental models and human epilepsy. However, the analysis of circulating miRNAs in rodent models is challenging, which relates both to the lack of standardized sampling protocols and to analysis of miRNAs. We will discuss the issues critical for preclinical plasma biomarker discovery, such as documentation, blood and brain tissue sampling and collection, plasma separation and storage, RNA extraction, quality control, and RNA detection. We propose a protocol for standardization of procedures for discovery of circulating miRNA biomarkers in rat models of epileptogenesis. Ultimately, we hope that the preclinical standardization will facilitate clinical biomarker discovery for epileptogenesis in man.

Journal article

Allen AS, Berkovic SF, Bridgers J, Cossette P, Dlugos D, Epstein MP, Glauser T, Goldstein DB, Heinzen EL, Jiang Y, Johnson MR, Kuzniecky R, Lowenstein DH, Marson AG, Mefford HC, O'Brien TJ, Ottman R, Petrou S, Petrovski S, Poduri A, Ren Z, Scheffer IE, Sherr E, Wang Q, Balling R, Barisic N, Baulac S, Caglayan H, Craiu D, De Jonghe P, Depienne C, Guerrini R, Helbig I, Hjalgrim H, Hoffman-Zacharska D, Jaehn J, Klein KM, Koeleman B, Komarek V, Krause R, Leguern E, Lehesjoki A-E, Lemke JR, Lerche H, Linnankivi T, Marini C, May P, Moller RS, Muhle H, Pal D, Palotie A, Rosenow F, Selmer K, Serratosa JM, Sisodiya S, Stephani U, Sterbova K, Striano P, Suls A, Talvik T, von Spiczak S, Weber Y, Weckhuysen S, Zara F, Abou-Khalil B, Alldredge BK, Amrom D, Andermann E, Andermann F, Bautista JF, Berkovic SF, Bluvstein J, Cascino GD, Consalvo D, Crumrine P, Devinsky O, Dlugos D, Epstein MP, Fiol ME, Fountain NB, French J, Friedman D, Glauser T, Haas K, Haut SR, Hayward J, Joshi S, Kanner A, Kirsch HE, Kossoff EH, Kuperman R, Kuzniecky R, Lowenstein DH, McGuire SM, Motika PV, Novotny EJ, Ottman R, Paolicchi JM, Parent J, Park K, Poduri A, Scheffer IE, Shellhaas RA, Sherr E, Sirven J, Smith MC, Sullivan J, Thio LL, Venkat A, Vining EPG, Von Allmen GK, Weisenberg JL, Widdess-Walsh P, Winawer MRet al., 2017, Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 25, Pages: 894-899, ISSN: 1018-4813

Journal article

Speed D, Cai N, Johnson MR, Nejentsev S, Balding DJet al., 2017, Reevaluation of SNP heritability in complex human traits, Nature Genetics, Vol: 49, Pages: 986-992, ISSN: 1061-4036

SNP heritability, the proportion of phenotypic variance explained by SNPs, has been reported for many hundreds of traits. Its estimation requires strong prior assumptions about the distribution of heritability across the genome, but current assumptions have not been thoroughly tested. By analyzing imputed data for a large number of human traits, we empirically derive a model that more accurately describes how heritability varies with minor allele frequency (MAF), linkage disequilibrium (LD) and genotype certainty. Across 19 traits, our improved model leads to estimates of common SNP heritability on average 43% (s.d. 3%) higher than those obtained from the widely used software GCTA and 25% (s.d. 2%) higher than those from the recently proposed extension GCTA-LDMS. Previously, DNase I hypersensitivity sites were reported to explain 79% of SNP heritability; using our improved heritability model, their estimated contribution is only 24%.

