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

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

      Nature genetics

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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 references 24

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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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            Acetylation: a regulatory modification to rival phosphorylation?

             T Kouzarides (2000)
            The fact that histones are modified by acetylation has been known for almost 30 years. The recent identification of enzymes that regulate histone acetylation has revealed a broader use of this modification than was suspected previously. Acetylases are now known to modify a variety of proteins, including transcription factors, nuclear import factors and alpha-tubulin. Acetylation regulates many diverse functions, including DNA recognition, protein-protein interaction and protein stability. There is even a conserved structure, the bromodomain, that recognizes acetylated residues and may serve as a signalling domain. If you think all this sounds familiar, it should be. These are features characteristic of kinases. So, is acetylation a modification analogous to phosphorylation? This review sets out what we know about the broader substrate specificity and regulation of acetyl- ases and goes on to compare acetylation with the process of phosphorylation.
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              • Abstract: found
              • Article: not found

              Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development.

              The adult heart responds to stress signals by hypertrophic growth, which is often accompanied by activation of a fetal cardiac gene program and eventual cardiac demise. We showed previously that histone deacetylase 9 (HDAC9) acts as a suppressor of cardiac hypertrophy and that mice lacking HDAC9 are sensitized to cardiac stress signals. Here we report that mice lacking HDAC5 display a similar cardiac phenotype and develop profoundly enlarged hearts in response to pressure overload resulting from aortic constriction or constitutive cardiac activation of calcineurin, a transducer of cardiac stress signals. In contrast, mice lacking either HDAC5 or HDAC9 show a hypertrophic response to chronic beta-adrenergic stimulation identical to that of wild-type littermates, suggesting that these HDACs modulate a specific subset of cardiac stress response pathways. We also show that compound mutant mice lacking both HDAC5 and HDAC9 show a propensity for lethal ventricular septal defects and thin-walled myocardium. These findings reveal central roles for HDACs 5 and 9 in the suppression of a subset of cardiac stress signals as well as redundant functions in the control of cardiac development.
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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

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