title: Genetic Factors Influencing Coagulation Factor XIII B-Subunit Contribute to Risk of Ischemic Stroke.
abstract: OBJECTIVE
  Abnormal coagulation has been implicated in the pathogenesis of ischemic stroke, but how this association is mediated and whether it differs between ischemic stroke subtypes is unknown. We determined the shared genetic risk between 14 coagulation factors and ischemic stroke and its subtypes.
  
  
  METHODS
  Using genome-wide association study results for 14 coagulation factors from the population-based TwinsUK sample (N≈2000 for each factor), meta-analysis results from the METASTROKE consortium ischemic stroke genome-wide association study (12 389 cases, 62 004 controls), and genotype data for 9520 individuals from the WTCCC2 ischemic stroke study (3548 cases, 5972 controls-the largest METASTROKE subsample), we explored shared genetic risk for coagulation and stroke. We performed three analyses: (1) a test for excess concordance (or discordance) in single nucleotide polymorphism effect direction across coagulation and stroke, (2) an estimation of the joint effect of multiple coagulation-associated single nucleotide polymorphisms in stroke, and (3) an evaluation of common genetic risk between coagulation and stroke.
  
  
  RESULTS
  One coagulation factor, factor XIII subunit B (FXIIIB), showed consistent effects in the concordance analysis, the estimation of polygenic risk, and the validation with genotype data, with associations specific to the cardioembolic stroke subtype. Effect directions for FXIIIB-associated single nucleotide polymorphisms were significantly discordant with cardioembolic disease (smallest P=5.7×10(-04)); the joint effect of FXIIIB-associated single nucleotide polymorphisms was significantly predictive of ischemic stroke (smallest P=1.8×10(-04)) and the cardioembolic subtype (smallest P=1.7×10(-04)). We found substantial negative genetic covariation between FXIIIB and ischemic stroke (rG=-0.71, P=0.01) and the cardioembolic subtype (rG=-0.80, P=0.03).
  
  
  CONCLUSIONS
  Genetic markers associated with low FXIIIB levels increase risk of ischemic stroke cardioembolic subtype.
authors.affiliation: From the Department of Medical & Molecular Genetics (K.B.H., C.M.L.), Department of Twin Research and Genetic Epidemiology (P.G.H., F.M.K.W.), and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience (C.M.L.), King's College London, London, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (M.T., S.B., H.S.M.); Institut für Schlaganfallund Demenzforschung, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 17, Munich, Germany (M.D.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford (P.M.R.); Center for Public Health Genomics, and Cardiovascular Research Center, University of Virginia, Charlottesville, VA (B.B.W); Department of Biostatistics, Boston University School of Public Health, Boston, MA (B.B.W); Department of Neurology, Boston University School of Medicine, Boston, MA (S.S.); and Division of Clinical Neurosciences, University of Edinburgh, UK (C.S.). ken.b.hanscombe@kcl.ac.uk.
authors.forename: Ken B
authors.initials: KB
authors.lastname: Hanscombe
authors.affiliation: From the Department of Medical & Molecular Genetics (K.B.H., C.M.L.), Department of Twin Research and Genetic Epidemiology (P.G.H., F.M.K.W.), and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience (C.M.L.), King's College London, London, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (M.T., S.B., H.S.M.); Institut für Schlaganfallund Demenzforschung, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 17, Munich, Germany (M.D.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford (P.M.R.); Center for Public Health Genomics, and Cardiovascular Research Center, University of Virginia, Charlottesville, VA (B.B.W); Department of Biostatistics, Boston University School of Public Health, Boston, MA (B.B.W); Department of Neurology, Boston University School of Medicine, Boston, MA (S.S.); and Division of Clinical Neurosciences, University of Edinburgh, UK (C.S.).