Journal article

Srivastava PK, Bagnati M, Delahaye-Duriez A, KO J-H, Rotival M, Langley SR, Shkura K, Mazzuferi M, Danis B, Eyll JV, Foerch P, Behmoaras J, Kaminski RM, Petretto E, Johnson MRet al., 2017, Genome-wide analysis of differential RNA editing in epilepsy, Genome Research, Vol: 27, Pages: 440-450, ISSN: 1549-5469

The recoding of genetic information through RNA editing contributes to proteomic diversity, but the extent and significance of RNA editing in disease is poorly understood. In particular, few studies have investigated the relationship between RNA editing and disease at a genome-wide level. Here, we developed a framework for the genome-wide detection of RNA sites that are differentially edited in disease. Using RNA-sequencing data from 100 hippocampi from mice with epilepsy (pilocarpine–temporal lobe epilepsy model) and 100 healthy control hippocampi, we identified 256 RNA sites (overlapping with 87 genes) that were significantly differentially edited between epileptic cases and controls. The degree of differential RNA editing in epileptic mice correlated with frequency of seizures, and the set of genes differentially RNA-edited between case and control mice were enriched for functional terms highly relevant to epilepsy, including “neuron projection” and “seizures.” Genes with differential RNA editing were preferentially enriched for genes with a genetic association to epilepsy. Indeed, we found that they are significantly enriched for genes that harbor nonsynonymous de novo mutations in patients with epileptic encephalopathy and for common susceptibility variants associated with generalized epilepsy. These analyses reveal a functional convergence between genes that are differentially RNA-edited in acquired symptomatic epilepsy and those that contribute risk for genetic epilepsy. Taken together, our results suggest a potential role for RNA editing in the epileptic hippocampus in the occurrence and severity of epileptic seizures.

Journal article

Symonds JD, Zuberi SM, Johnson MR, 2017, Advances in epilepsy gene discovery and implications for epilepsy diagnosis and treatment, CURRENT OPINION IN NEUROLOGY, Vol: 30, Pages: 193-199, ISSN: 1350-7540

Purpose of review: Epilepsy genetics is shifting from the academic pursuit of gene discovery to a clinical discipline based on molecular diagnosis and stratified medicine. We consider the latest developments in epilepsy genetics and review how gene discovery in epilepsy is influencing the clinical classification of epilepsy and informing new therapeutic approaches and drug discovery.Recent findings: Recent studies highlighting the importance of mutation in GABA receptors, NMDA receptors, potassium channels, G-protein coupled receptors, mammalian target of rapamycin pathway and chromatin remodeling are discussed. Examples of precision medicine in epilepsy targeting gain-of-function mutations in KCNT1, GRIN2A, GRIN2D and SCN8A are presented. Potential reasons for the paucity of examples of precision medicine for loss-of-function mutations or in non-ion channel epilepsy genes are explored. We highlight how systems genetics and gene network analyses have suggested that pathways disrupted in epilepsy overlap with those of other neurodevelopmental traits including human cognition. We review how network-based computational approaches are now being applied to epilepsy drug discovery.Summary: We are living in an unparalleled era of epilepsy gene discovery. Advances in clinical care from this progress are already materializing through improved clinical diagnosis and stratified medicine. The application of targeted drug repurposing based on single gene defects has shown promise for epilepsy arising from gain-of-function mutations in ion-channel subunit genes, but important barriers remain to translating these approaches to non-ion channel epilepsy genes and loss-of-function mutations. Gene network analysis offers opportunities to discover new pathways for epilepsy, to decipher epilepsy's relationship to other neurodevelopmental traits and to frame a new approach to epilepsy drug discovery.

Journal article

Miller TD, Chong TT-J, Davies AMA, Ng TWC, Johnson MR, Irani SR, Vincent A, Husain M, Jacob S, Maddison P, Kennard C, Gowland PA, Rosenthal CRet al., 2017, Focal CA3 hippocampal subfield atrophy following LGI1 VGKC-complex antibody limbic encephalitis, BRAIN, Vol: 140, Pages: 1212-1219, ISSN: 0006-8950

