Title: Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies
Authors: Traylor, Matthew
Farrall, Martin
Holliday, Elizabeth G
Sudlow, Cathie
Hopewell, Jemma C
Cheng, Yu-Ching
Fornage, Myriam
Ikram, M Arfan
Malik, Rainer
Bevan, Steve
Thorsteinsdottir, Unnur
Nalls, Mike A
Longstreth, Wt
Wiggins, Kerri L
Yadav, Sunaina
Parati, Eugenio A
Destefano, Anita L
Worrall, Bradford B
Kittner, Steven J
Khan, Muhammad Saleem
Reiner, Alex P
Helgadottir, Anna
Achterberg, Sefanja
Fernandez-Cadenas, Israel
Abboud, Sherine
Schmidt, Reinhold
Walters, Matthew
Chen, Wei-Min
Ringelstein, E Bernd
O'Donnell, Martin
Ho, Weang Kee
Pera, Joanna
Lemmens, Robin
Norrving, Bo
Higgins, Peter
Benn, Marianne
Sale, Michele
Kuhlenbäumer, Gregor
Doney, Alexander S F
Vicente, Astrid M
Delavaran, Hossein
Algra, Ale
Davies, Gail
Oliveira, Sofia A
Palmer, Colin N A
Deary, Ian
Schmidt, Helena
Pandolfo, Massimo
Montaner, Joan
Carty, Cara
de Bakker, Paul I W
Kostulas, Konstantinos
Ferro, Jose M
van Zuydam, Natalie R
Valdimarsson, Einar
Nordestgaard, Børge G
Lindgren, Arne
Thijs, Vincent
Slowik, Agnieszka
Saleheen, Danish
Paré, Guillaume
Berger, Klaus
Thorleifsson, Gudmar
The Australian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2)
Hofman, Albert
Mosley, Thomas H
Mitchell, Braxton D
Furie, Karen
Clarke, Robert
Levi, Christopher
Seshadri, Sudha
Gschwendtner, Andreas
Boncoraglio, Giorgio B
Sharma, Pankaj
Bis, Joshua C
Gretarsdottir, Solveig
Psaty, Bruce M
Rothwell, Peter M
Rosand, Jonathan
Meschia, James F
Stefansson, Kari
Dichgans, Martin
Markus, Hugh S ×
on behalf of the International Stroke Genetics Consortium #
Issue Date: Nov-2012
Publisher: Lancet Pub. Group
Series Title: The Lancet Neurology vol:11 issue:11 pages:951-962
Article number: S1474-4422(12)70234-X
Abstract: BACKGROUND: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. METHODS: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls. FINDINGS: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10(-6). However, we were unable to replicate any of these novel associations in the replication cohort. INTERPRETATION: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes. FUNDING: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).
ISSN: 1474-4422
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Neurobiology
× corresponding author
# (joint) last author

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