authors.forename: Matthew
authors.initials: M
authors.lastname: Traylor
authors.affiliation: From the Department of Medical & Molecular Genetics (K.B.H., C.M.L.), Department of Twin Research and Genetic Epidemiology (P.G.H., F.M.K.W.), and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience (C.M.L.), King's College London, London, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (M.T., S.B., H.S.M.); Institut für Schlaganfallund Demenzforschung, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 17, Munich, Germany (M.D.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford (P.M.R.); Center for Public Health Genomics, and Cardiovascular Research Center, University of Virginia, Charlottesville, VA (B.B.W); Department of Biostatistics, Boston University School of Public Health, Boston, MA (B.B.W); Department of Neurology, Boston University School of Medicine, Boston, MA (S.S.); and Division of Clinical Neurosciences, University of Edinburgh, UK (C.S.).
authors.forename: Pirro G
authors.initials: PG
authors.lastname: Hysi
authors.affiliation: From the Department of Medical & Molecular Genetics (K.B.H., C.M.L.), Department of Twin Research and Genetic Epidemiology (P.G.H., F.M.K.W.), and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience (C.M.L.), King's College London, London, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (M.T., S.B., H.S.M.); Institut für Schlaganfallund Demenzforschung, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 17, Munich, Germany (M.D.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford (P.M.R.); Center for Public Health Genomics, and Cardiovascular Research Center, University of Virginia, Charlottesville, VA (B.B.W); Department of Biostatistics, Boston University School of Public Health, Boston, MA (B.B.W); Department of Neurology, Boston University School of Medicine, Boston, MA (S.S.); and Division of Clinical Neurosciences, University of Edinburgh, UK (C.S.).
authors.forename: Stephen
authors.initials: S
authors.lastname: Bevan
authors.affiliation: From the Department of Medical & Molecular Genetics (K.B.H., C.M.L.), Department of Twin Research and Genetic Epidemiology (P.G.H., F.M.K.W.), and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience (C.M.L.), King's College London, London, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (M.T., S.B., H.S.M.); Institut für Schlaganfallund Demenzforschung, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 17, Munich, Germany (M.D.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford (P.M.R.); Center for Public Health Genomics, and Cardiovascular Research Center, University of Virginia, Charlottesville, VA (B.B.W); Department of Biostatistics, Boston University School of Public Health, Boston, MA (B.B.W); Department of Neurology, Boston University School of Medicine, Boston, MA (S.S.); and Division of Clinical Neurosciences, University of Edinburgh, UK (C.S.).
authors.forename: Martin
authors.initials: M
authors.lastname: Dichgans
authors.affiliation: From the Department of Medical & Molecular Genetics (K.B.H., C.M.L.), Department of Twin Research and Genetic Epidemiology (P.G.H., F.M.K.W.), and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience (C.M.L.), King's College London, London, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (M.T., S.B., H.S.M.); Institut für Schlaganfallund Demenzforschung, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 17, Munich, Germany (M.D.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford (P.M.R.); Center for Public Health Genomics, and Cardiovascular Research Center, University of Virginia, Charlottesville, VA (B.B.W); Department of Biostatistics, Boston University School of Public Health, Boston, MA (B.B.W); Department of Neurology, Boston University School of Medicine, Boston, MA (S.S.); and Division of Clinical Neurosciences, University of Edinburgh, UK (C.S.).
authors.forename: Peter M
authors.initials: PM
authors.lastname: Rothwell
authors.affiliation: From the Department of Medical & Molecular Genetics (K.B.H., C.M.L.), Department of Twin Research and Genetic Epidemiology (P.G.H., F.M.K.W.), and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience (C.M.L.), King's College London, London, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (M.T., S.B., H.S.M.); Institut für Schlaganfallund Demenzforschung, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 17, Munich, Germany (M.D.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford (P.M.R.); Center for Public Health Genomics, and Cardiovascular Research Center, University of Virginia, Charlottesville, VA (B.B.W); Department of Biostatistics, Boston University School of Public Health, Boston, MA (B.B.W); Department of Neurology, Boston University School of Medicine, Boston, MA (S.S.); and Division of Clinical Neurosciences, University of Edinburgh, UK (C.S.).