Magnetic resonance imaging has linked chronic voltage-gated potassium channel (VGKC) complex antibody-mediated limbic encephalitis with generalized hippocampal atrophy. However, autoantibodies bind to specific rodent hippocampal subfields. Here, human hippocampal subfield (subiculum, cornu ammonis 1-3, and dentate gyrus) targets of immunomodulation-treated LGI1 VGKC-complex antibody-mediated limbic encephalitis were investigated using in vivo ultra-high resolution (0.39 × 0.39 × 1.0 mm3) 7.0 T magnetic resonance imaging [n = 18 patients, 17 patients (94%) positive for LGI1 antibody and one patient negative for LGI1/CASPR2 but positive for VGKC-complex antibodies, mean age: 64.0 ± 2.55 years, median 4 years post-limbic encephalitis onset; n = 18 controls]. First, hippocampal subfield quantitative morphometry indicated significant volume loss confined to bilateral CA3 [F(1,34) = 16.87, P < 0.0001], despite hyperintense signal evident in 5 of 18 patients on presentation. Second, early and later intervention (<3 versus >3 months from symptom onset) were associated with CA3 atrophy. Third, whole-brain voxel-by-voxel morphometry revealed no significant grey matter loss. Fourth, CA3 subfield atrophy was associated with severe episodic but not semantic amnesia for postmorbid autobiographical events that was predicted by variability in CA3 volume. The results raise important questions about the links with histopathology, the impact of the observed focal atrophy on other CA3-mediated reconstructive and episodic mechanisms, and the role of potential antibody-mediated pathogenicity as part of the pathophysiology cascade in humans.

Journal article

Allen AS, Bellows ST, Berkovic SF, Bridgers J, Burgess R, Cavalleri G, Chung S-K, Cossette P, Delanty N, Dlugos D, Epstein MP, Freyer C, Goldstein DB, Heinzen EL, Hildebrand MS, Johnson MR, Kuzniecky R, Lowenstein DH, Marson AG, Mayeux R, Mebane C, Mefford HC, O'Brien TJ, Ottman R, Petrou S, Petrovski S, Pickrell WO, Poduri A, Radtke RA, Rees MI, Regan BM, Ren Z, Scheffer IE, Sills GJ, Thomas RH, Wang Q, Abou-Khalil B, Alldredge BK, Amrom D, Andermann E, Andermann F, Bautista JF, Berkovic SF, Bluvstein J, Boro A, Cascino GD, Consalvo D, Crumrine P, Devinsky O, Dlugos D, Epstein MP, Fiol M, Fountain NB, French J, Freyer C, Friedman D, Geller EB, Glauser T, Glynn S, Haas K, Haut SR, Hayward J, Helmers SL, Joshi S, Kanner A, Kirsch HE, Knowlton RC, Kossoff EH, Kuperman R, Kuzniecky R, Lowenstein DH, Motika PV, Novotny EJ, Ottman R, Paolicchi JM, Parent JM, Park K, Poduri A, Sadleir LG, Scheffer IE, Shellhaas RA, Sherr EH, Shih JJ, Shinnar S, Singh RK, Sirven J, Smith MC, Sullivan J, Thio LL, Venkat A, Vining EPG, Von Allmen GK, Weisenberg JL, Widdess-Walsh P, Winawer MRet al., 2017, Ultra-rare genetic variation in common epilepsies: a case-control sequencing study, The Lancet Neurology, Vol: 16, Pages: 135-143, ISSN: 1474-4422

BackgroundDespite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies.MethodsWe did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies.FindingsWe separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7–3·2, p=9·1 × 10−8; familial non-acquired focal epilepsy 3·6, 2·7–4·9, p=1·1 × 10−17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting fo

Journal article

Delahaye-Duriez A, Srivastava P, Shkura K, Langley SR, Laaniste L, Moreno-Moral A, Danis B, Foerch P, Gazina EV, Richards K, Petrou S, Kaminski R, Petretto E, Johnson MRet al., 2016, Rare and common epilepsies converge on a shared gene regulatory network providing opportunities for novel antiepileptic drug discovery, Genome Biology, Vol: 17, ISSN: 1474-760X

BackgroundThe relationship between monogenic and polygenic forms of epilepsy is poorly understood, and the extent to which the genetic and acquired epilepsies share common pathways is unclear. Here, we use an integrated systems-level analysis of brain gene expression data to identify molecular networks disrupted in epilepsy.ResultsWe identify a co-expression network of 320 genes (M30), which is significantly enriched for non-synonymous de novo mutations ascertained from patients with monogenic epilepsy, and for common variants associated with polygenic epilepsy. The genes in M30 network are expressed widely in the human brain under tight developmental control, and encode physically interacting proteins involved in synaptic processes. The most highly connected proteins within M30 network are preferentially disrupted by deleterious de novo mutations for monogenic epilepsy, in line with the centrality-lethality hypothesis. Analysis of M30 expression revealed consistent down-regulation in the epileptic brain in heterogeneous forms of epilepsy including human temporal lobe epilepsy, a mouse model of acquired temporal lobe epilepsy, and a mouse model of monogenic Dravet (SCN1A) disease. These results suggest functional disruption of M30 via gene mutation or altered expression as a convergent mechanismregulating susceptibility to epilepsy broadly. Using the large collection of drug-induced gene expression data from Connectivity Map, several drugs were predicted to preferentially restore the down-regulation of M30 in epilepsy toward health, most notably valproic acid, whose effect on M30 expression was replicated in neurons.ConclusionsTaken together, our results suggest targeting the expression of M30 as a potential new therapeutic strategy in epilepsy.

