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      Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies

      research-article
      a , b , c , d , e , f , g , h , i , j , k , l , a , m , n , o , p , q , r , s , t , u , v , w , x , y , s , z , c , m , n , aa , ab , ac , ad , ae , m , af , ag , ah , ai , aj , ak , al , am , an , ae , ao , af , ap , aq , ar , as , an , aa , at , au , av , ar , au , aw , ac , ab , z , ax , ay , az , ba , bb , ar , bc , ao , bd , an , ak , al , am , aj , ai , be , bf , bg , bh , m , The Australian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2), i , k , bi , g , bj , f , bk , bl , l , t , s , r , m , bm , bn , ay , bi , bo , bp , m , n , l , a , * , on behalf of the International Stroke Genetics Consortium
      Lancet Neurology
      Lancet Pub. Group
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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.

          Summary

          Background

          Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.

          Methods

          We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.

          Findings

          We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10 −16) and ZFHX3 (p=2·28×10 −8), and for large-vessel stroke at a 9p21 locus (p=3·32×10 −5) and HDAC9 (p=2·03×10 −12). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance ( PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10 −6. However, we were unable to replicate any of these novel associations in the replication cohort.

          Interpretation

          Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.

          Funding

          Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

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          Most cited references16

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          • Article: not found

          A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium.

          The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.
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            Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

            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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              • Article: not found

              Genomewide association studies of stroke.

              The genes underlying the risk of stroke in the general population remain undetermined. We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. A genetic locus on chromosome 12p13 is associated with an increased risk of stroke. 2009 Massachusetts Medical Society
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                Author and article information

                Journal
                Lancet Neurol
                Lancet Neurol
                Lancet Neurology
                Lancet Pub. Group
                1474-4422
                1474-4465
                November 2012
                November 2012
                : 11
                : 11
                : 951-962
                Affiliations
                [a ]Stroke and Dementia Research Centre, St George's University of London, London, UK
                [b ]Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
                [c ]Department of Cardiovascular Medicine, University of Oxford, Oxford, UK
                [d ]Centrw for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, and Center for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, NSW, Australia
                [e ]Division of Clinical Neurosciences and Insititute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
                [f ]Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, UK
                [g ]University of Maryland School of Medicine, Department of Medicine, Baltimore, MD, USA
                [h ]University of Texas Health Science Center at Houston, Houston, TX, USA
                [i ]Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, Netherlands
                [j ]Department of Neurology and Department of Radiology, Erasmus MC University Medical Center, Rotterdam, Netherlands
                [k ]Netherlands Consortium for Healthy Ageing, Leiden, Netherlands
                [l ]Institute for Stroke and Dementia Research, Klinikum der Universitát München, Ludwig-Maximilians-Universität, and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
                [m ]deCODE Genetics, Reykjavik, Iceland
                [n ]Faculty of Medicine, University of Iceland, Reykjavik, Iceland
                [o ]Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA
                [p ]Department of Neurology, University of Washington, Seattle, WA, USA
                [q ]Department of Epidemiology, University of Washington, Seattle, WA, USA
                [r ]Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
                [s ]Imperial College Cerebrovascular Research Unit (ICCRU), Imperial College London, London, UK
                [t ]Department of Cereberovascular Disease, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Neurologico Carlo Besta, Milan, Italy
                [u ]Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
                [v ]Department of Neurology, University of Virginia, Charlottesville, VA, USA
                [w ]Department of Public Health Science, University of Virginia, Charlottesville, VA, USA
                [x ]Department of Neurology, Veterans Affairs Medical Center, Baltimore, MA, USA
                [y ]Department of Neurology, University of Maryland School of Medicine, MA, USA
                [z ]Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
                [aa ]Department of Neurology and Neurosurgery, Utrecht Stroke Center, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, Netherlands
                [ab ]Neurovascular Research Laboratory, Neurology and Medicine Departments, Universitat Autònoma de Barcelona and Institute of Research Vall d'Hebrón Hospital, Barcelona, Spain
                [ac ]Laboratory of Experimental Neurology, Brussels, Belgium
                [ad ]Department of Neurology, Division of Neurogeriatrics, Medical University Graz, Graz, Austria
                [ae ]Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
                [af ]Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
                [ag ]Department of Neurology, University of Münster, Münster, Germany
                [ah ]National University of Ireland Galway, Galway, Ireland
                [ai ]Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
                [aj ]Department of Neurology, Jagiellonian University, Krakow, Poland
                [ak ]Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium
                [al ]Experimental Neurology and Leuven Research Institute for Neurodegenerative Diseases (LIND), University of Leuven (KU Leuven), Leuven, Belgium
                [am ]Department of Neurology, University Hospital Leuven, Leuven, Belgium
                [an ]Department of Clinical Sciences Lund, Neurology, Lund University, and Department of Neurology, Skåne University Hospital, Lund, Sweden
                [ao ]Department of Clinical Biochemistry and The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
                [ap ]Division of Cardiovascular Medicine, Department of Internal Medicine, University of Virginia, Charlottesville, VA, USA
                [aq ]Institute for Experimental Medicine, University of Kiel, Germany
                [ar ]Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
                [as ]Departamento Promoção da Saúde e Doenças Crónicas, Instituto Nacional de Saúde Dr Ricardo Jorge, Lisbon, Portugal
                [at ]Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
                [au ]Department of Psychology, and Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
                [av ]Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
                [aw ]Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria
                [ax ]Department of Medical Genetics and Department of Epidemiology, University Medical Centre Utrecht, Utrecht, Netherlands
                [ay ]Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
                [az ]Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
                [ba ]Department of Neurology, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden
                [bb ]Serviço de Neurologia, Centro de Estudos Egas Moniz, Hospital de Santa Maria, Lisbon, Portugal
                [bc ]Landspitali, University Hospital, Reykjavik, Iceland
                [bd ]The Copenhagen City Heart Study, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark
                [be ]Centre for Non-Communicable Diseases, Karachi, Pakistan
                [bf ]Department of Medicine, University of Pennsylvania, PA, USA
                [bg ]Department of Pathology & Molecular Medicine and Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, ON, Canada
                [bh ]Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
                [bi ]University of Mississippi Medical Center, Jackson, MS, USA
                [bj ]Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
                [bk ]Centre for Translational Neuroscience and Mental Health Research, University of Newcastle, and Hunter Medical Research Institute, New Lambton, NSW, Australia
                [bl ]Department of Neurology, Boston University School of Medicine, Boston, MA, USA
                [bm ]Department of Epidemiology, Department of Medicine, and Department of Health Services, University of Washington, and Group Health Research Institute, Group Health Seattle, WA, USA
                [bn ]Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK
                [bo ]Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
                [bp ]Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
                Author notes
                [* ]Correspondence to: Dr Hugh S Markus, Stroke and Dementia Research Centre, St George's University of London, Cranmer Terrace, London, SW17 0RE, UK hmarkus@ 123456sgul.ac.uk
                Article
                LANEUR70234
                10.1016/S1474-4422(12)70234-X
                3490334
                23041239
                fe8fa956-a77b-4258-8972-0f35f3894922
                © 2012 Elsevier Ltd. All rights reserved.

                This document may be redistributed and reused, subject to certain conditions.

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