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Worrall
authors.affiliation: From the Department of Medical & Molecular Genetics (K.B.H., C.M.L.), Department of Twin Research and Genetic Epidemiology (P.G.H., F.M.K.W.), and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience (C.M.L.), King's College London, London, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (M.T., S.B., H.S.M.); Institut für Schlaganfallund Demenzforschung, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 17, Munich, Germany (M.D.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford (P.M.R.); Center for Public Health Genomics, and Cardiovascular Research Center, University of Virginia, Charlottesville, VA (B.B.W); Department of Biostatistics, Boston University School of Public Health, Boston, MA (B.B.W); Department of Neurology, Boston University School of Medicine, Boston, MA (S.S.); and Division of Clinical Neurosciences, University of Edinburgh, UK (C.S.).
authors.forename: Sudha
authors.initials: S
authors.lastname: Seshadri
authors.affiliation: From the Department of Medical & Molecular Genetics (K.B.H., C.M.L.), Department of Twin Research and Genetic Epidemiology (P.G.H., F.M.K.W.), and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience (C.M.L.), King's College London, London, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (M.T., S.B., H.S.M.); Institut für Schlaganfallund Demenzforschung, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 17, Munich, Germany (M.D.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford (P.M.R.); Center for Public Health Genomics, and Cardiovascular Research Center, University of Virginia, Charlottesville, VA (B.B.W); Department of Biostatistics, Boston University School of Public Health, Boston, MA (B.B.W); Department of Neurology, Boston University School of Medicine, Boston, MA (S.S.); and Division of Clinical Neurosciences, University of Edinburgh, UK (C.S.).
authors.forename: Cathie
authors.initials: C
authors.lastname: Sudlow
authors.affiliation: From the Department of Medical & Molecular Genetics (K.B.H., C.M.L.), Department of Twin Research and Genetic Epidemiology (P.G.H., F.M.K.W.), and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience (C.M.L.), King's College London, London, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (M.T., S.B., H.S.M.); Institut für Schlaganfallund Demenzforschung, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 17, Munich, Germany (M.D.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford (P.M.R.); Center for Public Health Genomics, and Cardiovascular Research Center, University of Virginia, Charlottesville, VA (B.B.W); Department of Biostatistics, Boston University School of Public Health, Boston, MA (B.B.W); Department of Neurology, Boston University School of Medicine, Boston, MA (S.S.); and Division of Clinical Neurosciences, University of Edinburgh, UK (C.S.).
authors.forename: Frances M K
authors.initials: FM
authors.lastname: Williams
authors.affiliation: From the Department of Medical & Molecular Genetics (K.B.H., C.M.L.), Department of Twin Research and Genetic Epidemiology (P.G.H., F.M.K.W.), and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience (C.M.L.), King's College London, London, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (M.T., S.B., H.S.M.); Institut für Schlaganfallund Demenzforschung, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 17, Munich, Germany (M.D.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford (P.M.R.); Center for Public Health Genomics, and Cardiovascular Research Center, University of Virginia, Charlottesville, VA (B.B.W); Department of Biostatistics, Boston University School of Public Health, Boston, MA (B.B.W); Department of Neurology, Boston University School of Medicine, Boston, MA (S.S.); and Division of Clinical Neurosciences, University of Edinburgh, UK (C.S.).
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Markus
authors.affiliation: From the Department of Medical & Molecular Genetics (K.B.H., C.M.L.), Department of Twin Research and Genetic Epidemiology (P.G.H., F.M.K.W.), and MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience (C.M.L.), King's College London, London, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK (M.T., S.B., H.S.M.); Institut für Schlaganfallund Demenzforschung, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 17, Munich, Germany (M.D.); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neurosciences, University of Oxford (P.M.R.); Center for Public Health Genomics, and Cardiovascular Research Center, University of Virginia, Charlottesville, VA (B.B.W); Department of Biostatistics, Boston University School of Public Health, Boston, MA (B.B.W); Department of Neurology, Boston University School of Medicine, Boston, MA (S.S.); and Division of Clinical Neurosciences, University of Edinburgh, UK (C.S.).
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Lewis
mesh_terms: D002545:Brain Ischemia / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D004200:Diseases in Twins / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D005176:Factor XIII / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D020521:Stroke / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D018433:Twin Studies as Topic
chemical_list: D005176:Factor XIII; C054380:factor XIIIb
keywords: coagulation; genome-wide association study; stroke