Journal article

Scott G, Mahmud M, Owen DR, Johnson MRet al., 2016, Microglial positron emission tomography (PET) imaging in epilepsy: applications, opportunities and pitfalls, Seizure-European Journal of Epilepsy, Vol: 44, Pages: 42-47, ISSN: 1059-1311

Neuroinflammation is increasingly implicated in epileptogenesis and epilepsy. Microglia are an important mediator of central nervous system inflammation, and the development of positron emission tomography (PET) radioligands which bind the Translocator Protein (TSPO), an outer mitochondrial membrane protein expressed by microglia, has enabled in vivo measurement of neuroinflammation. Here, we outline the principles and potential pitfalls of TSPO PET imaging in relation to epilepsy, and opportunities for using TSPO imaging as a biomarker for future anti-inflammatory based therapeutics in epilepsy.

Journal article

Johnson MR, Shkura K, Langley SR, Delahaye-Duriez A, Srivastava P, Hill WD, Rackham OJL, Davies G, Harris SE, Moreno-Moral A, Rotival M, Speed D, Petrovski S, Katz A, Hayward C, Porteous DJ, Smith BH, Padmanabhan S, Hocking LJ, Starr JM, Liewald DC, Visconti A, Falchi M, Bottolo L, Rossetti T, Danis B, Mazzuferi M, Foerch P, Grote A, Helmstaedter C, Becker AJ, Kaminski RM, Deary IJ, Petretto Eet al., 2016, Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease, Nature Neuroscience, Vol: 19, Pages: 223-232, ISSN: 1546-1726

Genetic determinants of cognition are poorly characterized, and their relationship to genes that confer risk for neurodevelopmental disease is unclear. Here we performed a systems-level analysis of genome-wide gene expression data to infer gene-regulatory networks conserved across species and brain regions. Two of these networks, M1 and M3, showed replicable enrichment for common genetic variants underlying healthy human cognitive abilities, including memory. Using exome sequence data from 6,871 trios, we found that M3 genes were also enriched for mutations ascertained from patients with neurodevelopmental disease generally, and intellectual disability and epileptic encephalopathy in particular. M3 consists of 150 genes whose expression is tightly developmentally regulated, but which are collectively poorly annotated for known functional pathways. These results illustrate how systems-level analyses can reveal previously unappreciated relationships between neurodevelopmental disease–associated genes in the developed human brain, and provide empirical support for a convergent gene-regulatory network influencing cognition and neurodevelopmental disease.

Journal article

Warburton A, Miyajima F, Shazadi K, Crossley J, Johnson MR, Marson AG, Baker GA, Quinn JP, Sills GJet al., 2016, NRSF and BDNF polymorphisms as biomarkers of cognitive dysfunction in adults with newly diagnosed epilepsy, Epilepsy & Behavior, Vol: 54, Pages: 117-127, ISSN: 1525-5069

Cognitive dysfunction is a common comorbidity in people with epilepsy, but its causes remain unclear. It may be related to the etiology of the disorder, the consequences of seizures, or the effects of antiepileptic drug treatment. Genetics may also play a contributory role. We investigated the influence of variants in the genes encoding neuron-restrictive silencer factor (NRSF) and brain-derived neurotrophic factor (BDNF), proteins previously associated with cognition and epilepsy, on cognitive function in people with newly diagnosed epilepsy. A total of 82 patients who had previously undergone detailed neuropsychological assessment were genotyped for single nucleotide polymorphisms (SNPs) across the NRSF and BDNF genes. Putatively functional SNPs were included in a genetic association analysis with specific cognitive domains, including memory, psychomotor speed, and information processing. Cross-sectional and longitudinal designs were used to explore genetic influences on baseline cognition at diagnosis and change from baseline over the first year since diagnosis, respectively. We found a statistically significant association between genotypic variation and memory function at both baseline (NRSF: rs1105434, rs2227902 and BDNF: rs1491850, rs2030324, rs11030094) and in our longitudinal analysis (NRSF: rs2227902 and BDNF: rs12273363). Psychomotor speed was also associated with genotype (NRSF rs3796529) in the longitudinal assessment. In line with our previous work on general cognitive function in the healthy aging population, we observed an additive interaction between risk alleles for the NRSF rs2227902 (G) and BDNF rs6265 (A) polymorphisms which was again consistent with a significantly greater decline in delayed recall over the first year since diagnosis. These findings support a role for the NRSF–BDNF pathway in the modulation of cognitive function in patients with newly diagnosed epilepsy.

