Publications
128 results found
Speed D, O'Brien TJ, Palotie A, et 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.
Raedisch S, Dickens D, Lang T, et 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
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- Citations: 5
Mirza N, Jorgensen A, Sills G, et al., 2014, WHICH GENETIC PATHWAYS UNDERLIE PHARMACORESISTANT EPILEPSY?, Meeting of the Associatiion-of-British-Neurologists, Publisher: BMJ PUBLISHING GROUP, ISSN: 0022-3050
Miller T, Gowland P, Johnson M, et al., 2014, RETROGRADE AMNESIA FOLLOWING AUTOIMMUNE LIMBIC ENCEPHALITIS, Meeting of the Associatiion-of-British-Neurologists, Publisher: BMJ PUBLISHING GROUP, ISSN: 0022-3050
Appenzeller S, Balling R, Barisic N, et 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
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
Speed D, Hoggart C, Petrovski S, et al., 2014, Genome-wide association study and biological pathway analysis of epilepsy prognosis in a prospective cohort of newly treated epilepsy, Human Molecular Genetics
Matthews PM, Edison P, Geraghty OC, et al., 2014, The emerging agenda of stratified medicine in neurology, NATURE REVIEWS NEUROLOGY, Vol: 10, Pages: 15-26, ISSN: 1759-4758
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- Citations: 23
Speed D, Hemani G, Johnson MR, et al., 2013, Response to Lee et al.: SNP-Based Heritability Analysis with Dense Data, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 93, Pages: 1155-1157, ISSN: 0002-9297
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- Citations: 12
Andrew S Allen1, Samuel F Berkovic2, Patrick Cossette3, et al., 2013, De novo mutations in epileptic encephalopathies, Nature, Vol: 501, Pages: 217-221, ISSN: 0028-0836
Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown1. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox–Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10−3). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10−10 and P = 7.8 × 10−12, respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10−8), as has been reported previously for autism spectrum disorders2.
Schneider SA, Irani SR, Stagg CJ, et al., 2013, Faciobrachial dystonic seizures: the influence ofimmunotherapy on seizure control and preventionof cognitive impairment in a broadening phenotype, Brain, Vol: 136, Pages: 3151-3162, ISSN: 0006-8950
Johnson MR, Perkin GD, 2013, Epilepsy in later Childhood and adulthood, Oxford Textbook of Medicine (5 ed.), Editors: Warrell, Cox, Firth, 2012
Miller TD, Rosenthal CR, Davies AA, et al., 2013, RE-THINKING THE ROLE OF THE HUMAN HIPPOCAMPUS IN RETROGRADE EPISODIC MEMORY, 20th Annual Meeting of the Cognitive-Neuroscience-Society, Publisher: MIT PRESS, Pages: 169-169, ISSN: 0898-929X
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- Citations: 1
Bellos E, Johnson MR, Coin LJ, 2012, cnvHiTSeq: integrative models for high-resolution copy number variation detection and genotyping using population sequencing data, Genome Biology, Vol: 13, ISSN: 1474-7596
Recent advances in sequencing technologies provide the means for identifying copy number variation (CNV) at an unprecedented resolution. A single next-generation sequencing experiment offers several features that can be used to detect CNV, yet current methods do not incorporate all available signatures into a unified model. cnvHiTSeq is an integrative probabilistic method for CNV discovery and genotyping that jointly analyzes multiple features at the population level. By combining evidence from complementary sources, cnvHiTSeq achieves high genotyping accuracy and a substantial improvement in CNV detection sensitivity over existing methods, while maintaining a low false discovery rate. cnvHiTSeq is available at http://sourceforge.net/projects/cnvhitseq
Johnson MR, Craig J, 2012, Reproductive Aspects of Epilepsy, Oxford Textbook of Epilepsy and Epileptic Seizures, Editors: Shorvon, Guerrini, Cook, Lhatoo, Shorvon, Guerrini, Cook, Lhatoo, Publisher: Oxford University Press, ISBN: 9780199659043
Part of the Oxford Textbooks in Clinical Neurology (OTCN) series, this volume covers the scientific basis, clinical diagnosis, and treatment of the reproductive aspects of epilepsy.
The Epi4K Consortium, 2012, Epi4K: gene discovery in 4,000 genomes., Epilepsia, Vol: 53, Pages: 1457-1467, ISSN: 0013-9580
A major challenge in epilepsy research is to unravel the complex genetic mechanisms underlying both common and rare forms of epilepsy, as well as the genetic determinants of response to treatment. To accelerate progress in this area, the National Institute of Neurological Disorders and Stroke (NINDS) recently offered funding for the creation of a “Center without Walls” to focus on the genetics of human epilepsy. This article describes Epi4K, the collaborative study supported through this grant mechanism and having the aim of analyzing the genomes of a minimum 4,000 subjects with highly selected and well‐characterized epilepsy.
