Ischemic Stroke Is Associated with the ABO Locus: The EuroCLOT Study
Identifieur interne : 002089 ( Pmc/Curation ); précédent : 002088; suivant : 002090Ischemic Stroke Is Associated with the ABO Locus: The EuroCLOT Study
Auteurs : Frances M K. Williams [Royaume-Uni] ; Angela M. Carter [Royaume-Uni] ; Pirro G. Hysi [Royaume-Uni] ; Gabriela Surdulescu [Royaume-Uni] ; Dylan Hodgkiss [Royaume-Uni] ; Nicole Soranzo [Royaume-Uni, États-Unis, Finlande] ; Matthew Traylor [Royaume-Uni] ; Steve Bevan [Royaume-Uni] ; Martin Dichgans [Allemagne] ; Peter M W. Rothwell [Royaume-Uni] ; Cathie Sudlow [Royaume-Uni] ; Martin Farrall [Royaume-Uni] ; Kaisa Silander [Finlande] ; Mari Kaunisto [Finlande] ; Peter Wagner [Finlande] ; Olli Saarela [Finlande] ; Kari Kuulasmaa [Finlande] ; Jarmo Virtamo [Finlande] ; Veikko Salomaa [Finlande] ; Philippe Amouyel [France] ; Dominique Arveiler [France] ; Jean Ferrieres [France] ; Per-Gunnar Wiklund [Suède] ; M. Arfan Ikram [Pays-Bas] ; Albert Hofman [Pays-Bas] ; Giorgio B. Boncoraglio [Italie] ; Eugenio A. Parati [Italie] ; Anna Helgadottir [Royaume-Uni, Islande] ; Solveig Gretarsdottir [Islande] ; Unnur Thorsteinsdottir [Islande] ; Gudmar Thorleifsson [Islande] ; Kari Stefansson [Islande] ; Sudha Seshadri [États-Unis] ; Anita Destefano [États-Unis] ; Andreas Gschwendtner [Allemagne] ; Bruce Psaty [États-Unis] ; Will Longstreth [États-Unis] ; Braxton D. Mitchell [Royaume-Uni] ; Yu-Ching Cheng [Royaume-Uni] ; Robert Clarke [Italie] ; Marco Ferrario [États-Unis] ; Joshua C. Bis [Australie] ; Christopher Levi [Australie, États-Unis] ; John Attia [Australie, États-Unis] ; Elizabeth G. Holliday [Australie, États-Unis] ; Rodney J. Scott [Australie, États-Unis] ; Myriam Fornage [Royaume-Uni] ; Pankaj Sharma [États-Unis] ; Karen L. Furie [États-Unis] ; Jonathan Rosand [États-Unis] ; Mike Nalls [États-Unis] ; James Meschia [États-Unis] ; Thomas H. Mosely [Royaume-Uni] ; Alun Evans ; Aarno Palotie [Royaume-Uni, États-Unis, Finlande] ; Hugh S. Markus [Royaume-Uni] ; Peter J. Grant [Royaume-Uni] ; Tim D. Spector [Royaume-Uni]Source :
- Annals of Neurology [ 0364-5134 ] ; 2013.
Abstract
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 REFVIDunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.
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).
Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (
Url:
DOI: 10.1002/ana.23838
PubMed: 23381943
PubMed Central: 3582024
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Locus: The EuroCLOT Study</title>
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<author><name sortKey="Virtamo, Jarmo" sort="Virtamo, Jarmo" uniqKey="Virtamo J" first="Jarmo" last="Virtamo">Jarmo Virtamo</name>
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<author><name sortKey="Arfan Ikram, M" sort="Arfan Ikram, M" uniqKey="Arfan Ikram M" first="M" last="Arfan Ikram">M. Arfan Ikram</name>
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<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
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<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
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<author><name sortKey="Boncoraglio, Giorgio B" sort="Boncoraglio, Giorgio B" uniqKey="Boncoraglio G" first="Giorgio B" last="Boncoraglio">Giorgio B. Boncoraglio</name>
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<author><name sortKey="Parati, Eugenio A" sort="Parati, Eugenio A" uniqKey="Parati E" first="Eugenio A" last="Parati">Eugenio A. Parati</name>
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<author><name sortKey="Helgadottir, Anna" sort="Helgadottir, Anna" uniqKey="Helgadottir A" first="Anna" last="Helgadottir">Anna Helgadottir</name>
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<author><name sortKey="Gretarsdottir, Solveig" sort="Gretarsdottir, Solveig" uniqKey="Gretarsdottir S" first="Solveig" last="Gretarsdottir">Solveig Gretarsdottir</name>
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<author><name sortKey="Thorsteinsdottir, Unnur" sort="Thorsteinsdottir, Unnur" uniqKey="Thorsteinsdottir U" first="Unnur" last="Thorsteinsdottir">Unnur Thorsteinsdottir</name>
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<author><name sortKey="Thorleifsson, Gudmar" sort="Thorleifsson, Gudmar" uniqKey="Thorleifsson G" first="Gudmar" last="Thorleifsson">Gudmar Thorleifsson</name>
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<author><name sortKey="Stefansson, Kari" sort="Stefansson, Kari" uniqKey="Stefansson K" first="Kari" last="Stefansson">Kari Stefansson</name>
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<author><name sortKey="Destefano, Anita" sort="Destefano, Anita" uniqKey="Destefano A" first="Anita" last="Destefano">Anita Destefano</name>
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<author><name sortKey="Gschwendtner, Andreas" sort="Gschwendtner, Andreas" uniqKey="Gschwendtner A" first="Andreas" last="Gschwendtner">Andreas Gschwendtner</name>
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<country xml:lang="fr">Allemagne</country>
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<author><name sortKey="Psaty, Bruce" sort="Psaty, Bruce" uniqKey="Psaty B" first="Bruce" last="Psaty">Bruce Psaty</name>
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<addr-line>Seattle, WA</addr-line>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Washington (État)</region>
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<affiliation wicri:level="2"><nlm:aff id="au24"><institution>Medicine, and Health Services, University of Washington</institution>
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Washington (État)</region>
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<affiliation wicri:level="2"><nlm:aff id="au25"><institution>Group Health Research Institute, Group Health</institution>
<addr-line>Seattle, WA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Washington (État)</region>
</placeName>
<wicri:cityArea>Seattle</wicri:cityArea>
</affiliation>
<affiliation><nlm:aff id="au26"><institution>Department of Neurology, University of Washington</institution>
<addr-line>WA</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Longstreth, Will" sort="Longstreth, Will" uniqKey="Longstreth W" first="Will" last="Longstreth">Will Longstreth</name>
<affiliation wicri:level="2"><nlm:aff id="au23"><institution>Epidemiology, Health Services, University of Washington</institution>
<addr-line>Seattle, WA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Washington (État)</region>
</placeName>
<wicri:cityArea>Seattle</wicri:cityArea>
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<affiliation wicri:level="2"><nlm:aff id="au24"><institution>Medicine, and Health Services, University of Washington</institution>
<addr-line>Seattle, WA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Washington (État)</region>
</placeName>
<wicri:cityArea>Seattle</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au27"><institution>Department of Medicine, University of Maryland</institution>
<addr-line>Baltimore, MD</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Maryland</region>
</placeName>
<wicri:cityArea>Baltimore</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Mitchell, Braxton D" sort="Mitchell, Braxton D" uniqKey="Mitchell B" first="Braxton D" last="Mitchell">Braxton D. Mitchell</name>
<affiliation wicri:level="1"><nlm:aff id="au28"><institution>Clinical Trial Service Unit, University of Oxford</institution>
<addr-line>Oxford, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Oxford</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Cheng, Yu Ching" sort="Cheng, Yu Ching" uniqKey="Cheng Y" first="Yu-Ching" last="Cheng">Yu-Ching Cheng</name>
<affiliation wicri:level="1"><nlm:aff id="au28"><institution>Clinical Trial Service Unit, University of Oxford</institution>
<addr-line>Oxford, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Oxford</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Clarke, Robert" sort="Clarke, Robert" uniqKey="Clarke R" first="Robert" last="Clarke">Robert Clarke</name>
<affiliation wicri:level="1"><nlm:aff id="au29"><institution>University of Insubria</institution>
<addr-line>Varese, Italy</addr-line>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Varese</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ferrario, Marco" sort="Ferrario, Marco" uniqKey="Ferrario M" first="Marco" last="Ferrario">Marco Ferrario</name>
<affiliation wicri:level="2"><nlm:aff id="au30"><institution>Cardiovascular Health Research Unit, Department of Medicine, University of Washington</institution>
