Effect of genetic variants associated with plasma homocysteine levels on stroke risk.
OBJECTIVE
Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes.


METHODS
Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs.


RESULTS
One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes.


CONCLUSIONS
This study found several potential associations with IS and its subtypes: an association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS.
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.). i.cotlarciuc@imperial.ac.uk.
Ioana
I
Cotlarciuc
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Rainer
R
Malik
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Elizabeth G
EG
Holliday
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Kourosh R
KR
Ahmadi
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Guillaume
G
Paré
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Bruce M
BM
Psaty
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Myriam
M
Fornage
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Nazeeha
N
Hasan
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Paul E
PE
Rinne
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
M Arfan
MA
Ikram
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Hugh S
HS
Markus
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Jonathan
J
Rosand
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Braxton D
BD
Mitchell
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Steven J
SJ
Kittner
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
James F
JF
Meschia
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Joyce B J
JB
van Meurs
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Andre G
AG
Uitterlinden
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Bradford B
BB
Worrall
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Martin
M
Dichgans
From the Department of Medicine, Imperial College Cerebrovascular Research Unit, Imperial College London, London, United Kingdom (I.C., N.H., P.E.R., P.S.); Institute for Stroke and Dementia Research, Medical Centre, Klinikum der Universität München, Ludwig-Maximilians-University, Munich, Germany (R.M., M.D.); Center for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (E.G.H.); Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom (K.R.A.); Department of Pathology, McMaster University, Hamilton, Ontario, Canada (G.P.); Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle (B.M.P.); Group Health Research Institute, Group Health, Seattle, WA (B.M.P.); University of Texas Health Science Center at Houston (M.F.); Departments of Epidemiology, Neurology, and Radiology (M.A.I.) and Internal Medicine (J.B.J.v.M., A.G.U.), Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (H.S.M.); Department of Neurology (J.R.) and Center for Human Genetic Research (J.R.), Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (J.R.); Veterans Affairs Medical Center, Baltimore, MD (B.D.M., S.J.K.); Departments of Medicine (B.D.M., S.J.K.) and Neurology (S.J.K.), University of Maryland School of Medicine, Baltimore; Department of Neurology, Mayo Clinic, Jacksonville, FL (J.F.M.); Departments of Neurology (B.B.W.) and Public Health Science (B.B.W.), University of Virginia, Charlottesville; and Munich Cluster for Systems Neurology, Munich, Germany (M.D.).
Pankaj
P
Sharma
D002545:Brain Ischemia / Q000097:blood / Q000235:genetics*; D015331:Cohort Studies; D005060:Europe; D056726:Genetic Association Studies; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D016678:Genome / Q000235:genetics; D006710:Homocysteine / Q000097:blood / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012306:Risk; D020521:Stroke / Q000097:blood / Q000235:genetics*
D006710:Homocysteine
genetic association studies; genetic risk score; homocysteine; stroke