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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; Fomage, Myriam; Ikram, M. Arfan; Malik, Rainer and Bevan, Steve, et al. (2012) In Lancet Neurology 11(11). p.951-962
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 nudeotide polymorphism in every... (More)
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 nudeotide 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=2.8x10(-16)) and ZFHX3 (p=2.28x10(-8)), and for large-vessel stroke at a 9p21 locus (p=3.32x10(-5)) and HDAC9 (p=2.03x10(-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<5x10(-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. (Less)
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Lancet Neurology
volume
11
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11
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951 - 962
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Lancet Ltd
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  • wos:000310422200011
  • scopus:84867645825
ISSN
1474-4465
DOI
10.1016/S1474-4422(12)70234-X
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English
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@article{b7a2d19c-8b4e-45f6-af7c-bacdb01ae8a9,
  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 nudeotide 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=2.8x10(-16)) and ZFHX3 (p=2.28x10(-8)), and for large-vessel stroke at a 9p21 locus (p=3.32x10(-5)) and HDAC9 (p=2.03x10(-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&lt;5x10(-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.},
  author       = {Traylor, Matthew and Farrall, Martin and Holliday, Elizabeth G. and Sudlow, Cathie and Hopewell, Jemma C. and Cheng, Yu-Ching and Fomage, Myriam and Ikram, M. Arfan and Malik, Rainer and Bevan, Steve and Thorsteinsdottir, Unnur and Nalls, Mike A. and Longstreth, W. T. and Wiggins, Kerri L. and Yadav, Sunaina and Parati, Eugenio A. and DeStefano, Anita L. and Worrall, Bradford B. and Kittner, Steven and Khan, Muhammad Saleem and Reiner, Alex P. and Helgadottir, Anna and Achterberg, Sefanja and Fernandez-Cadenas, Israel and Abboud, Sherine and Schmidt, Reinhold and Walters, Matthew and Chen, Wei-Min and Ringelstein, E. Bernd and O'Donnell, Martin and Ho, Weang Kee and Pera, Joanna and Lemmens, Robin and Norrving, Bo and Higgins, Peter and Benn, Marianne and Sale, Michele and Kuhlenbaeumer, Gregor and Doney, Alexander S. F. and Vicente, Astrid M. and Delavaran, Hossein and Algra, Ale and Davies, Gail and Oliveira, Sofia A. and Palmer, Colin N. A. and Deary, Ian and Schmidt, Helena and Pandolfo, Massimo and Montaner, Joan and Carty, Cara and de Bakker, Paul I. W. and Kostulas, Konstantinos and Ferro, Jose M. and van Zuydam, Natalie R. and Valdimarsson, Einar and Nordestgaard, Borge G. and Lindgren, Arne and Thijs, Vincent and Slowik, Agnieszka and Saleheen, Danish and Pare, Guillaume and Berger, Klaus and Thorleifsson, Gudmar and Hofman, Albert and Mosley, Thomas H. and Mitchell, Braxton D. and Furie, Karen and Clarke, Robert and Levi, Christopher and Seshadri, Sudha and Gschwendtner, Andreas and Boncoraglio, Giorgio B. and Sharma, Pankaj and Bis, Joshua C. and Gretarsdottir, Solveig and Psaty, Bruce M. and Rothwell, Peter M. and Rosand, Jonathan and Meschia, James F. and Stefansson, Kan and Dichgans, Martin and Markus, Hugh S.},
  issn         = {1474-4465},
  language     = {eng},
  number       = {11},
  pages        = {951--962},
  publisher    = {Lancet Ltd},
  series       = {Lancet Neurology},
  title        = {Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies},
  url          = {http://dx.doi.org/10.1016/S1474-4422(12)70234-X},
  volume       = {11},
  year         = {2012},
}