<addr-line>Seattle, WA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Washington (État)</region>
</placeName>
<wicri:cityArea>Seattle</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Bis, Joshua C" sort="Bis, Joshua C" uniqKey="Bis J" first="Joshua C" last="Bis">Joshua C. Bis</name>
<affiliation wicri:level="1"><nlm:aff id="au31"><institution>University of Newcastle</institution>
<addr-line>Callaghan, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Callaghan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Levi, Christopher" sort="Levi, Christopher" uniqKey="Levi C" first="Christopher" last="Levi">Christopher Levi</name>
<affiliation wicri:level="1"><nlm:aff id="au32"><institution>John Hunter Hospital</institution>
<addr-line>New Lambton Heights, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>New Lambton Heights</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="au33"><institution>Hunter Medical Research Institute</institution>
<addr-line>New Lambton, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>New Lambton</wicri:regionArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au34"><institution>Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Sciences Center</institution>
<addr-line>Houston, TX</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Texas</region>
</placeName>
<wicri:cityArea>Houston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Attia, John" sort="Attia, John" uniqKey="Attia J" first="John" last="Attia">John Attia</name>
<affiliation wicri:level="1"><nlm:aff id="au32"><institution>John Hunter Hospital</institution>
<addr-line>New Lambton Heights, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>New Lambton Heights</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="au33"><institution>Hunter Medical Research Institute</institution>
<addr-line>New Lambton, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>New Lambton</wicri:regionArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au34"><institution>Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Sciences Center</institution>
<addr-line>Houston, TX</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Texas</region>
</placeName>
<wicri:cityArea>Houston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Holliday, Elizabeth G" sort="Holliday, Elizabeth G" uniqKey="Holliday E" first="Elizabeth G" last="Holliday">Elizabeth G. Holliday</name>
<affiliation wicri:level="1"><nlm:aff id="au32"><institution>John Hunter Hospital</institution>
<addr-line>New Lambton Heights, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>New Lambton Heights</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="au33"><institution>Hunter Medical Research Institute</institution>
<addr-line>New Lambton, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>New Lambton</wicri:regionArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au34"><institution>Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Sciences Center</institution>
<addr-line>Houston, TX</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Texas</region>
</placeName>
<wicri:cityArea>Houston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Scott, Rodney J" sort="Scott, Rodney J" uniqKey="Scott R" first="Rodney J" last="Scott">Rodney J. Scott</name>
<affiliation wicri:level="1"><nlm:aff id="au32"><institution>John Hunter Hospital</institution>
<addr-line>New Lambton Heights, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>New Lambton Heights</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="au33"><institution>Hunter Medical Research Institute</institution>
<addr-line>New Lambton, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>New Lambton</wicri:regionArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au34"><institution>Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Sciences Center</institution>
<addr-line>Houston, TX</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Texas</region>
</placeName>
<wicri:cityArea>Houston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Fornage, Myriam" sort="Fornage, Myriam" uniqKey="Fornage M" first="Myriam" last="Fornage">Myriam Fornage</name>
<affiliation wicri:level="1"><nlm:aff id="au35"><institution>Imperial College Cerebrovascular Research Unit, Imperial College London</institution>
<addr-line>London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sharma, Pankaj" sort="Sharma, Pankaj" uniqKey="Sharma P" first="Pankaj" last="Sharma">Pankaj Sharma</name>
<affiliation wicri:level="2"><nlm:aff id="au36"><institution>Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School</institution>
<addr-line>Boston, MA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Boston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Furie, Karen L" sort="Furie, Karen L" uniqKey="Furie K" first="Karen L" last="Furie">Karen L. Furie</name>
<affiliation wicri:level="1"><nlm:aff id="au37"><institution>Department of Neurology, Mayo Clinic</institution>
<addr-line>Jacksonville, FL, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Jacksonville, FL</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Rosand, Jonathan" sort="Rosand, Jonathan" uniqKey="Rosand J" first="Jonathan" last="Rosand">Jonathan Rosand</name>
<affiliation wicri:level="1"><nlm:aff id="au37"><institution>Department of Neurology, Mayo Clinic</institution>
<addr-line>Jacksonville, FL, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Jacksonville, FL</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Nalls, Mike" sort="Nalls, Mike" uniqKey="Nalls M" first="Mike" last="Nalls">Mike Nalls</name>
<affiliation wicri:level="2"><nlm:aff id="au38"><institution>University of Mississippi Medical Center</institution>
<addr-line>Jackson, MS</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">État du Mississippi</region>
</placeName>
<wicri:cityArea>Jackson</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Meschia, James" sort="Meschia, James" uniqKey="Meschia J" first="James" last="Meschia">James Meschia</name>
<affiliation wicri:level="2"><nlm:aff id="au38"><institution>University of Mississippi Medical Center</institution>
<addr-line>Jackson, MS</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">État du Mississippi</region>
</placeName>
<wicri:cityArea>Jackson</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Mosely, Thomas H" sort="Mosely, Thomas H" uniqKey="Mosely T" first="Thomas H" last="Mosely">Thomas H. Mosely</name>
<affiliation wicri:level="1"><nlm:aff id="au39"><institution>Queen's University of Belfast</institution>
<addr-line>Belfast, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Belfast</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Evans, Alun" sort="Evans, Alun" uniqKey="Evans A" first="Alun" last="Evans">Alun Evans</name>
</author>
<author><name sortKey="Palotie, Aarno" sort="Palotie, Aarno" uniqKey="Palotie A" first="Aarno" last="Palotie">Aarno Palotie</name>
<affiliation wicri:level="1"><nlm:aff id="au3"><institution>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus</institution>
<addr-line>Hinxton, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Hinxton</wicri:regionArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au4"><institution>Program in Medical and Population Genetics and Genetic Analysis Platform, Broad Institute of Massachusetts Institute of Technology and Harvard</institution>
<addr-line>Cambridge, MA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Cambridge</wicri:cityArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="au5"><institution>Department of Medical Genetics, University of Helsinki and University Central Hospital</institution>
<addr-line>Helsinki, Finland</addr-line>
</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Helsinki</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="au11"><institution>Institute for Molecular Medicine Finland, University of Helsinki</institution>
<addr-line>Helsinki, Finland</addr-line>
</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Helsinki</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Markus, Hugh S" sort="Markus, Hugh S" uniqKey="Markus H" first="Hugh S" last="Markus">Hugh S. Markus</name>
<affiliation wicri:level="1"><nlm:aff id="au6"><institution>Stroke and Dementia Research Centre, St George's University of London</institution>
<addr-line>London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Grant, Peter J" sort="Grant, Peter J" uniqKey="Grant P" first="Peter J" last="Grant">Peter J. Grant</name>
<affiliation wicri:level="1"><nlm:aff id="au2"><institution>Division of Cardiovascular and Diabetes Research, University of Leeds</institution>
