102 results found
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
© Cambridge University Press 2011. 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, 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
Calboli FCF, Tozzi F, Galwey NW, et al., 2010, A genome-wide association study of neuroticism in a population-based sample, PLoS ONE, Vol: 5, ISSN: 1932-6203
Neuroticism is a moderately heritable personality trait considered to be a risk factor for developing major depression, anxiety disorders and dementia. We performed a genome-wide association study in 2,235 participants drawn from a population-based study of neuroticism, making this the largest association study for neuroticism to date. Neuroticism was measured by the Eysenck Personality Questionnaire. After Quality Control, we analysed 430,000 autosomal SNPs together with an additional 1.2 million SNPs imputed with high quality from the Hap Map CEU samples. We found a very small effect of population stratification, corrected using one principal component, and some cryptic kinship that required no correction. NKAIN2 showed suggestive evidence of association with neuroticism as a main effect (p<10−6) and GPC6 showed suggestive evidence for interaction with age (p≈10−7). We found support for one previously-reported association (PDE4D), but failed to replicate other recent reports. These results suggest common SNP variation does not strongly influence neuroticism. Our study was powered to detect almost all SNPs explaining at least 2% of heritability, and so our results effectively exclude the existence of loci having a major effect on neuroticism.
Kasperaviciute D, Catarino CB, Heinzen EL, et al., 2010, Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study, Brain, Vol: 133, Pages: 2136-2147, ISSN: 1460-2156
Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.
Heinzen EL, Radtke RA, Urban TJ, et al., 2010, Rare Deletions at 16p13.11 Predispose to a Diverse Spectrum of Sporadic Epilepsy Syndromes, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 86, Pages: 707-718, ISSN: 0002-9297
Baranzini SE, Wang J, Gibson RA, et al., 2009, Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis, HUMAN MOLECULAR GENETICS, Vol: 18, Pages: 767-778, ISSN: 0964-6906
Johnson MR, 2009, Multi-SNP predictors of epilepsy outcome. (Invited Speaker)., Annual Scientific Meeting of the American Epilepsy Society
Johnson MR, 2009, Epilepsy and pregnancy. (Invited Speaker)., The World Congress of Neurology
Johnson MR, 2009, Lecturer: ILAE Specialist Registrar Teaching Weekend in Epilepsy
Johnson MR, 2009, Epilepsy genetics: has the promise been fulfilled? (Invited Speaker), The World Congress of Neurology
Irani SR, Buckley C, Vincent A, et al., 2008, IMMUNOTHERAPY-RESPONSIVE SEIZURE-LIKE EPISODES WITH POTASSIUM CHANNEL ANTIBODIES, NEUROLOGY, Vol: 71, Pages: 1647-1648, ISSN: 0028-3878
Tachmazidou I, Andrew T, Verzilli CJ, et al., 2008, Bayesian survival analysis in genetic association studies, Bioinformatics, Vol: 24, Pages: 2030-2036, ISSN: 1367-4803
Motivation: Large-scale genetic association studies are carried out with the hope of discovering single nucleotide polymorphisms involved in the etiology of complex diseases. There are several existing methods in the literature for performing this kind of analysis for case-control studies, but less work has been done for prospective cohort studies. We present a Bayesian method for linking markers to censored survival outcome by clustering haplotypes using gene trees. Coalescent-based approaches are promising for LD mapping, as the coalescent offers a good approximation to the evolutionary history of mutations.Results: We compare the performance of the proposed method in simulation studies to the univariate Cox regression and to dimension reduction methods, and we observe that it performs similarly in localizing the causal site, while offering a clear advantage in terms of false positive associations. Moreover, it offers computational advantages. Applying our method to a real prospective study, we observe potential association between candidate ABC transporter genes and epilepsy treatment outcomes.