Journal article

Roncon P, Soukupova M, Binaschi A, Falcicchia C, Zucchini S, Ferracin M, Langley SR, Petretto E, Johnson MR, Marucci G, Michelucci R, Rubboli G, Simonato Met al., 2015, MicroRNA profiles in hippocampal granule cells and plasma of rats with pilocarpine-induced epilepsy - comparison with human epileptic samples, Scientific Reports, Vol: 5, ISSN: 2045-2322

The identification of biomarkers of the transformation of normal to epileptic tissue would help to stratify patients at risk of epilepsy following brain injury, and inform new treatment strategies. MicroRNAs (miRNAs) are an attractive option in this direction. In this study, miRNA microarrays were performed on laser-microdissected hippocampal granule cell layer (GCL) and on plasma, at different time points in the development of pilocarpine-induced epilepsy in the rat: latency, first spontaneous seizure and chronic epileptic phase. Sixty-three miRNAs were differentially expressed in the GCL when considering all time points. Three main clusters were identified that separated the control and chronic phase groups from the latency group and from the first spontaneous seizure group. MiRNAs from rats in the chronic phase were compared to those obtained from the laser-microdissected GCL of epileptic patients, identifying several miRNAs (miR-21-5p, miR-23a-5p, miR-146a-5p and miR-181c-5p) that were up-regulated in both human and rat epileptic tissue. Analysis of plasma samples revealed different levels between control and pilocarpine-treated animals for 27 miRNAs. Two main clusters were identified that segregated controls from all other groups. Those miRNAs that are altered in plasma before the first spontaneous seizure, like miR-9a-3p, may be proposed as putative biomarkers of epileptogenesis.

Journal article

Epilepsy PhenomeGenome Project & Epi4K Consortium, 2015, Copy number variant analysis from exome data in 349 patients with epileptic encephalopathy, Annals of Neurology, Vol: 78, Pages: 323-328, ISSN: 0364-5134

Infantile spasms (IS) and Lennox–Gastaut syndrome (LGS) are epileptic encephalopathies characterized by early onset, intractable seizures, and poor developmental outcomes. De novo sequence mutations and copy number variants (CNVs) are causative in a subset of cases. We used exome sequence data in 349 trios with IS or LGS to identify putative de novo CNVs. We confirm 18 de novo CNVs in 17 patients (4.8%), 10 of which are likely pathogenic, giving a firm genetic diagnosis for 2.9% of patients. Confirmation of exome-predicted CNVs by array-based methods is still required due to false-positive rates of prediction algorithms. Our exome-based results are consistent with recent array-based studies in similar cohorts and highlight novel candidate genes for IS and LGS.

Journal article

Dhindsa RS, Bradrick SS, Yao X, Heinzen EL, Petrovski S, Krueger BJ, Johnson MR, Frankel WN, Petrou S, Boumil RM, Goldstein DBet al., 2015, Epileptic encephalopathy-causing mutations in DNM1 impair synaptic vesicle endocytosis, Neurology: Genetics, Vol: 1, ISSN: 2376-7839