<addr-line>Leeds, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Leeds</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Spector, Tim D" sort="Spector, Tim D" uniqKey="Spector T" first="Tim D" last="Spector">Tim D. Spector</name>
<affiliation wicri:level="1"><nlm:aff id="au1"><institution>Department of Twin Research and Genetic Epidemiology, King's College London</institution>
<addr-line>London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>London</wicri:regionArea>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">23381943</idno>
<idno type="pmc">3582024</idno>
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<idno type="RBID">PMC:3582024</idno>
<idno type="doi">10.1002/ana.23838</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Ischemic Stroke Is Associated with the <italic>ABO</italic>
Locus: The EuroCLOT Study</title>
<author><name sortKey="Williams, Frances M K" sort="Williams, Frances M K" uniqKey="Williams F" first="Frances M K" last="Williams">Frances M K. Williams</name>
<affiliation wicri:level="1"><nlm:aff id="au1"><institution>Department of Twin Research and Genetic Epidemiology, King's College London</institution>
<addr-line>London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Carter, Angela M" sort="Carter, Angela M" uniqKey="Carter A" first="Angela M" last="Carter">Angela M. Carter</name>
<affiliation wicri:level="1"><nlm:aff id="au2"><institution>Division of Cardiovascular and Diabetes Research, University of Leeds</institution>
<addr-line>Leeds, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Leeds</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hysi, Pirro G" sort="Hysi, Pirro G" uniqKey="Hysi P" first="Pirro G" last="Hysi">Pirro G. Hysi</name>
<affiliation wicri:level="1"><nlm:aff id="au1"><institution>Department of Twin Research and Genetic Epidemiology, King's College London</institution>
<addr-line>London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Surdulescu, Gabriela" sort="Surdulescu, Gabriela" uniqKey="Surdulescu G" first="Gabriela" last="Surdulescu">Gabriela Surdulescu</name>
<affiliation wicri:level="1"><nlm:aff id="au1"><institution>Department of Twin Research and Genetic Epidemiology, King's College London</institution>
<addr-line>London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hodgkiss, Dylan" sort="Hodgkiss, Dylan" uniqKey="Hodgkiss D" first="Dylan" last="Hodgkiss">Dylan Hodgkiss</name>
<affiliation wicri:level="1"><nlm:aff id="au1"><institution>Department of Twin Research and Genetic Epidemiology, King's College London</institution>
<addr-line>London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Soranzo, Nicole" sort="Soranzo, Nicole" uniqKey="Soranzo N" first="Nicole" last="Soranzo">Nicole Soranzo</name>
<affiliation wicri:level="1"><nlm:aff id="au3"><institution>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus</institution>
<addr-line>Hinxton, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Hinxton</wicri:regionArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au4"><institution>Program in Medical and Population Genetics and Genetic Analysis Platform, Broad Institute of Massachusetts Institute of Technology and Harvard</institution>
<addr-line>Cambridge, MA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Cambridge</wicri:cityArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="au5"><institution>Department of Medical Genetics, University of Helsinki and University Central Hospital</institution>
<addr-line>Helsinki, Finland</addr-line>
</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Helsinki</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Traylor, Matthew" sort="Traylor, Matthew" uniqKey="Traylor M" first="Matthew" last="Traylor">Matthew Traylor</name>
<affiliation wicri:level="1"><nlm:aff id="au6"><institution>Stroke and Dementia Research Centre, St George's University of London</institution>
<addr-line>London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bevan, Steve" sort="Bevan, Steve" uniqKey="Bevan S" first="Steve" last="Bevan">Steve Bevan</name>
<affiliation wicri:level="1"><nlm:aff id="au6"><institution>Stroke and Dementia Research Centre, St George's University of London</institution>
<addr-line>London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Dichgans, Martin" sort="Dichgans, Martin" uniqKey="Dichgans M" first="Martin" last="Dichgans">Martin Dichgans</name>
<affiliation wicri:level="1"><nlm:aff id="au7"><institution>Institute for Stroke and Dementia Research, Klinikum der Universität Munich, Ludwig-Maximilians-University</institution>
<addr-line>Munich, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Munich</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Rothwell, Peter M W" sort="Rothwell, Peter M W" uniqKey="Rothwell P" first="Peter M W" last="Rothwell">Peter M W. Rothwell</name>
<affiliation wicri:level="1"><nlm:aff id="au8"><institution>Stroke Prevention Research Unit, University Department of Clinical Neurology, Oxford University</institution>
<addr-line>Oxford, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Oxford</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sudlow, Cathie" sort="Sudlow, Cathie" uniqKey="Sudlow C" first="Cathie" last="Sudlow">Cathie Sudlow</name>
<affiliation wicri:level="1"><nlm:aff id="au9"><institution>Division of Clinical Neurosciences, University of Edinburgh</institution>
<addr-line>Edinburgh, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Edinburgh</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Farrall, Martin" sort="Farrall, Martin" uniqKey="Farrall M" first="Martin" last="Farrall">Martin Farrall</name>
<affiliation wicri:level="1"><nlm:aff id="au10"><institution>Wellcome Trust Centre for Human Genetics and Department of Cardiovascular Medicine, University of Oxford</institution>
<addr-line>Oxford, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Oxford</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Silander, Kaisa" sort="Silander, Kaisa" uniqKey="Silander K" first="Kaisa" last="Silander">Kaisa Silander</name>
<affiliation wicri:level="1"><nlm:aff id="au11"><institution>Institute for Molecular Medicine Finland, University of Helsinki</institution>
<addr-line>Helsinki, Finland</addr-line>
</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Helsinki</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kaunisto, Mari" sort="Kaunisto, Mari" uniqKey="Kaunisto M" first="Mari" last="Kaunisto">Mari Kaunisto</name>
<affiliation wicri:level="1"><nlm:aff id="au11"><institution>Institute for Molecular Medicine Finland, University of Helsinki</institution>
<addr-line>Helsinki, Finland</addr-line>
</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Helsinki</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Wagner, Peter" sort="Wagner, Peter" uniqKey="Wagner P" first="Peter" last="Wagner">Peter Wagner</name>
<affiliation wicri:level="1"><nlm:aff id="au11"><institution>Institute for Molecular Medicine Finland, University of Helsinki</institution>
<addr-line>Helsinki, Finland</addr-line>
</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Helsinki</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Saarela, Olli" sort="Saarela, Olli" uniqKey="Saarela O" first="Olli" last="Saarela">Olli Saarela</name>
<affiliation wicri:level="1"><nlm:aff id="au12"><institution>Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare</institution>
<addr-line>Helsinki, Finland</addr-line>
</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Helsinki</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kuulasmaa, Kari" sort="Kuulasmaa, Kari" uniqKey="Kuulasmaa K" first="Kari" last="Kuulasmaa">Kari Kuulasmaa</name>
<affiliation wicri:level="1"><nlm:aff id="au12"><institution>Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare</institution>
<addr-line>Helsinki, Finland</addr-line>
</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Helsinki</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Virtamo, Jarmo" sort="Virtamo, Jarmo" uniqKey="Virtamo J" first="Jarmo" last="Virtamo">Jarmo Virtamo</name>
<affiliation wicri:level="1"><nlm:aff id="au12"><institution>Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare</institution>
<addr-line>Helsinki, Finland</addr-line>
</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Helsinki</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Salomaa, Veikko" sort="Salomaa, Veikko" uniqKey="Salomaa V" first="Veikko" last="Salomaa">Veikko Salomaa</name>
