Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): A meta-analysis of genome-wide association studies

Matthew Traylor, Martin Farrall, Elizabeth G. Holliday, Cathie Sudlow, Jemma C. Hopewell, Yu Ching Cheng, Myriam Fornage, M. Arfan Ikram, Rainer Malik, Steve Bevan, Unnur Thorsteinsdottir, Mike A. Nalls, W. T. Longstreth, Kerri L. Wiggins, Sunaina Yadav, Eugenio A. Parati, Anita L. DeStefano, Bradford B. Worrall, Steven J. Kittner, Muhammad Saleem KhanAlex P. Reiner, Anna Helgadottir, Sefanja Achterberg, Israel Fernandez-Cadenas, Sherine Abboud, Reinhold Schmidt, Matthew Walters, Wei Min Chen, E. Bernd Ringelstein, Martin O'Donnell, Weang Kee Ho, Joanna Pera, Robin Lemmens, Bo Norrving, Peter Higgins, Marianne Benn, Michele Sale, Gregor Kuhlenbäumer, Alexander S.F. Doney, Astrid M. Vicente, Hossein Delavaran, Ale Algra, Gail Davies, Sofia A. Oliveira, Colin N.A. Palmer, Ian Deary, Helena Schmidt, Massimo Pandolfo, Joan Montaner, Cara Carty, Paul I.W. de Bakker, Konstantinos Kostulas, Jose M. Ferro, Natalie R. van Zuydam, Einar Valdimarsson, Børge G. Nordestgaard, Arne Lindgren, Vincent Thijs, Agnieszka Slowik, Danish Saleheen, Guillaume Paré, Klaus Berger, Gudmar Thorleifsson, Albert Hofman, Thomas H. Mosley, Braxton D. Mitchell, Karen Furie, Robert Clarke, Christopher Levi, Sudha Seshadri, Andreas Gschwendtner, Giorgio B. Boncoraglio, Pankaj Sharma, Joshua C. Bis, Solveig Gretarsdottir, Bruce M. Psaty, Peter M. Rothwell, Jonathan Rosand, James F. Meschia, Kari Stefansson, Martin Dichgans, Hugh S. Markus*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

361 Citations (Scopus)


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).

Original languageEnglish
Pages (from-to)951-962
Number of pages12
JournalThe Lancet Neurology
Issue number11
Publication statusPublished - Nov 2012


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