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

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, W.T., 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, Kee, Weang, 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, including Jonathan Golledge, 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, and Markus, Hugh S. (2012) Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies. Lancet Neurology, 11 (11). pp. 951-962.

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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.

Item ID: 39258
Item Type: Article (Research - C1)
ISSN: 1474-4465
Additional Information:

"Open Access funded by Medical Research Council"

Funders: Wellcome Trust (WT), UK Medical Research Council (MRC), National Health and Medical Research Council (NHMRC), National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI), National Institute on Aging (NIA), National Human Genome Research Institute (NHGRI), National Institute of Neurological Disorders and Stroke (NINDS)
Date Deposited: 04 Aug 2016 02:11
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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