<affiliation wicri:level="1"><nlm:aff id="au12"><institution>Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare</institution>
<addr-line>Helsinki, Finland</addr-line>
</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Helsinki</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Amouyel, Philippe" sort="Amouyel, Philippe" uniqKey="Amouyel P" first="Philippe" last="Amouyel">Philippe Amouyel</name>
<affiliation wicri:level="1"><nlm:aff id="au13"><institution>Department of Epidemiology and Public Health, Pasteur Institute of Lille</institution>
<addr-line>Lille, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Lille</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Arveiler, Dominique" sort="Arveiler, Dominique" uniqKey="Arveiler D" first="Dominique" last="Arveiler">Dominique Arveiler</name>
<affiliation wicri:level="1"><nlm:aff id="au14"><institution>Department of Epidemiology and Public Health, University of Strasbourg</institution>
<addr-line>Strasbourg, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Strasbourg</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ferrieres, Jean" sort="Ferrieres, Jean" uniqKey="Ferrieres J" first="Jean" last="Ferrieres">Jean Ferrieres</name>
<affiliation wicri:level="1"><nlm:aff id="au15"><institution>Department of Epidemiology, Faculty of Medicine</institution>
<addr-line>Toulouse-Purpan, Toulouse, France</addr-line>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Toulouse-Purpan, Toulouse</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Wiklund, Per Gunnar" sort="Wiklund, Per Gunnar" uniqKey="Wiklund P" first="Per-Gunnar" last="Wiklund">Per-Gunnar Wiklund</name>
<affiliation wicri:level="1"><nlm:aff id="au16"><institution>Department of Internal Medicine, University of Umeå</institution>
<addr-line>Umeå, Sweden</addr-line>
</nlm:aff>
<country xml:lang="fr">Suède</country>
<wicri:regionArea>Umeå</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Arfan Ikram, M" sort="Arfan Ikram, M" uniqKey="Arfan Ikram M" first="M" last="Arfan Ikram">M. Arfan Ikram</name>
<affiliation wicri:level="1"><nlm:aff id="au17"><institution>Department of Epidemiology, Erasmus University Medical Center</institution>
<addr-line>Rotterdam, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Rotterdam</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Hofman, Albert" sort="Hofman, Albert" uniqKey="Hofman A" first="Albert" last="Hofman">Albert Hofman</name>
<affiliation wicri:level="1"><nlm:aff id="au17"><institution>Department of Epidemiology, Erasmus University Medical Center</institution>
<addr-line>Rotterdam, the Netherlands</addr-line>
</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">Pays-Bas</country>
<wicri:regionArea>Rotterdam</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Boncoraglio, Giorgio B" sort="Boncoraglio, Giorgio B" uniqKey="Boncoraglio G" first="Giorgio B" last="Boncoraglio">Giorgio B. Boncoraglio</name>
<affiliation wicri:level="1"><nlm:aff id="au18"><institution>Department of Neurology, Research Hospital of the Neurological Institute “Carlo Besta,”</institution>
<addr-line>Milan, Italy</addr-line>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Milan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Parati, Eugenio A" sort="Parati, Eugenio A" uniqKey="Parati E" first="Eugenio A" last="Parati">Eugenio A. Parati</name>
<affiliation wicri:level="1"><nlm:aff id="au18"><institution>Department of Neurology, Research Hospital of the Neurological Institute “Carlo Besta,”</institution>
<addr-line>Milan, Italy</addr-line>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Milan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Helgadottir, Anna" sort="Helgadottir, Anna" uniqKey="Helgadottir A" first="Anna" last="Helgadottir">Anna Helgadottir</name>
<affiliation wicri:level="1"><nlm:aff id="au10"><institution>Wellcome Trust Centre for Human Genetics and Department of Cardiovascular Medicine, University of Oxford</institution>
<addr-line>Oxford, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Oxford</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="au19"><institution>DeCODE Genetics</institution>
<addr-line>Reykjavik, Iceland</addr-line>
</nlm:aff>
<country xml:lang="fr">Islande</country>
<wicri:regionArea>Reykjavik</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Gretarsdottir, Solveig" sort="Gretarsdottir, Solveig" uniqKey="Gretarsdottir S" first="Solveig" last="Gretarsdottir">Solveig Gretarsdottir</name>
<affiliation wicri:level="1"><nlm:aff id="au19"><institution>DeCODE Genetics</institution>
<addr-line>Reykjavik, Iceland</addr-line>
</nlm:aff>
<country xml:lang="fr">Islande</country>
<wicri:regionArea>Reykjavik</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Thorsteinsdottir, Unnur" sort="Thorsteinsdottir, Unnur" uniqKey="Thorsteinsdottir U" first="Unnur" last="Thorsteinsdottir">Unnur Thorsteinsdottir</name>
<affiliation wicri:level="1"><nlm:aff id="au19"><institution>DeCODE Genetics</institution>
<addr-line>Reykjavik, Iceland</addr-line>
</nlm:aff>
<country xml:lang="fr">Islande</country>
<wicri:regionArea>Reykjavik</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Thorleifsson, Gudmar" sort="Thorleifsson, Gudmar" uniqKey="Thorleifsson G" first="Gudmar" last="Thorleifsson">Gudmar Thorleifsson</name>
<affiliation wicri:level="1"><nlm:aff id="au19"><institution>DeCODE Genetics</institution>
<addr-line>Reykjavik, Iceland</addr-line>
</nlm:aff>
<country xml:lang="fr">Islande</country>
<wicri:regionArea>Reykjavik</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Stefansson, Kari" sort="Stefansson, Kari" uniqKey="Stefansson K" first="Kari" last="Stefansson">Kari Stefansson</name>
<affiliation wicri:level="1"><nlm:aff id="au19"><institution>DeCODE Genetics</institution>
<addr-line>Reykjavik, Iceland</addr-line>
</nlm:aff>
<country xml:lang="fr">Islande</country>
<wicri:regionArea>Reykjavik</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Seshadri, Sudha" sort="Seshadri, Sudha" uniqKey="Seshadri S" first="Sudha" last="Seshadri">Sudha Seshadri</name>
<affiliation wicri:level="2"><nlm:aff id="au20"><institution>Boston University Schools of Medicine and Public Health</institution>
<addr-line>Boston, MA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Boston</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au21"><institution>Framingham Heart Study</institution>
<addr-line>Framingham, MA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Framingham</wicri:cityArea>
</affiliation>
<affiliation><nlm:aff id="au22"><institution>Departments of Health Services, University of Washington</institution>
<addr-line>Seattlem WA</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Destefano, Anita" sort="Destefano, Anita" uniqKey="Destefano A" first="Anita" last="Destefano">Anita Destefano</name>
<affiliation wicri:level="2"><nlm:aff id="au20"><institution>Boston University Schools of Medicine and Public Health</institution>
<addr-line>Boston, MA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Boston</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au21"><institution>Framingham Heart Study</institution>
<addr-line>Framingham, MA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Framingham</wicri:cityArea>
</affiliation>
<affiliation><nlm:aff id="au22"><institution>Departments of Health Services, University of Washington</institution>
<addr-line>Seattlem WA</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gschwendtner, Andreas" sort="Gschwendtner, Andreas" uniqKey="Gschwendtner A" first="Andreas" last="Gschwendtner">Andreas Gschwendtner</name>
<affiliation wicri:level="1"><nlm:aff id="au7"><institution>Institute for Stroke and Dementia Research, Klinikum der Universität Munich, Ludwig-Maximilians-University</institution>
<addr-line>Munich, Germany</addr-line>
</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Munich</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Psaty, Bruce" sort="Psaty, Bruce" uniqKey="Psaty B" first="Bruce" last="Psaty">Bruce Psaty</name>
<affiliation wicri:level="2"><nlm:aff id="au23"><institution>Epidemiology, Health Services, University of Washington</institution>
<addr-line>Seattle, WA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Washington (État)</region>
</placeName>
<wicri:cityArea>Seattle</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au24"><institution>Medicine, and Health Services, University of Washington</institution>
<addr-line>Seattle, WA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Washington (État)</region>
</placeName>
<wicri:cityArea>Seattle</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au25"><institution>Group Health Research Institute, Group Health</institution>
