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

Monday,2013-04-22 18:04 America/Los_Angeles — eenright
TitleGenetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies.
Publication TypeJournal Article
Year of Publication2012
AuthorsTraylor, M, Farrall, M, Holliday, EG, Sudlow, C, Hopewell, JC, Cheng, Y-C, Fornage, M, Ikram, AM, Malik, R, Bevan, S, Thorsteinsdottir, U, Nalls, MA, Longstreth, W, Wiggins, KL, Yadav, S, Parati, EA, DeStefano, AL, Worrall, BB, Kittner, SJ, Khan, MSaleem, Reiner, AP, Helgadottir, A, Achterberg, S, Fernandez-Cadenas, I, Abboud, S, Schmidt, R, Walters, M, Chen, W-M, E Ringelstein, B, O'Donnell, M, Ho, WKee, Pera, J, Lemmens, R, Norrving, B, Higgins, P, Benn, M, Sale, M, Kuhlenbäumer, G, Doney, ASF, Vicente, AM, Delavaran, H, Algra, A, Davies, G, Oliveira, SA, Palmer, CNA, Deary, I, Schmidt, H, Pandolfo, M, Montaner, J, Carty, C, de Bakker, PIW, Kostulas, K, Ferro, JM, van Zuydam, NR, Valdimarsson, E, Nordestgaard, BG, Lindgren, A, Thijs, V, Slowik, A, Saleheen, D, Paré, G, Berger, K, Thorleifsson, G, Hofman, A, Mosley, TH, Mitchell, BD, Furie, K, Clarke, R, Levi, C, Seshadri, S, Gschwendtner, A, Boncoraglio, GB, Sharma, P, Bis, JC, Gretarsdottir, S, Psaty, BM, Rothwell, PM, Rosand, J, Meschia, JF, Stefansson, K, Dichgans, M, Markus, HS
Corporate/Institutional AuthorsAustralian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2),, International Stroke Genetics Consortium,
JournalLancet Neurol
Volume11
Issue11
Pagination951-62
Date Published2012 Nov
ISSN1474-4465
KeywordsBrain Ischemia, Databases, Genetic, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Risk Factors, Stroke
Abstract<p><b>BACKGROUND: </b>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.</p><p><b>METHODS: </b>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.</p><p><b>FINDINGS: </b>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.</p><p><b>INTERPRETATION: </b>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.</p><p><b>FUNDING: </b>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).</p>
DOI10.1016/S1474-4422(12)70234-X
Alternate JournalLancet Neurol
PubMed ID23041239
PubMed Central IDPMC3490334
Grant ListN01HC55020 / HL / NHLBI NIH HHS / United States
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U01 HG005160 / HG / NHGRI NIH HHS / United States
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U01 HG004446 / HG / NHGRI NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
095626 / / Wellcome Trust / United Kingdom
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UL1 RR025005 / RR / NCRR NIH HHS / United States
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R56 AG020098 / AG / NIA NIH HHS / United States
/ / Medical Research Council / United Kingdom
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
G0500987 / / Medical Research Council / United Kingdom
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U01 HG004402 / HG / NHGRI NIH HHS / United States
U01 HG004424 / HG / NHGRI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
MR/K026992/1 / / Medical Research Council / United Kingdom
MC_U137686857 / / Medical Research Council / United Kingdom
N01HC55015 / HL / NHLBI NIH HHS / United States
R01 HL093029 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
G0601325 / / Medical Research Council / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268200782096C / HG / NHGRI NIH HHS / United States
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HHSN268201100005I / HL / NHLBI NIH HHS / United States
RP-PG-0606-1146 / / Department of Health / United Kingdom
090532 / / Wellcome Trust / United Kingdom
N01HC55016 / HL / NHLBI NIH HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
U01 HG005157 / HG / NHGRI NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
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HHSN268201100009C / HL / NHLBI NIH HHS / United States
OSRP2/1006 / / The Dunhill Medical Trust / United Kingdom
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
G0700704 / / Medical Research Council / United Kingdom
HHSN268201100007I / HL / NHLBI NIH HHS / United States
BB/F019394/1 / / Biotechnology and Biological Sciences Research Council / United Kingdom
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/ / Wellcome Trust / United Kingdom
N01 HC035129 / HC / NHLBI NIH HHS / United States
R56 AG023629 / AG / NIA NIH HHS / United States
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Z01 AG000954 / AG / NIA NIH HHS / United States

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