Risk variants for atrial fibrillation on chromosome 4q25 associate with ischemic stroke†
Corresponding Author
Solveig Gretarsdottir PhD
DeCODE Genetics, Reykjavik, Iceland
Solveig Gretarsdottir, deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland
Kari Stefansson, deCODe Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland
Search for more papers by this authorAndreas Gschwendtner MD
Department of Neurology, Klinikum of Grosshadern, Ludwig-Maximilians-Universität, München, Germany
Search for more papers by this authorKonstantinos Kostulas MD, PhD
Department of Neurology, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden
Search for more papers by this authorGregor Kuhlenbäumer MD
Department of Neurology and Leibniz-Institute for Atherosclerosis Research, University of Münster, Münster, Germany
Institute of Experimental Medicine, Molecular Neurobiology, University of Kiel, Kiel, Germany
Search for more papers by this authorSteve Bevan PhD
Department of Clinical Neuroscience, St. George's University of London, London, United Kingdom
Search for more papers by this authorDavid O. Arnar MD, PhD
Landspitali, University Hospital, Reykjavik, Iceland
Search for more papers by this authorGudmundur Thorgeirsson MD, PhD
Landspitali, University Hospital, Reykjavik, Iceland
Search for more papers by this authorEinar Mar Valdimarsson MD
Landspitali, University Hospital, Reykjavik, Iceland
Search for more papers by this authorSigurlaug Sveinbjörnsdottir MD
Landspitali, University Hospital, Reykjavik, Iceland
Search for more papers by this authorChristian Gieger PhD
Helmholtz Zentrum Munich, German Research Center for Environmental Health Institute of Epidemiology, Research for Environmental Health, Neuherberg, Germany
IBE Department of Epidemiology, Ludwig Maximilians University, Munich, Germany
Search for more papers by this authorKlaus Berger MD
Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
Search for more papers by this authorH-Erich Wichmann MD
Helmholtz Zentrum Munich, German Research Center for Environmental Health Institute of Epidemiology, Research for Environmental Health, Neuherberg, Germany
IBE Department of Epidemiology, Ludwig Maximilians University, Munich, Germany
Search for more papers by this authorJan Hillert MD
Department of Neurology, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden
Search for more papers by this authorHugh Markus MD
Department of Clinical Neuroscience, St. George's University of London, London, United Kingdom
Search for more papers by this authorJeffrey Robert Gulcher MD, PhD
DeCODE Genetics, Reykjavik, Iceland
Search for more papers by this authorE. Bernd Ringelstein MD
Department of Neurology and Leibniz-Institute for Atherosclerosis Research, University of Münster, Münster, Germany
Search for more papers by this authorMartin Dichgans MD
Department of Neurology, Klinikum of Grosshadern, Ludwig-Maximilians-Universität, München, Germany
Search for more papers by this authorDaniel Fannar Gudbjartsson PhD
DeCODE Genetics, Reykjavik, Iceland
Search for more papers by this authorUnnur Thorsteinsdottir PhD
DeCODE Genetics, Reykjavik, Iceland
University of Iceland, School of Medicine, Reykjavik, Iceland
Search for more papers by this authorCorresponding Author
Kari Stefansson MD, PhD
DeCODE Genetics, Reykjavik, Iceland
University of Iceland, School of Medicine, Reykjavik, Iceland
Solveig Gretarsdottir, deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland
Kari Stefansson, deCODe Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland
Search for more papers by this authorCorresponding Author
Solveig Gretarsdottir PhD
DeCODE Genetics, Reykjavik, Iceland
Solveig Gretarsdottir, deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland
Kari Stefansson, deCODe Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland
Search for more papers by this authorAndreas Gschwendtner MD
Department of Neurology, Klinikum of Grosshadern, Ludwig-Maximilians-Universität, München, Germany
Search for more papers by this authorKonstantinos Kostulas MD, PhD
Department of Neurology, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden
Search for more papers by this authorGregor Kuhlenbäumer MD
Department of Neurology and Leibniz-Institute for Atherosclerosis Research, University of Münster, Münster, Germany
Institute of Experimental Medicine, Molecular Neurobiology, University of Kiel, Kiel, Germany
Search for more papers by this authorSteve Bevan PhD
Department of Clinical Neuroscience, St. George's University of London, London, United Kingdom
Search for more papers by this authorDavid O. Arnar MD, PhD
Landspitali, University Hospital, Reykjavik, Iceland
Search for more papers by this authorGudmundur Thorgeirsson MD, PhD
Landspitali, University Hospital, Reykjavik, Iceland
Search for more papers by this authorEinar Mar Valdimarsson MD
Landspitali, University Hospital, Reykjavik, Iceland
Search for more papers by this authorSigurlaug Sveinbjörnsdottir MD
Landspitali, University Hospital, Reykjavik, Iceland
Search for more papers by this authorChristian Gieger PhD
Helmholtz Zentrum Munich, German Research Center for Environmental Health Institute of Epidemiology, Research for Environmental Health, Neuherberg, Germany
IBE Department of Epidemiology, Ludwig Maximilians University, Munich, Germany
Search for more papers by this authorKlaus Berger MD
Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
Search for more papers by this authorH-Erich Wichmann MD
