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      Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

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      International Stroke Genetics Consortium (ISGC), Wellcome Trust Case Control Consortium 2 (WTCCC2)
      Nature genetics

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          Abstract

          Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9 ( HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10 −11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes.

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          Most cited references39

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          Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment

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            Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment.

            The etiology of ischemic stroke affects prognosis, outcome, and management. Trials of therapies for patients with acute stroke should include measurements of responses as influenced by subtype of ischemic stroke. A system for categorization of subtypes of ischemic stroke mainly based on etiology has been developed for the Trial of Org 10172 in Acute Stroke Treatment (TOAST). A classification of subtypes was prepared using clinical features and the results of ancillary diagnostic studies. "Possible" and "probable" diagnoses can be made based on the physician's certainty of diagnosis. The usefulness and interrater agreement of the classification were tested by two neurologists who had not participated in the writing of the criteria. The neurologists independently used the TOAST classification system in their bedside evaluation of 20 patients, first based only on clinical features and then after reviewing the results of diagnostic tests. The TOAST classification denotes five subtypes of ischemic stroke: 1) large-artery atherosclerosis, 2) cardioembolism, 3) small-vessel occlusion, 4) stroke of other determined etiology, and 5) stroke of undetermined etiology. Using this rating system, interphysician agreement was very high. The two physicians disagreed in only one patient. They were both able to reach a specific etiologic diagnosis in 11 patients, whereas the cause of stroke was not determined in nine. The TOAST stroke subtype classification system is easy to use and has good interobserver agreement. This system should allow investigators to report responses to treatment among important subgroups of patients with ischemic stroke. Clinical trials testing treatments for acute ischemic stroke should include similar methods to diagnose subtypes of stroke.
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              Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.

              By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                6 January 2012
                05 February 2012
                01 September 2012
                : 44
                : 3
                : 328-333
                Affiliations
                [1 ]Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK
                [2 ]Stroke and Dementia Research Group, St George’s University of London, London, UK
                [3 ]Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Germany
                [4 ]Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford
                [5 ]Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK
                [6 ]Division of Applied Medicine, University of Aberdeen, Aberdeen, UK
                [7 ]Department of Neurology, Jagiellonian University Medical College, Botaniczna 3 str. 31-503 Krakow, Poland
                [8 ]Department of Clinical Sciences Lund, Neurology, Lund University, Sweden
                [9 ]Department of Neurology, Skåne University Hospital, Lund, Sweden
                [10 ]Department of Neurology, University Hospitals Leuven, Belgium
                [11 ]Vesalius Research Center, VIB, Leuven, Belgium
                [12 ]Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, Fulham Palace Rd, London, UK
                [13 ]Wellcome Trust Clinical Research Facility Genetics Core Laboratory, University of Edinburgh, Western General Hospital, Edinburgh. UK
                [14 ]Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, Boston, USA
                [15 ]Program in Medical and Population Genetics, Broad Institute, Cambridge MA, USA
                [16 ]University of Maryland School of Medicine, Departments of Medicine, Epidemiology and Public Health, Baltimore USA
                [17 ]University of Cincinnati College of Medicine, Cincinnati, OH, USA
                [18 ]Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, Maryland, USA
                [19 ]Max Planck Institute of Psychiatry, Munich, Germany
                [20 ]Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Epidemiology II, Neuherberg, Germany
                [21 ]Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany
                [22 ]Division of Geriatric Medicine, University Hospital Leuven, Leuven, Belgium
                [23 ]Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
                [24 ]deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland
                [25 ]University of Iceland, Faculty of Medicine, 101 Reykjavik, Iceland
                [26 ]Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
                [27 ]Centre for Brain and Mental Health Research, University of Newcastle, Hunter Medical Research Institute, Newcastle, NSW, Australia
                [28 ]Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
                [29 ]Department of Cardiovascular Medicine, University of Oxford, Oxford, UK
                [30 ]Centre for Child Health Research, University of Western Australia, West Perth, Australia
                [31 ]Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, UK
                [32 ]Division of Psychological Medicine and Psychiatry, Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King’s College London, UK
                [33 ]The University of Queensland Diamantina Institute, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia
                [34 ]Dept Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
                [35 ]Department of Epidemiology and Public Health, University College London, UK
                [36 ]Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Eire
                [37 ]Molecular and Physiological Sciences, The Wellcome Trust, London, UK
                [38 ]Centre for Gastroenterology, Bart’s and the London School of Medicine and Dentistry, London, UK
                [39 ]Division of Clinical Pharmacology, University of Oxford, Oxford, UK
                [40 ]Dept Medical and Molecular Genetics, King’s College London School of Medicine, Guy’s Hospital, London, UK
                [41 ]Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, UK
                [42 ]Social, Genetic and Developmental Psychiatry Centre, King’s College London Institute of Psychiatry, Denmark Hill, London, UK
                [43 ]University of Cambridge Dept Clinical Neurosciences, Addenbrooke’s Hospital, Cambridge, UK
                [44 ]NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
                [45 ]Dept Molecular Neuroscience, Institute of Neurology, Queen Square, London, UK
                [46 ]University of Virginia Departments of Neurology and Public Health Sciences, Charlottesville, Virginia, USA
                [47 ]Baltimore Veterans Administration Medical Center and University of Maryland School of Medicine, Department of Neurology and the Geriatric Research, Education, and Clinical Center, Baltimore, USA
                [48 ]Mayo Clinic, Department of Neurology, Jacksonville, Florida, USA
                [49 ]Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
                [50 ]Dept Statistics, University of Oxford, Oxford, UK
                Author notes
                Corresponding Authors: Hugh S Markus, Stroke and Dementia Research Centre, Clinical Sciences, St George’s University of London, London, UK, SW17 ORE, hmarkus@ 123456sgul.ac.uk ; Peter Donnelly, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK, peter.donnelly@ 123456well.ox.ac.uk
                [*]

                A full list of authors appears at the end of this article. A full list of members of WTCCC2 appears in the Supplementary Material.

                Article
                UKMS40301
                10.1038/ng.1081
                3303115
                22306652
                d1836b13-41ee-4327-859c-f6b60a11d9b8

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                History
                Funding
                Funded by: Wellcome Trust :
                Award ID: 085475 || WT
                Funded by: Wellcome Trust :
                Award ID: 084724 || WT
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                Genetics
                Genetics

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