The discovery sample consisted of 15 cohorts of patients with ischaemic stroke who were of European ancestry from Europe, North America, and Australia, together with controls of matched ancestry. All studies used a case-control methodology. Most participating studies were cross-sectional, whereas four were in large, prospective, population-based cohorts (table 1).
Description of cohorts used in analysis by study population
Number of cases
Number of CS cases
Number of LVD cases
Number of SVD cases
Number of controls
Ancestry
Study design
Genotyping
Discovery cohorts
ARIC
385
93
31
63
8803
European
Population-based
Affymetrix 6.0
ASGC
1162
240
421
310
1244
European
Cross-sectional
Illumina 610
BRAINS
361
29
120
97
444
European
Cross-sectional
Illumina 660
CHS
454
147
..
73
2817
European
Population-based
Illumina 370
deCODE
2391
399
255
240
26 970
European
Cross-sectional
Illumina 317/370
FHS
171
48
..
..
4164
European
Population-based
Affymetrix 550
GEOS
448
90
37
54
498
European
Cross-sectional
Illumina HumanOmni1
HPS
578
..
..
..
468
European
Cross-sectional
Illumina 610
HVH
566
88
61
173
1290
European
Cross-sectional
Illumina 370
ISGS/SWISS
1070
247
229
201
2329
European
Cross-sectional
Illumina 550/610/660
MGH-GASROS
516
169
95
38
1202
European
Cross-sectional
Affymetrix 6.0
Milano
372
25
74
65
407
European
Cross-sectional
Illumina 610/660
Rotterdam
367
..
..
..
5396
European
Population-based
Illumina 550
WTCCC2-Munich
1174
330
346
106
797
European
Cross-sectional
Illumina 660
WTCCC2-UK
2374
460
498
474
5175
European
Cross-sectional
Illumina 660
Total (discovery)
12 389
2365
2167
1894
62 004
..
..
..
Replication cohorts
Barcelona
439
179
110
150
404
European
Cross-sectional
Sequenom
BSS
225
11
93
90
312
European
Cross-sectional
Sequenom
Copenhagen
730
..
..
..
1545
European
Cross-sectional
TaqMan
ESS
276
40
20
69
940
European
Cross-sectional
TaqMan/Illumina 610
Glasgow
675
125
91
150
940
European
Cross-sectional
Sequenom/Illumina 610
Go-Darts*
737
130
259
..
8424
European
Cross-sectional
Affymetrix 6.0/Illumina Cardio-metabochip
Graz
657
116
108
207
848
European
Cross-sectional
Sequenom/Illumina 610
Interstroke*
872
143
198
238
926
European
Cross-sectional
Illumina Cardio-metabochip
Krakow
1235
377
152
171
584
European
Cross-sectional
Sequenom
Leuven
458
195
83
63
391
European
Cross-sectional
Sequenom
Lund
424
140
21
94
466
European
Cross-sectional
Sequenom
Munster
1232
478
528
224
1053
European
Cross-sectional
Sequenom
Portugal
539
..
..
..
507
European
Cross-sectional
Sequenom
RACE (Pakistan)*
1322
225
195
189
1143
Pakistani
Cross-sectional
Illumina 660
SMART
623
30
368
195
6712
European
Population-based
Sequenom
Sweden
876
157
177
75
742
European
Cross-sectional
Sequenom
VISP*
1725
..
..
..
1047
European
Cross-sectional
Illumina HumanOmni1
WHI*
302
42
31
78
2099
European
Population-based
Illumina Omni-Quad
Total (replication)
13 347
2388
2434
1993
29 083
..
..
..
CS=cardioembolic stroke. LVD=large-vessel disease. SVD=small-vessel disease. ARIC=The Atherosclerosis Risk in Communities study. ASGC=Australian Stroke Genetics Collabarative. BRAINS=Bio-Repository of DNA in stroke. CHS=Cardiovascular Health Study. FHS=Framingham Heart Study. GEOS=Genetics of Early-Onset Stroke. HPS=Heart Protection Study. HVH=The Heart and Vascular Health Study. ISGS/SWISS=The Ischemic Stroke Genetics Study/Sibling with Ischaemic Stroke Study. MGH-GASROS=The MGH Genes Affecting Stroke Risk and Outcome Study. WTCCC2-Munich=The Wellcome Trust Case-Control Consortium II Munich. WTCCC2-UK=The Wellcome Trust Case-Control Consortium II UK. BSS=Belgium Stroke Study. ESS=Edinburgh Stroke Study. Go-Darts=Genetics of Diabetes Audit and Research in Tayside Study. RACE=Risk Assessment of Cerebrovascular Events Study, Pakistan. SMART=Second Manifestations of ARTerial disease. VISP=The Vitamin Intervention for Stroke Prevention Trial. WHI=The Women's Health Initiative.
