F. M. K. Williams, A. M. Carter, P. G. Hysi, G. Surdulescu, D. Hodgkiss, N. Soranzo, M. Traylor, S. Bevan, M. Dichgans, P. M. W. Rothwell, C. Sudlow, M. Farrall, K. Silander, M. Kaunisto, P. Wagner, O. Saarela, K. Kuulasmaa, J. Virtamo, V. Salomaa, P. Amouyel, D. Arveiler, J. Ferrieres, P. G. Wiklund, M. A. Ikram, A. Hofman, G. B. Boncoraglio, E. A. Parati, A. Helgadottir, S. Gretarsdottir, U. Thorsteinsdottir, G. Thorleifsson, K. Stefansson, S. Seshadri, A. DeStefano, A. Gschwendtner, B. Psaty, W. Longstreth, B. D. Mitchell, Y. C. Cheng, R. Clarke, M. Ferrario, J. C. Bis, C. Levi, J. Attia, E. G. Holliday, R. J. Scott, M. Fornage, P. Sharma, K. L. Furie, J. Rosand, M. Nalls, J. Meschia, T. H. Mosely, A. Evans, A. Palotie, H. S. Markus, P. J. Grant, T. D. Spector, EuroCLOT Investigators , Wellcome Trust Case Control Consor , Int Stroke Genetics Consortium



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Annals of Neurology

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Author Address

Williams, FMK Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Hosp Campus,3rd Floor S Wing,Block 8,We, London SE1 7EH, England Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England Univ Leeds, Div Cardiovasc & Diabet Res, Leeds, W Yorkshire, England Wellcome Trust Sanger Inst, Hinxton, England Broad Inst Massachusetts Inst Technol & Harvard, Program Med & Populat Genet & Genet Anal Platform, Cambridge, MA USA Univ Helsinki, Dept Med Genet, Helsinki, Finland Univ Cent Hosp, Helsinki, Finland St Georges Univ London, Stroke & Dementia Res Ctr, London, England Univ Munich, Klinikum Univ Munich, Inst Stroke & Dementia Res, Munich, Germany Univ Oxford, Dept Clin Neurol, Stroke Prevent Res Unit, Oxford, England Univ Edinburgh, Div Clin Neurosci, Edinburgh, Midlothian, Scotland Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England Univ Oxford, Dept Cardiovasc Med, Oxford, England Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland Natl Inst Hlth & Welf, Chron Dis Epidemiol & Prevent Unit, Helsinki, Finland Pasteur Inst Lille, Dept Epidemiol & Publ Hlth, Lille, France Univ Strasbourg, Dept Epidemiol & Publ Hlth, Strasbourg, France Fac Med, Dept Epidemiol, Toulouse, France Umea Univ, Dept Internal Med, Umea, Sweden Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands Res Hosp, Neurol Inst Carlo Besta, Dept Neurol, Milan, Italy DeCODE Genet, Reykjavik, Iceland Boston Univ, Sch Med, Boston, MA 02118 USA Boston Univ, Sch Publ Hlth, Boston, MA USA Framingham Heart Dis Epidemiol Study, Framingham, MA USA Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA Univ Washington, Seattle, WA 98195 USA Grp Hlth Res Inst, Grp Hlth, Seattle, WA USA Univ Washington, Dept Neurol, Seattle, WA 98195 USA Univ Maryland, Dept Med, Baltimore, MD 21201 USA Univ Oxford, Clin Trial Serv Unit, Oxford, England Univ Insubria, Varese, Italy Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA Univ Newcastle, Callaghan, NSW 2308, Australia John Hunter Hosp, New Lambton Hts, Australia Hunter Med Res Inst, New Lambton, Australia Univ Texas Houston, Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA Univ Texas Houston, Hlth Sci Ctr, Inst Mol Med, Houston, TX USA Univ London Imperial Coll Sci Technol & Med, Cerebrovasc Res Unit, London, England Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA Harvard Univ, Sch Med, Boston, MA USA Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA Univ Mississippi, Med Ctr, Jackson, MS 39216 USA Queens Univ Belfast, Belfast, Antrim, North Ireland

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Objective: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.
Methods: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).
Results: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 x 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 x 10(-186)), rs10665 with FVII (p = 2.4 x 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 x 10(-57)) and factor VIII (p = 1.2 x 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811). Interpretation: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype. ANN NEUROL 2012;73:16-31