Rogawski MA, Johnson MR, 2008, Intrinsic severity as a determinant of antiepileptic drug refractoriness., Epilepsy Curr, Vol: 8, Pages: 127-130, ISSN: 1535-7597
For the most part, resistance to medications in epilepsy is independent of the choice of antiepileptic drug. This simple clinical observation constrains the possible biological mechanisms for drug refractory epilepsy by imposing a requirement to explain resistance for a diverse set of chemical structures that act on an even more varied group of molecular targets. To date, research on antiepileptic drug refractoriness has been guided by the "drug transporter overexpression" and the "reduced drug-target sensitivity" hypotheses. These concepts posit that drug refractoriness is a condition separate from the underlying epilepsy. Inadequacies in both hypotheses mandate a fresh approach to the problem. In this article, we propose a novel approach that considers epilepsy pharmacoresistance in terms of intrinsic disease severity. We suggest that neurobiological factors that confer increased disease severity lead to drug intractability. The occurrence of frequent seizures at disease onset is an important factor that signals increased severity.
Thomas P, Keightley A, Kamble R, et al., 2008, Sigmoid sinus thrombosis presenting with posterior alexia in a patient with Behçet's disease and polycythaemia: A case report, Journal of Medical Case Reports, Vol: 2, ISSN: 1752-1947
Introduction: A 59-year-old Caucasian woman presented with an acute onset of alexia, noticed whilst driving. She described how while she could read car number plates, she had lost the ability to read and understand words on roadside advertisements and car window stickers. Case presentation: Neurological examination was unremarkable apart from the inability to read full words or sentences. Imaging of the brain, initially computed tomography, followed by magnetic resonance venography, confirmed a diagnosis of sigmoid sinus thrombosis with associated venous infarction. The patient's past medical history revealed that she had suffered an ischemic stroke and following investigation for this, had undergone a nephrectomy for renal cell carcinoma. This was complicated by postoperative deep venous thrombosis. She had a persistent polycythaemia that was managed with venesection, and recently she had been diagnosed with Behçet's disease. Prior to this presentation, she had recently stopped her prophylactic antiplatelet medication as she was due to undergo a total knee replacement for osteoarthritis. She was managed with weight-adjusted, low molecular weight heparin followed by oral anticoagulation, and made a good recovery from her symptoms. Conclusion: This case illustrates a classical neurological syndrome, highlights the importance of cerebral venous and sinus thrombosis as a cause of stroke, and the importance of remaining vigilant to a person's changing risk of venous thrombosis with evolving comorbidity. © 2008 Thomas et al; licensee BioMed Central Ltd.
Johnson MR, 2008, Comprehensive meta-analysis of epilepsy genetic association studies., International League Against Epilepsy Annual Scientific Meeting
Leschziner GD, Jorgensen AL, Andrews T, et al., 2007, The association between polymorphisms in RLIP76 and drug response in epilepsy, PHARMACOGENOMICS, Vol: 8, Pages: 1715-1722, ISSN: 1462-2416
Leschziner GD, Andrew T, Pirmohamed M, et al., 2007, ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research, PHARMACOGENOMICS JOURNAL, Vol: 7, Pages: 154-179, ISSN: 1470-269X
Johnson MR, 2007, Discussion, Epileptic Disorders, Vol: 9, ISSN: 1294-9361
Sisodiya S, Cross JH, Blumcke I, et al., 2007, Genetics of epilepsy: Epilepsy Research Foundation workshop report., Epileptic Disorders, Vol: 9, Pages: 194-236
Leschziner GD, Andrew T, Leach JP, et al., 2007, Common ABCB1 polymorphisms are not associated with multidrug resistance in epilepsy using a gene-wide tagging approach, PHARMACOGENETICS AND GENOMICS, Vol: 17, Pages: 217-220, ISSN: 1744-6872
Leschziner G, Jorgensen AL, Andrew T, et al., 2006, Clinical factors and ABCB1 polymorphisms in prediction of antiepileptic drug response: a prospective cohort study, LANCET NEUROLOGY, Vol: 5, Pages: 668-676, ISSN: 1474-4422
Leschziner G, Zabaneh D, Pirmohamed M, et al., 2006, Exon sequencing and high resolution haplotype analysis of ABC transporter genes implicated in drug resistance, PHARMACOGENETICS AND GENOMICS, Vol: 16, Pages: 439-450, ISSN: 1744-6872