<addr-line>Seattle, WA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Washington (État)</region>
</placeName>
<wicri:cityArea>Seattle</wicri:cityArea>
</affiliation>
<affiliation><nlm:aff id="au26"><institution>Department of Neurology, University of Washington</institution>
<addr-line>WA</addr-line>
</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Longstreth, Will" sort="Longstreth, Will" uniqKey="Longstreth W" first="Will" last="Longstreth">Will Longstreth</name>
<affiliation wicri:level="2"><nlm:aff id="au23"><institution>Epidemiology, Health Services, University of Washington</institution>
<addr-line>Seattle, WA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Washington (État)</region>
</placeName>
<wicri:cityArea>Seattle</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au24"><institution>Medicine, and Health Services, University of Washington</institution>
<addr-line>Seattle, WA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Washington (État)</region>
</placeName>
<wicri:cityArea>Seattle</wicri:cityArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au27"><institution>Department of Medicine, University of Maryland</institution>
<addr-line>Baltimore, MD</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Maryland</region>
</placeName>
<wicri:cityArea>Baltimore</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Mitchell, Braxton D" sort="Mitchell, Braxton D" uniqKey="Mitchell B" first="Braxton D" last="Mitchell">Braxton D. Mitchell</name>
<affiliation wicri:level="1"><nlm:aff id="au28"><institution>Clinical Trial Service Unit, University of Oxford</institution>
<addr-line>Oxford, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Oxford</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Cheng, Yu Ching" sort="Cheng, Yu Ching" uniqKey="Cheng Y" first="Yu-Ching" last="Cheng">Yu-Ching Cheng</name>
<affiliation wicri:level="1"><nlm:aff id="au28"><institution>Clinical Trial Service Unit, University of Oxford</institution>
<addr-line>Oxford, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Oxford</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Clarke, Robert" sort="Clarke, Robert" uniqKey="Clarke R" first="Robert" last="Clarke">Robert Clarke</name>
<affiliation wicri:level="1"><nlm:aff id="au29"><institution>University of Insubria</institution>
<addr-line>Varese, Italy</addr-line>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Varese</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ferrario, Marco" sort="Ferrario, Marco" uniqKey="Ferrario M" first="Marco" last="Ferrario">Marco Ferrario</name>
<affiliation wicri:level="2"><nlm:aff id="au30"><institution>Cardiovascular Health Research Unit, Department of Medicine, University of Washington</institution>
<addr-line>Seattle, WA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Washington (État)</region>
</placeName>
<wicri:cityArea>Seattle</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Bis, Joshua C" sort="Bis, Joshua C" uniqKey="Bis J" first="Joshua C" last="Bis">Joshua C. Bis</name>
<affiliation wicri:level="1"><nlm:aff id="au31"><institution>University of Newcastle</institution>
<addr-line>Callaghan, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Callaghan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Levi, Christopher" sort="Levi, Christopher" uniqKey="Levi C" first="Christopher" last="Levi">Christopher Levi</name>
<affiliation wicri:level="1"><nlm:aff id="au32"><institution>John Hunter Hospital</institution>
<addr-line>New Lambton Heights, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>New Lambton Heights</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="au33"><institution>Hunter Medical Research Institute</institution>
<addr-line>New Lambton, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>New Lambton</wicri:regionArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au34"><institution>Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Sciences Center</institution>
<addr-line>Houston, TX</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Texas</region>
</placeName>
<wicri:cityArea>Houston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Attia, John" sort="Attia, John" uniqKey="Attia J" first="John" last="Attia">John Attia</name>
<affiliation wicri:level="1"><nlm:aff id="au32"><institution>John Hunter Hospital</institution>
<addr-line>New Lambton Heights, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>New Lambton Heights</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="au33"><institution>Hunter Medical Research Institute</institution>
<addr-line>New Lambton, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>New Lambton</wicri:regionArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au34"><institution>Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Sciences Center</institution>
<addr-line>Houston, TX</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Texas</region>
</placeName>
<wicri:cityArea>Houston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Holliday, Elizabeth G" sort="Holliday, Elizabeth G" uniqKey="Holliday E" first="Elizabeth G" last="Holliday">Elizabeth G. Holliday</name>
<affiliation wicri:level="1"><nlm:aff id="au32"><institution>John Hunter Hospital</institution>
<addr-line>New Lambton Heights, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>New Lambton Heights</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="au33"><institution>Hunter Medical Research Institute</institution>
<addr-line>New Lambton, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>New Lambton</wicri:regionArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au34"><institution>Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Sciences Center</institution>
<addr-line>Houston, TX</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Texas</region>
</placeName>
<wicri:cityArea>Houston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Scott, Rodney J" sort="Scott, Rodney J" uniqKey="Scott R" first="Rodney J" last="Scott">Rodney J. Scott</name>
<affiliation wicri:level="1"><nlm:aff id="au32"><institution>John Hunter Hospital</institution>
<addr-line>New Lambton Heights, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>New Lambton Heights</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="au33"><institution>Hunter Medical Research Institute</institution>
<addr-line>New Lambton, Australia</addr-line>
</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>New Lambton</wicri:regionArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au34"><institution>Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Sciences Center</institution>
<addr-line>Houston, TX</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Texas</region>
</placeName>
<wicri:cityArea>Houston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Fornage, Myriam" sort="Fornage, Myriam" uniqKey="Fornage M" first="Myriam" last="Fornage">Myriam Fornage</name>
<affiliation wicri:level="1"><nlm:aff id="au35"><institution>Imperial College Cerebrovascular Research Unit, Imperial College London</institution>
<addr-line>London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sharma, Pankaj" sort="Sharma, Pankaj" uniqKey="Sharma P" first="Pankaj" last="Sharma">Pankaj Sharma</name>
<affiliation wicri:level="2"><nlm:aff id="au36"><institution>Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School</institution>
<addr-line>Boston, MA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Boston</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Furie, Karen L" sort="Furie, Karen L" uniqKey="Furie K" first="Karen L" last="Furie">Karen L. Furie</name>
<affiliation wicri:level="1"><nlm:aff id="au37"><institution>Department of Neurology, Mayo Clinic</institution>
<addr-line>Jacksonville, FL, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Jacksonville, FL</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Rosand, Jonathan" sort="Rosand, Jonathan" uniqKey="Rosand J" first="Jonathan" last="Rosand">Jonathan Rosand</name>
<affiliation wicri:level="1"><nlm:aff id="au37"><institution>Department of Neurology, Mayo Clinic</institution>
<addr-line>Jacksonville, FL, USA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Jacksonville, FL</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Nalls, Mike" sort="Nalls, Mike" uniqKey="Nalls M" first="Mike" last="Nalls">Mike Nalls</name>
<affiliation wicri:level="2"><nlm:aff id="au38"><institution>University of Mississippi Medical Center</institution>
<addr-line>Jackson, MS</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">État du Mississippi</region>