Helmholtz Zentrum Munich, German Research Center for Environmental Health Institute of Epidemiology, Research for Environmental Health, Neuherberg, Germany
IBE Department of Epidemiology, Ludwig Maximilians University, Munich, Germany
Search for more papers by this authorJan Hillert MD
Department of Neurology, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden
Search for more papers by this authorHugh Markus MD
Department of Clinical Neuroscience, St. George's University of London, London, United Kingdom
Search for more papers by this authorJeffrey Robert Gulcher MD, PhD
DeCODE Genetics, Reykjavik, Iceland
Search for more papers by this authorE. Bernd Ringelstein MD
Department of Neurology and Leibniz-Institute for Atherosclerosis Research, University of Münster, Münster, Germany
Search for more papers by this authorMartin Dichgans MD
Department of Neurology, Klinikum of Grosshadern, Ludwig-Maximilians-Universität, München, Germany
Search for more papers by this authorDaniel Fannar Gudbjartsson PhD
DeCODE Genetics, Reykjavik, Iceland
Search for more papers by this authorUnnur Thorsteinsdottir PhD
DeCODE Genetics, Reykjavik, Iceland
University of Iceland, School of Medicine, Reykjavik, Iceland
Search for more papers by this authorCorresponding Author
Kari Stefansson MD, PhD
DeCODE Genetics, Reykjavik, Iceland
University of Iceland, School of Medicine, Reykjavik, Iceland
Solveig Gretarsdottir, deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland
Kari Stefansson, deCODe Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland
Search for more papers by this authorPotential conflict of interest: The authors Solveig Gretarsdottir, Gudmar Thorleifsson, Andrei Manolescu, Unnur Styrkarsdottir, Anna Helgadottir, Thorbjörg Jonsdottir, Hjördis Bjarnason, Jona Saemundsdottir, Stefan Palsson, Hilma Holm, Jeffery Robert Gulcher, Augustine Kong, Daniel Fannar Gudbjartsson, Unnur Thorsteinsdottir and Kari Stefansson are employees and/or shareholders of deCODE genetics.
Abstract
Objective
To find sequence variants that associate with the risk for ischemic stroke (IS), we performed a genome-wide association study.
Methods
We genotyped 1,661 Icelandic IS patients and 10,815 control subjects using the Infinium HumanHap300 chip (Illumina, San Diego, CA). A total of 310,881 single nucleotide polymorphisms (SNPs) were tested for association with IS, and the most significant signals were replicated in two large European IS sample sets (2,224 cases/2,583 control subjects). Two SNPs, rs2200733 and rs10033464, were tested further in additional European IS samples (2,327 patients and 16,760 control subjects).
Results
In the Icelandic samples and the two replication sets combined, rs2200733 associated significantly with cardioembolic stroke (CES) (odds ratio [OR], 1.54; p = 8.05 × 10−9). No other variants associated with IS or any of its subtypes. rs2200733 associated significantly with IS in all sample sets combined (OR, 1.26; p = 2.18 × 10−10), and both rs2200733 and its neighbour, rs10033464 associated strongly with CES (rs2200733: OR, 1.52; p = 5.8 × 10−12; rs10033464: OR, 1.27; p = 6.1 × 10−4). Interestingly, rs2200733 also showed significant association to IS not classified as CES.
Interpretation
We discovered that variants previously shown to associate with atrial fibrillation (AF), rs2200733 and rs10033464, significantly associated with IS, with the strongest risk for CES. The association with noncardiogenic stroke is intriguing and suggests that atrial fibrillation may be underdiagnosed in patients presenting with stroke. This discovery may have implications for workup and treatment of IS. Ann Neurol 2008;64:402–409
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
|---|---|
| ana_21480_sm_SupFig1.JPG812.5 KB | Supplementary Figure 1: Q-Q Plot of genome-wide association results for the 310.881 SNPs genotyped in the initial Icelandic stroke cases and controls. The blue points correspond to unadjusted results and the red points correspond to the results adjusted using the method of genomic control. The adjustment factors were 1.07 for ischemic, 1.04 for cardioembolic, 1.06 for large vessel, and 1.02 for small vessel stroke. |
| ana_21480_sm_SupTab1.doc438 KB | Supplementary Table 1. Association to ischemic stroke in the Icelandic discovery group and the replication groups from Sweden and Germany-S. |
| ana_21480_sm_SupTab2.doc437 KB | Supplementary Table 2. Association to cardioembolic stroke in the in the Icelandic discovery group and the replication groups from Sweden and Germany-S. |
| ana_21480_sm_SupTab3.doc437 KB | Supplementary Table 3. Association to large artery atherosclerosis in the Icelandic discovery group and the replication groups from Sweden and Germany-S. |
| ana_21480_sm_SupTab4.doc436.5 KB | Supplementary Table 4. Association to small vessel disease in the Icelandic discovery group and the replication groups from Sweden and Germany-S. |
| ana_21480_sm_SupTab5.doc78.5 KB | Supplementary Table 5. Association between rs7319076 and rs6065574 and Ischemic stroke |
| ana_21480_sm_SupTab6.doc53.5 KB | Supplementary Table 6. Association between rs2200733-T and rs1033464-T and the Ischemic TOAST subtypes other cause, more than one cause and unknown cause. |
| ana_21480_sm_SupTab7.doc31.5 KB | Supplementary Table 7. Heterogeneity P values |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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