OBJECTIVE: To elucidate the functional consequences of epileptic encephalopathy-causing de novo mutations in DNM1 (A177P, K206N, G359A), which encodes a large mechanochemical GTPase essential for neuronal synaptic vesicle endocytosis. METHODS: HeLa and COS-7 cells transfected with wild-type and mutant DNM1 constructs were used for transferrin assays, high-content imaging, colocalization studies, Western blotting, and electron microscopy (EM). EM was also conducted on the brain sections of mice harboring a middle-domain Dnm1 mutation (Dnm1 (Ftfl)). RESULTS: We demonstrate that the expression of each mutant protein decreased endocytosis activity in a dominant-negative manner. One of the G-domain mutations, K206N, decreased protein levels. The G359A mutation, which occurs in the middle domain, disrupted higher-order DNM1 oligomerization. EM of mutant DNM1-transfected HeLa cells and of the Dnm1 (Ftfl) mouse brain revealed vesicle defects, indicating that the mutations likely interfere with DNM1's vesicle scission activity. CONCLUSION: Together, these data suggest that the dysfunction of vesicle scission during synaptic vesicle endocytosis can lead to serious early-onset epilepsies.

Journal article

Johnson MR, Behmoaras J, Bottolo L, Krishnan ML, Pernhorst K, Santoscoy PL, Rossetti T, Speed D, Srivastava PK, Chadeau-Hyam M, Hajji N, Dabrowska A, Rotival M, Razzaghi B, Kovac S, Wanisch K, Grillo FW, Slaviero A, Langley SR, Shkura K, Roncon P, De T, Mattheisen M, Niehusmann P, O'Brien TJ, Petrovski S, von Lehe M, Hoffmann P, Eriksson J, Coffey AJ, Cichon S, Walker M, Simonato M, Danis B, Mazzuferi M, Foerch P, Schoch S, De Paola V, Kaminski RM, Cunliffe VT, Becker AJ, Petretto Eet al., 2015, Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus., Nat Commun, Vol: 6

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 preserved across-species, specific to the epileptic hippocampus and upregulated in chronic epilepsy. In the TLE patients, we map the trans-acting genetic control of this proconvulsive module to Sestrin 3 (SESN3), and demonstrate that SESN3 positively regulates the module in macrophages, microglia and neurons. Morpholino-mediated Sesn3 knockdown in zebrafish confirms the regulation of the transcriptional module, and attenuates chemically induced behavioural seizures in vivo.

Journal article

Rackham OJL, Shihab HA, Johnson MR, Petretto Eet al., 2014, EvoTol: a protein-sequence based evolutionary intolerance framework for disease-gene prioritization, Nucleic Acids Research, Vol: 43, ISSN: 0305-1048

Methods to interpret personal genome sequences are increasingly required. Here, we report a novel framework (EvoTol) to identify disease-causing genes using patient sequence data from within protein coding-regions. EvoTol quantifies a gene's intolerance to mutation using evolutionary conservation of protein sequences and can incorporate tissue-specific gene expression data. We apply this framework to the analysis of whole-exome sequence data in epilepsy and congenital heart disease, and demonstrate EvoTol's ability to identify known disease-causing genes is unmatched by competing methods. Application of EvoTol to the human interactome revealed networks enriched for genes intolerant to protein sequence variation, informing novel polygenic contributions to human disease.

Journal article

Shazadi K, Petrovski S, Roten A, Miller H, Huggins RM, Brodie MJ, Pirmohamed M, Johnson MR, Marson AG, O'Brien TJ, Sills GJet al., 2014, Validation of a multigenic model to predict seizure control in newly treated epilepsy, EPILEPSY RESEARCH, Vol: 108, Pages: 1797-1805, ISSN: 0920-1211

Journal article

Speed D, O'Brien TJ, Palotie A, Shkura K, Marson AG, Balding DJ, Johnson MRet al., 2014, Describing the genetic architecture of epilepsy through heritability analysis, Brain, Vol: 137, Pages: 2680-2689, ISSN: 1460-2156