</placeName>
<wicri:cityArea>Jackson</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Meschia, James" sort="Meschia, James" uniqKey="Meschia J" first="James" last="Meschia">James Meschia</name>
<affiliation wicri:level="2"><nlm:aff id="au38"><institution>University of Mississippi Medical Center</institution>
<addr-line>Jackson, MS</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">État du Mississippi</region>
</placeName>
<wicri:cityArea>Jackson</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Mosely, Thomas H" sort="Mosely, Thomas H" uniqKey="Mosely T" first="Thomas H" last="Mosely">Thomas H. Mosely</name>
<affiliation wicri:level="1"><nlm:aff id="au39"><institution>Queen's University of Belfast</institution>
<addr-line>Belfast, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Belfast</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Evans, Alun" sort="Evans, Alun" uniqKey="Evans A" first="Alun" last="Evans">Alun Evans</name>
</author>
<author><name sortKey="Palotie, Aarno" sort="Palotie, Aarno" uniqKey="Palotie A" first="Aarno" last="Palotie">Aarno Palotie</name>
<affiliation wicri:level="1"><nlm:aff id="au3"><institution>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus</institution>
<addr-line>Hinxton, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Hinxton</wicri:regionArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="au4"><institution>Program in Medical and Population Genetics and Genetic Analysis Platform, Broad Institute of Massachusetts Institute of Technology and Harvard</institution>
<addr-line>Cambridge, MA</addr-line>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Massachusetts</region>
</placeName>
<wicri:cityArea>Cambridge</wicri:cityArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="au5"><institution>Department of Medical Genetics, University of Helsinki and University Central Hospital</institution>
<addr-line>Helsinki, Finland</addr-line>
</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Helsinki</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="au11"><institution>Institute for Molecular Medicine Finland, University of Helsinki</institution>
<addr-line>Helsinki, Finland</addr-line>
</nlm:aff>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Helsinki</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Markus, Hugh S" sort="Markus, Hugh S" uniqKey="Markus H" first="Hugh S" last="Markus">Hugh S. Markus</name>
<affiliation wicri:level="1"><nlm:aff id="au6"><institution>Stroke and Dementia Research Centre, St George's University of London</institution>
<addr-line>London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Grant, Peter J" sort="Grant, Peter J" uniqKey="Grant P" first="Peter J" last="Grant">Peter J. Grant</name>
<affiliation wicri:level="1"><nlm:aff id="au2"><institution>Division of Cardiovascular and Diabetes Research, University of Leeds</institution>
<addr-line>Leeds, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Leeds</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Spector, Tim D" sort="Spector, Tim D" uniqKey="Spector T" first="Tim D" last="Spector">Tim D. Spector</name>
<affiliation wicri:level="1"><nlm:aff id="au1"><institution>Department of Twin Research and Genetic Epidemiology, King's College London</institution>
<addr-line>London, United Kingdom</addr-line>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>London</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Annals of Neurology</title>
<idno type="ISSN">0364-5134</idno>
<idno type="eISSN">1531-8249</idno>
<imprint><date when="2013">2013</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Objective</title>
<p>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 REFVIDunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.</p>
</sec>
<sec><title>Methods</title>
<p>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).</p>
</sec>
<sec><title>Results</title>
<p>Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (<italic>p</italic>
< 5 × 10<sup>–8</sup>
) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (<italic>p</italic>
= 2.6 × 10<sup>–186</sup>
), rs10665 with FVII (<italic>p</italic>
= 2.4 × 10<sup>–47</sup>
), and rs505922 in the <italic>ABO</italic>
gene with both von Willebrand factor (<italic>p</italic>
= 4.7 × 10<sup>–57</sup>
) and factor VIII (<italic>p</italic>
= 1.2 × 10<sup>–36</sup>
). 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, <italic>p</italic>
= 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), <italic>p</italic>
= 0.001, a finding specific to large-vessel and cardioembolic stroke (<italic>p</italic>
= 0.001 and <italic>p</italic>
= < 0.001, respectively) but not seen with small-vessel stroke (<italic>p</italic>
= 0.811).</p>
</sec>
<sec><title>Interpretation</title>
<p><italic>ABO</italic>
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 2013</p>
</sec>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Ann Neurol</journal-id>
<journal-id journal-id-type="iso-abbrev">Ann. Neurol</journal-id>
<journal-id journal-id-type="publisher-id">ana</journal-id>
<journal-title-group><journal-title>Annals of Neurology</journal-title>
</journal-title-group>
<issn pub-type="ppub">0364-5134</issn>
<issn pub-type="epub">1531-8249</issn>
<publisher><publisher-name>Wiley Subscription Services, Inc., A Wiley Company</publisher-name>
<publisher-loc>Hoboken</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">23381943</article-id>
<article-id pub-id-type="pmc">3582024</article-id>
<article-id pub-id-type="doi">10.1002/ana.23838</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Rapid Communication</subject>
</subj-group>
</article-categories>
<title-group><article-title>Ischemic Stroke Is Associated with the <italic>ABO</italic>
Locus: The EuroCLOT Study</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Williams</surname>
<given-names>Frances M K</given-names>
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<degrees>PhD, FRCP(E)</degrees>
<xref ref-type="aff" rid="au1">1</xref>
</contrib>
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<given-names>Angela M</given-names>
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<degrees>PhD</degrees>
<xref ref-type="aff" rid="au2">2</xref>
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<given-names>Pirro G</given-names>
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<degrees>PhD</degrees>
<xref ref-type="aff" rid="au1">1</xref>
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<given-names>Gabriela</given-names>
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<degrees>MSc</degrees>
<xref ref-type="aff" rid="au1">1</xref>
</contrib>
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<given-names>Dylan</given-names>
</name>
<degrees>MSc</degrees>
<xref ref-type="aff" rid="au1">1</xref>
</contrib>
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<given-names>Nicole</given-names>
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<degrees>PhD</degrees>
<xref ref-type="aff" rid="au3">3</xref>
<xref ref-type="aff" rid="au4">4</xref>
<xref ref-type="aff" rid="au5">5</xref>
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<contrib contrib-type="author"><name><surname>Traylor</surname>
<given-names>Matthew</given-names>
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<degrees>MSc</degrees>
<xref ref-type="aff" rid="au6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bevan</surname>
<given-names>Steve</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dichgans</surname>
<given-names>Martin</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="au7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rothwell</surname>
<given-names>Peter M W</given-names>
</name>
<degrees>MD, PhD, FMedSci</degrees>
<xref ref-type="aff" rid="au8">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sudlow</surname>
<given-names>Cathie</given-names>
</name>
<degrees>DPhil, FRCP(E)</degrees>
<xref ref-type="aff" rid="au9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Farrall</surname>
<given-names>Martin</given-names>
</name>
<degrees>PhD, FRCPath</degrees>
<xref ref-type="aff" rid="au10">10</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Silander</surname>
<given-names>Kaisa</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au11">11</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kaunisto</surname>
<given-names>Mari</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au11">11</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wagner</surname>
<given-names>Peter</given-names>
</name>
<degrees>BSc</degrees>