Constable S, Johnson MR, Pirmohamed M, 2006, Pharmacogenetics in clinical practice: considerations for testing, EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, Vol: 6, Pages: 193-205, ISSN: 1473-7159
Sharma P, Middelberg RPS, Andrew T, et al., 2006, Heritability of left ventricular mass in a large cohort of twins, JOURNAL OF HYPERTENSION, Vol: 24, Pages: 321-324, ISSN: 0263-6352
Sharma P, Middelberg RPS, Andrew T, et al., 2006, Heritability of left ventricular mass in a large cohort of twins, Journal of Hypertension, Vol: 24, Pages: 321-324, ISSN: 0263-6352
Introduction: Left ventricular hypertrophy is recognized as one of the most important independent predictors of adverse cardiovascular outcome. The aetiology of LVH includes a number of well-recognized causes but there is considerable interest in the genetics of cardiac muscle hypertrophy. We used a large prospective twin database in order to establish the heritability of left ventricular mass (LVM). Methods: Normotensive twins were prospectively recruited. Demographic data were collected. The LVM was determined using the Penn formulae derived from data collected from echocardiography. Results: A total of 376 Caucasian twin pairs (182 monozygotic and 194 dizygotic) aged 25-79 years were recruited. All subjects were normotensive with no significant differences in blood pressure (mean blood pressure: monozygotic twins, 132/83 mmHg; dizygotic twins, 131/ 82 mmHg) or body mass index between the monozygotic and dizygotic twins. The mean LVM for monozygotic twins was 140.9 g, compared with 140.2 g for dizygotic twins. Heritability estimates suggest that the genetic variance of LVM is 0.59 (95% confidence interval, 0.5-0.67). No common shared environmental effects were identified under this model. Conclusion: Our data from the largest set of twin pairs studied to date show that LVM has a sizeable genetic basis that is probably polygenic. This result has important implications for the understanding of normal and abnormal cardiac morphology at the molecular level. © 2006 Lippincott Williams & Wilkins.
Johnson M, 2006, Pharmacokinetic pharmacogenomics as applied to epilepsy, 7th European Congress on Epileptology, Publisher: BLACKWELL PUBLISHING, Pages: 250-250, ISSN: 0013-9580
Walker MC, Johnson MR, Patsalos PN, 2005, Pharmacogenetic aspects, Antiepileptic Drugs: Combination Therapy and Interactions, Pages: 26-44, ISBN: 9780521822190
© Cambridge University Press 2005 and Cambridge University Press, 2009. Introduction Pharmacogenetics and pharmacogenomics are fields which show how the genetic make-up of an individual can influence drugs effects. In epilepsy it is one part of a number of influences that determine drug responsiveness. Other contributors are age, sex, concomitant medication, other illnesses and cause and type of epilepsy. The cause and type of epilepsy may have a complex interaction with the genetics of drug response, as the genes that contribute to epilepsy can directly affect drug responsiveness (see below), and epilepsy itself may influence genetic expression. The observation that inherited differences can affect drug disposition, adverse effects and responsiveness is not new. The observation that there are slow metabolizers of phenytoin was made in the 1960s (Kutt et al., 1964), and later this was noted to be an inherited familial trait (Vasko et al., 1980; Vermeij et al., 1988). The human genome project will undoubtedly revolutionize the practice of medicine. The relatively small number of human genes (approximately 30,000–40,000; International Human Genome Sequencing Consortium, 2001) and the growth of rapid sequencing technology has brought the possibility of complete genome screening closer to reality. Variation in these genes, environmental factors, and their joint interactions determine our individual response to drugs. Human genetic variation mostly consists of single nucleotide polymorphisms (SNPs) and small insertion or deletion (INDELS) polymorphisms. Over 1.4 million SNPs were identified in the initial sequencing of the human genome (International SNP Map Working Group, 2001).
Walker MC, Johnson MR, Patsalos PN, 2005, Pharmacogenetic issues, Antiepileptic drugs: Combination therapy and interactions, Editors: Majkowski, Bougeois, Patsalos, Mattson, Publisher: University Press
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