Epilepsy is a disease with substantial missing heritability; despite its high genetic component, genetic association studies have had limited success detecting common variants which influence susceptibility. In this paper, we reassess the role of common variants on epilepsy using extensions of heritability analysis. Our data set consists of 1258 UK patients with epilepsy, of which 958 have focal epilepsy, and 5129 population control subjects, with genotypes recorded for over 4 million common single nucleotide polymorphisms. Firstly, we show that on the liability scale, common variants collectively explain at least 26% (standard deviation 5%) of phenotypic variation for all epilepsy and 27% (standard deviation 5%) for focal epilepsy. Secondly we provide a new method for estimating the number of causal variants for complex traits; when applied to epilepsy, our most optimistic estimate suggests that at least 400 variants influence disease susceptibility, with potentially many thousands. Thirdly, we use bivariate analysis to assess how similar the genetic architecture of focal epilepsy is to that of non-focal epilepsy; we demonstrate both significant differences (P = 0.004) and significant similarities (P = 0.01) between the two subtypes, indicating that although the clinical definition of focal epilepsy does identify a genetically distinct epilepsy subtype, there is also scope to improve the classification of epilepsy by incorporating genotypic information. Lastly, we investigate the potential value in using genetic data to diagnose epilepsy following a single epileptic seizure; we find that a prediction model explaining 10% of phenotypic variation could have clinical utility for deciding which single-seizure individuals are likely to benefit from immediate anti-epileptic drug therapy.

Journal article

Raedisch S, Dickens D, Lang T, Bonnett L, Arlanov R, Johnson MR, Schwab M, Marson AG, Pirmohamed Met al., 2014, A comprehensive functional and clinical analysis of ABCC2 and its impact on treatment response to carbamazepine, PHARMACOGENOMICS JOURNAL, Vol: 14, Pages: 481-487, ISSN: 1470-269X

Journal article

Appenzeller S, Balling R, Barisic N, Baulac S, Caglayan H, Craiu D, DeJonghe P, Depienne C, Dimova P, Djémié T, Gormley P, Guerrini R, Helbig I, Hjalgrim H, Hoffman-Zacharska D, Jähn J, Klein KM, Koeleman B, Komarek V, Krause R, Kuhlenbäumer G, Leguern E, Lehesjoki A-E, Lemke JR, Lerche H, Linnankivi T, Marini C, May P, Møller RS, Muhle H, Pal D, Palotie A, Pendziwiat M, Robbiano A, Roelens F, Rosenow F, Selmer K, Serratosa JM, Sisodiya S, Stephani U, Sterbova K, Striano P, Suls A, Talvik T, vonSpiczak S, Weber Y, Weckhuysen S, Zara F, Abou-Khalil B, Alldredge BK, Andermann E, Andermann F, Amron D, Bautista JF, Berkovic SF, Bluvstein J, Boro A, Cascino G, Consalvo D, Crumrine P, Devinsky O, Dlugos D, Epstein MP, Fiol M, Fountain NB, French J, Friedman D, Geller EB, Glauser T, Glynn S, Haas K, Haut SR, Hayward J, Helmers SL, Joshi S, Kanner A, Kirsch HE, Knowlton RC, Kossoff EH, Kuperman R, Kuzniecky R, Lowenstein DH, McGuire SM, Motika PV, Novotny EJ, Ottman R, Paolicchi JM, Parent J, Park K, Poduri A, Sadleir L, Scheffer IE, Shellhaas RA, Sherr E, Shih JJ, Singh R, Sirven J, Smith MC, Sullivan J, Thio LL, Venkat A, Vining EPG, VonAllmen GK, Weisenberg JL, Widdess-Walsh P, Winawer MR, Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, Epstein MP, Glauser T, Goldstein DB, Han Y, Heinzen EL, Johnson MR, Kuzniecky R, Lowenstein DH, Marson AG, Mefford HC, Nieh SE, OBrien TJ, Ottman R, Petrou S, Petrovski S, Poduri A, Ruzzo EK, Scheffer IE, Sherr Eet al., 2014, De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies, The American Journal of Human Genetics, Vol: 95, Pages: 360-370, ISSN: 0002-9297

Journal article

International League Against Epilepsy Consortium on Complex Epilepsies, 2014, Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies, Lancet Neurology, Vol: 13, Pages: 893-903, ISSN: 1474-4465

BACKGROUND: The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). METHODS: We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at p<1·66 × 10(-8). FINDINGS: We included 8696 cases and 26 157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8·71 × 10(-10)), implicating SCN1A, and at 4p15.1 (p=5·44 × 10(-9)), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9·99 × 10(-9)), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy. INTERPRETATION: This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these dis

Journal article

Matthews PM, Edison P, Geraghty OC, Johnson MRet al., 2014, The emerging agenda of stratified medicine in neurology, NATURE REVIEWS NEUROLOGY, Vol: 10, Pages: 15-26, ISSN: 1759-4758

Journal article

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