Speed D, Hemani G, Johnson MR, et al., 2012, Improved heritability estimation from genome-wide SNP data., American Journal of Human Genetics, Vol: 91
Schneider S, Johnson MR, 2012, Monozygotic twins with LRRK2 mutations: genetically identical but phenotypically discordant., Movement Disorders, Vol: 27, Pages: 1203-1204
Johnson MR, 2012, A rational approach to prescribing add-on anti-epilepsy drugs. (Invited Speaker)., First Annual Oxford Neurology Course, Oxford, UK
Johnson MR, Shorvon SD, 2011, Heredity in epilepsy: Neurodevelopment, comorbidity, and the neurological trait, EPILEPSY & BEHAVIOR, Vol: 22, Pages: 421-427, ISSN: 1525-5050
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- Citations: 32
Leschziner GD, Coffey AJ, Andrew T, et al., 2011, <i>Q8IYL2</i> is a candidate gene for the familial epilepsy syndrome of Partial Epilepsy with Pericentral Spikes (PEPS), EPILEPSY RESEARCH, Vol: 96, Pages: 109-115, ISSN: 0920-1211
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- Citations: 14
Johnson MR, Tan NCK, Kwan P, et al., 2011, Newly diagnosed epilepsy and pharmacogenomics research: A step in the right direction?, EPILEPSY & BEHAVIOR, Vol: 22, Pages: 3-8, ISSN: 1525-5050
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- Citations: 10
Irani SR, Michell AW, Johnson MR, et al., 2011, Faciobrachial Dystonic Attacks: Seizures or Movement Disorder? Reply, ANNALS OF NEUROLOGY, Vol: 70, Pages: 180-180, ISSN: 0364-5134
McCormack M, Alfirevic A, Bourgeois S, et al., 2011, HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans., N Engl J Med 2011, Vol: 364, Pages: 1134-1143
AbstractBACKGROUND: Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations.METHODS: We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions.RESULTS: The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18).CONCLUSIONS: The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.).
Irani SR, Michell AW, Lang B, et al., 2011, Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis, Ann Neurol 2011, Vol: 69, Pages: 892-900
Johnson MR, 2011, The genetic contribution to epilepsy: The known and missing heritability, The Causes of Epilepsy: Common and Uncommon Causes in Adults and Children, Pages: 62-66, ISBN: 9780521114479
Introduction: how much of epilepsy is genetic? Broad sense heritability (h<sup>2</sup>) refers to the proportion of phenotypic variance of a trait from all possible genetic contributions, including additive, dominance, and epistatic (multigenic) effects. There is no agreed estimate of h<sup>2</sup> for epilepsy, reflecting the different approaches used to measure heritability, such as twin and familial aggregation studies and their various specific designs and statistical analyses, as well as the heterogeneity of epilepsy. Thus, published estimates of heritability for epilepsy from twin studies range from 8–27% (Sillanpää et al. 1991) to 69–88% (Miller et al. 1998; Kjeldsen et al. 2001). An alternative approach to the question of “how much of epilepsy is genetic,” is to estimate the percentage of epilepsy that would be prevented if known environmental risk factors were completely eliminated. The proportion of epilepsy attributable to environmental causes can be estimated from knowledge of the relative risk for epilepsy associated with the known environmental risk factors (such as head injury, stroke, tumors, infections, etc.) and exposure frequencies. On this basis, an estimated 68% of all epilepsy may have no cause other than an inherited predisposition (Herman 2002). Attempts to describe the overall genetic contributions to epilepsy are also confounded by inadequate and non-uniform terminology. Thus, there is no agreed definition as to what constitutes an “epilepsy gene.” For example, where epilepsy results from an inherited anomaly of cerebral structure, should the underlying molecular genetic defect be considered an “epilepsy gene” or simply refer to its causal role in determining the underlying brain malformation?.
Johnson MR, 2011, Comment on "Blinders, phenotype, and fashionable genetic analysis: A critical examination of the current state of epilepsy genetic studies", EPILEPSIA, Vol: 52, Pages: 191-191, ISSN: 0013-9580
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- Citations: 1
Johnson MR, 2011, The genetic contribution to epilepsy: the known and missing heritability, The causes of epilepsy, Editors: Shorvon, Andermann, Guerrini, United Kingdom, Publisher: Cambridge University Press, Pages: 63-67
Tachmazidou I, Johnson M, De Iorio M, 2010, Bayesian Variable Selection for Survival Regression in Genetics, 19th Annual Meeting of the International-Genetic-Epidemiology-Society, Publisher: WILEY-BLACKWELL, Pages: 985-985, ISSN: 0741-0395
Tachmazidou I, Johnson MR, De Iorio M, 2010, Bayesian Variable Selection for Survival Regression in Genetics, GENETIC EPIDEMIOLOGY, Vol: 34, Pages: 689-701, ISSN: 0741-0395
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- Citations: 2
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