Contributed genome-wide data.
Additionally, 18 cohorts were analysed in the replication phase. These cohorts were included for replication only, most did not have GWAS data available; and those with GWAS data were not available at the time of the discovery analysis. 17 of the included cohorts contained individuals of solely European ancestry, and one contained individuals of Pakistani ancestry (table 1). Most cohorts (16) were cross-sectional, whereas two were population-based. The appendix includes detailed descriptions of the design and clinical characteristics of the participating studies. Stroke was defined as a typical clinical syndrome with radiological confirmation. Stroke subtyping was done with the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system.18 Where subtyping was done, brain CT or MRI was undertaken for more than 95% of cases in all the discovery cohorts. Participating studies were approved by relevant institutional review boards, and all participants gave written or oral consent for study participation, including genetic research, as approved by the local institutional body.
Traylor M., Farrall M., Holliday E.G., Sudlow C., Hopewell J.C., Cheng Y.C., Fornage M., Ikram M.A., Malik R., Bevan S., Thorsteinsdottir U., Nalls M.A., Longstreth W., Wiggins K.L., Yadav S., Parati E.A., DeStefano A.L., Worrall B.B., Kittner S.J., Khan M.S., Reiner A.P., Helgadottir A., Achterberg S., Fernandez-Cadenas I., Abboud S., Schmidt R., Walters M., Chen W.M., Ringelstein E.B., O'Donnell M., Ho W.K., Pera J., Lemmens R., Norrving B., Higgins P., Benn M., Sale M., Kuhlenbäumer G., Doney A.S., Vicente A.M., Delavaran H., Algra A., Davies G., Oliveira S.A., Palmer C.N., Deary I., Schmidt H., Pandolfo M., Montaner J., Carty C., de Bakker P.I., Kostulas K., Ferro J.M., van Zuydam N.R., Valdimarsson E., Nordestgaard B.G., Lindgren A., Thijs V., Slowik A., Saleheen D., Paré G., Berger K., Thorleifsson G., Hofman A., Mosley T.H., Mitchell B.D., Furie K., Clarke R., Levi C., Seshadri S., Gschwendtner A., Boncoraglio G.B., Sharma P., Bis J.C., Gretarsdottir S., Psaty B.M., Rothwell P.M., Rosand J., Meschia J.F., Stefansson K., Dichgans M, & Markus H.S. (2012). Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies. The Lancet. Neurology, 11(11), 951-962.
Corresponding Organization : St George's, University of London
Other organizations :
University of Oxford, Wellcome Centre for Human Genetics, Hunter Medical Research Institute, University of Edinburgh, University of Maryland, Baltimore, The University of Texas Health Science Center at Houston, Netherlands Consortium for Healthy Ageing, Erasmus MC, Munich Cluster for Systems Neurology, Ludwig-Maximilians-Universität München, University of Iceland, deCODE Genetics (Iceland), National Institute on Aging, University of Washington, Imperial College London, Fondazione IRCCS Istituto Neurologico Carlo Besta, Istituti di Ricovero e Cura a Carattere Scientifico, Boston University, University of Virginia, Veterans Health Administration, Fred Hutch Cancer Center, University Medical Center Utrecht, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Medical University of Graz, University of Glasgow, University of Münster, Ollscoil na Gaillimhe – University of Galway, University of Cambridge, Jagiellonian University, KU Leuven, Lund University, Skåne University Hospital, University of Copenhagen, Herlev Hospital, Copenhagen University Hospital, Ninewells Hospital, University of Dundee, National Institute of Health Dr. Ricardo Jorge, University of Lisbon, Broad Institute, Brigham and Women's Hospital, Harvard University, Karolinska University Hospital, Karolinska Institutet, Hospital de Santa Maria, Reykjavík University, National University Hospital of Iceland, Bispebjerg Hospital, University of Pennsylvania, Center for Non-Communicable Diseases, McMaster University, University of Mississippi Medical Center, Jackson Memorial Hospital, Massachusetts General Hospital, Group Health Cooperative, Kaiser Permanente Washington Health Research Institute, Center for Human Genetics, Mayo Clinic in Florida, WinnMed
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