<xref ref-type="aff" rid="au11">11</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Saarela</surname>
<given-names>Olli</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au12">12</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kuulasmaa</surname>
<given-names>Kari</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au12">12</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Virtamo</surname>
<given-names>Jarmo</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="au12">12</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Salomaa</surname>
<given-names>Veikko</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="au12">12</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Amouyel</surname>
<given-names>Philippe</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="au13">13</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Arveiler</surname>
<given-names>Dominique</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="au14">14</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ferrieres</surname>
<given-names>Jean</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="au15">15</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wiklund</surname>
<given-names>Per-Gunnar</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="au16">16</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Arfan Ikram</surname>
<given-names>M</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="au17">17</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hofman</surname>
<given-names>Albert</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="au17">17</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Boncoraglio</surname>
<given-names>Giorgio B</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="au18">18</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Parati</surname>
<given-names>Eugenio A</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="au18">18</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Helgadottir</surname>
<given-names>Anna</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="au10">10</xref>
<xref ref-type="aff" rid="au19">19</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gretarsdottir</surname>
<given-names>Solveig</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au19">19</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Thorsteinsdottir</surname>
<given-names>Unnur</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au19">19</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Thorleifsson</surname>
<given-names>Gudmar</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au19">19</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Stefansson</surname>
<given-names>Kari</given-names>
</name>
<degrees>PhD, Dr med</degrees>
<xref ref-type="aff" rid="au19">19</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Seshadri</surname>
<given-names>Sudha</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="au20">20</xref>
<xref ref-type="aff" rid="au21">21</xref>
<xref ref-type="aff" rid="au22">22</xref>
</contrib>
<contrib contrib-type="author"><name><surname>DeStefano</surname>
<given-names>Anita</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au20">20</xref>
<xref ref-type="aff" rid="au21">21</xref>
<xref ref-type="aff" rid="au22">22</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gschwendtner</surname>
<given-names>Andreas</given-names>
</name>
<degrees>Dr med</degrees>
<xref ref-type="aff" rid="au7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Psaty</surname>
<given-names>Bruce</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="au23">23</xref>
<xref ref-type="aff" rid="au24">24</xref>
<xref ref-type="aff" rid="au25">25</xref>
<xref ref-type="aff" rid="au26">26</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Longstreth</surname>
<given-names>Will</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="au23">23</xref>
<xref ref-type="aff" rid="au24">24</xref>
<xref ref-type="aff" rid="au27">27</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mitchell</surname>
<given-names>Braxton D</given-names>
</name>
<degrees>MPH, PhD</degrees>
<xref ref-type="aff" rid="au28">28</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cheng</surname>
<given-names>Yu-Ching</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au28">28</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Clarke</surname>
<given-names>Robert</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="au29">29</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ferrario</surname>
<given-names>Marco</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="au30">30</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bis</surname>
<given-names>Joshua C</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au31">31</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Levi</surname>
<given-names>Christopher</given-names>
</name>
<degrees>BSc, MBBS</degrees>
<xref ref-type="aff" rid="au32">32</xref>
<xref ref-type="aff" rid="au33">33</xref>
<xref ref-type="aff" rid="au34">34</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Attia</surname>
<given-names>John</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="au32">32</xref>
<xref ref-type="aff" rid="au33">33</xref>
<xref ref-type="aff" rid="au34">34</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Holliday</surname>
<given-names>Elizabeth G</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au32">32</xref>
<xref ref-type="aff" rid="au33">33</xref>
<xref ref-type="aff" rid="au34">34</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Scott</surname>
<given-names>Rodney J</given-names>
</name>
<degrees>PhD, FRCPath</degrees>
<xref ref-type="aff" rid="au32">32</xref>
<xref ref-type="aff" rid="au33">33</xref>
<xref ref-type="aff" rid="au34">34</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fornage</surname>
<given-names>Myriam</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au35">35</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sharma</surname>
<given-names>Pankaj</given-names>
</name>
<degrees>PhD, FRCP</degrees>
<xref ref-type="aff" rid="au36">36</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Furie</surname>
<given-names>Karen L</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="au37">37</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rosand</surname>
<given-names>Jonathan</given-names>
</name>
<degrees>MD, MSc</degrees>
<xref ref-type="aff" rid="au37">37</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nalls</surname>
<given-names>Mike</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au38">38</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Meschia</surname>
<given-names>James</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="au38">38</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mosely</surname>
<given-names>Thomas H</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au39">39</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Evans</surname>
<given-names>Alun</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author"><name><surname>Palotie</surname>
<given-names>Aarno</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="au3">3</xref>
<xref ref-type="aff" rid="au4">4</xref>
<xref ref-type="aff" rid="au5">5</xref>
<xref ref-type="aff" rid="au11">11</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Markus</surname>
<given-names>Hugh S</given-names>
</name>
<degrees>MD, FRCP</degrees>
<xref ref-type="aff" rid="au6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Grant</surname>
<given-names>Peter J</given-names>
</name>
<degrees>MD, FRCP</degrees>
<xref ref-type="aff" rid="au2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Spector</surname>
<given-names>Tim D</given-names>
</name>
<degrees>MD, FRCP</degrees>
<xref ref-type="aff" rid="au1">1</xref>
</contrib>
<contrib contrib-type="author"><collab>on Behalf of the EuroCLOT Investigators, the Wellcome Trust Case Control Consortium 2, MOnica Risk, Genetics, Archiving and Monograph, MetaStroke, and the International Stroke Genetics Consortium</collab>
</contrib>
<aff id="au1"><label>1</label>
<institution>Department of Twin Research and Genetic Epidemiology, King's College London</institution>
<addr-line>London, United Kingdom</addr-line>
</aff>
<aff id="au2"><label>2</label>
<institution>Division of Cardiovascular and Diabetes Research, University of Leeds</institution>
<addr-line>Leeds, United Kingdom</addr-line>
</aff>
<aff id="au3"><label>3</label>
<institution>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus</institution>
<addr-line>Hinxton, United Kingdom</addr-line>
</aff>
<aff id="au4"><label>4</label>
<institution>Program in Medical and Population Genetics and Genetic Analysis Platform, Broad Institute of Massachusetts Institute of Technology and Harvard</institution>
<addr-line>Cambridge, MA</addr-line>
</aff>
<aff id="au5"><label>5</label>
<institution>Department of Medical Genetics, University of Helsinki and University Central Hospital</institution>
<addr-line>Helsinki, Finland</addr-line>
</aff>
<aff id="au6"><label>6</label>
<institution>Stroke and Dementia Research Centre, St George's University of London</institution>
<addr-line>London, United Kingdom</addr-line>
</aff>
<aff id="au7"><label>7</label>
<institution>Institute for Stroke and Dementia Research, Klinikum der Universität Munich, Ludwig-Maximilians-University</institution>
<addr-line>Munich, Germany</addr-line>
</aff>
<aff id="au8"><label>8</label>
<institution>Stroke Prevention Research Unit, University Department of Clinical Neurology, Oxford University</institution>
<addr-line>Oxford, United Kingdom</addr-line>
</aff>
<aff id="au9"><label>9</label>
<institution>Division of Clinical Neurosciences, University of Edinburgh</institution>
<addr-line>Edinburgh, United Kingdom</addr-line>
</aff>
<aff id="au10"><label>10</label>
<institution>Wellcome Trust Centre for Human Genetics and Department of Cardiovascular Medicine, University of Oxford</institution>
<addr-line>Oxford, United Kingdom</addr-line>
</aff>
<aff id="au11"><label>11</label>
<institution>Institute for Molecular Medicine Finland, University of Helsinki</institution>
<addr-line>Helsinki, Finland</addr-line>
</aff>
<aff id="au12"><label>12</label>
<institution>Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare</institution>
<addr-line>Helsinki, Finland</addr-line>
</aff>
<aff id="au13"><label>13</label>
<institution>Department of Epidemiology and Public Health, Pasteur Institute of Lille</institution>
<addr-line>Lille, France</addr-line>
</aff>
<aff id="au14"><label>14</label>
<institution>Department of Epidemiology and Public Health, University of Strasbourg</institution>
<addr-line>Strasbourg, France</addr-line>
</aff>
<aff id="au15"><label>15</label>
<institution>Department of Epidemiology, Faculty of Medicine</institution>
<addr-line>Toulouse-Purpan, Toulouse, France</addr-line>
</aff>
<aff id="au16"><label>16</label>
<institution>Department of Internal Medicine, University of Umeå</institution>
<addr-line>Umeå, Sweden</addr-line>
</aff>
<aff id="au17"><label>17</label>
<institution>Department of Epidemiology, Erasmus University Medical Center</institution>
<addr-line>Rotterdam, the Netherlands</addr-line>
</aff>
<aff id="au18"><label>18</label>
<institution>Department of Neurology, Research Hospital of the Neurological Institute “Carlo Besta,”</institution>
<addr-line>Milan, Italy</addr-line>
</aff>
<aff id="au19"><label>19</label>
<institution>DeCODE Genetics</institution>
<addr-line>Reykjavik, Iceland</addr-line>
</aff>
<aff id="au20"><label>20</label>
<institution>Boston University Schools of Medicine and Public Health</institution>
<addr-line>Boston, MA</addr-line>
</aff>
<aff id="au21"><label>21</label>
<institution>Framingham Heart Study</institution>
<addr-line>Framingham, MA</addr-line>
</aff>
<aff id="au22"><label>22</label>
<institution>Departments of Health Services, University of Washington</institution>
<addr-line>Seattlem WA</addr-line>
</aff>
<aff id="au23"><label>23</label>
<institution>Epidemiology, Health Services, University of Washington</institution>
<addr-line>Seattle, WA</addr-line>
</aff>
<aff id="au24"><label>24</label>
<institution>Medicine, and Health Services, University of Washington</institution>
<addr-line>Seattle, WA</addr-line>
</aff>
<aff id="au25"><label>25</label>
<institution>Group Health Research Institute, Group Health</institution>
<addr-line>Seattle, WA</addr-line>
</aff>
<aff id="au26"><label>26</label>
<institution>Department of Neurology, University of Washington</institution>
<addr-line>WA</addr-line>
</aff>
<aff id="au27"><label>27</label>
<institution>Department of Medicine, University of Maryland</institution>
<addr-line>Baltimore, MD</addr-line>
</aff>
<aff id="au28"><label>28</label>
<institution>Clinical Trial Service Unit, University of Oxford</institution>
<addr-line>Oxford, United Kingdom</addr-line>
</aff>
<aff id="au29"><label>29</label>
<institution>University of Insubria</institution>
<addr-line>Varese, Italy</addr-line>
</aff>
<aff id="au30"><label>30</label>
<institution>Cardiovascular Health Research Unit, Department of Medicine, University of Washington</institution>
<addr-line>Seattle, WA</addr-line>
</aff>
<aff id="au31"><label>31</label>
<institution>University of Newcastle</institution>
<addr-line>Callaghan, Australia</addr-line>
</aff>
<aff id="au32"><label>32</label>
<institution>John Hunter Hospital</institution>
<addr-line>New Lambton Heights, Australia</addr-line>
</aff>
<aff id="au33"><label>33</label>
<institution>Hunter Medical Research Institute</institution>
<addr-line>New Lambton, Australia</addr-line>
</aff>
<aff id="au34"><label>34</label>
<institution>Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Sciences Center</institution>
<addr-line>Houston, TX</addr-line>
</aff>
<aff id="au35"><label>35</label>
<institution>Imperial College Cerebrovascular Research Unit, Imperial College London</institution>
<addr-line>London, United Kingdom</addr-line>
</aff>
<aff id="au36"><label>36</label>
<institution>Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School</institution>
<addr-line>Boston, MA</addr-line>
</aff>
<aff id="au37"><label>37</label>
<institution>Department of Neurology, Mayo Clinic</institution>
<addr-line>Jacksonville, FL, USA</addr-line>
</aff>
<aff id="au38"><label>38</label>
<institution>University of Mississippi Medical Center</institution>
<addr-line>Jackson, MS</addr-line>
</aff>
<aff id="au39"><label>39</label>
<institution>Queen's University of Belfast</institution>
<addr-line>Belfast, United Kingdom</addr-line>
</aff>
</contrib-group>
<author-notes><corresp id="cor1">Address correspondence to Dr Williams, Department of Twin Research and Genetic Epidemiology, King's College London, St Thomas' Hospital Campus, 3rd Floor South Wing Block 8, Westminster Bridge Road, London, SE1 7EH. E-mail: <email>frances.williams@kcl.ac.uk</email>
</corresp>
<fn><p>Wellcome Trust Case Control Consortium 2 members are listed in the Appendix on page 29.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><month>1</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>04</day>
<month>2</month>
<year>2013</year>
</pub-date>
<volume>73</volume>
<issue>1</issue>
<fpage>16</fpage>
<lpage>31</lpage>
<history><date date-type="received"><day>27</day>
<month>4</month>
<year>2012</year>
</date>
<date date-type="rev-recd"><day>21</day>
<month>9</month>
<year>2012</year>
</date>
<date date-type="accepted"><day>29</day>
<month>10</month>
<year>2012</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2012 American Neurological Association</copyright-statement>
<copyright-year>2012</copyright-year>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/2.5/"><license-p>Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.</license-p>
</license>
</permissions>
<abstract><sec><title>Objective</title>
<p>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 REFVIDunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.</p>
</sec>
<sec><title>Methods</title>
<p>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).</p>
</sec>
<sec><title>Results</title>
<p>Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (<italic>p</italic>
< 5 × 10<sup>–8</sup>
) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (<italic>p</italic>
= 2.6 × 10<sup>–186</sup>
), rs10665 with FVII (<italic>p</italic>
= 2.4 × 10<sup>–47</sup>
), and rs505922 in the <italic>ABO</italic>
gene with both von Willebrand factor (<italic>p</italic>
= 4.7 × 10<sup>–57</sup>
) and factor VIII (<italic>p</italic>
= 1.2 × 10<sup>–36</sup>
). 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, <italic>p</italic>
= 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), <italic>p</italic>
= 0.001, a finding specific to large-vessel and cardioembolic stroke (<italic>p</italic>
= 0.001 and <italic>p</italic>
= < 0.001, respectively) but not seen with small-vessel stroke (<italic>p</italic>
= 0.811).</p>
</sec>
<sec><title>Interpretation</title>
<p><italic>ABO</italic>
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 2013</p>
</sec>
</abstract>
</article-meta>
</front>
</pmc>
</record>
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