Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies.
Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies.
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DOI：
10.1016/s1474-4422(12)70234-x
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发表时间：
2012-11
期刊：
影响因子：
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通讯作者：
International Stroke Genetics Consortium
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作者：
Traylor M;Farrall M;Holliday EG;Sudlow C;Hopewell JC;Cheng YC;Fornage M;Ikram MA;Malik R;Bevan S;Thorsteinsdottir U;Nalls MA;Longstreth W;Wiggins KL;Yadav S;Parati EA;Destefano AL;Worrall BB;Kittner SJ;Khan MS;Reiner AP;Helgadottir A;Achterberg S;Fernandez-Cadenas I;Abboud S;Schmidt R;Walters M;Chen WM;Ringelstein EB;O'Donnell M;Ho WK;Pera J;Lemmens R;Norrving B;Higgins P;Benn M;Sale M;Kuhlenbäumer G;Doney AS;Vicente AM;Delavaran H;Algra A;Davies G;Oliveira SA;Palmer CN;Deary I;Schmidt H;Pandolfo M;Montaner J;Carty C;de Bakker PI;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;Australian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2);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;International Stroke Genetics Consortium
在缺血性脑卒中方面已经进行了多项全基因组关联研究（GWAS），确定了一些与该疾病相关的基因位点，但样本量为3500例或更少。我们建立了METASTROKE合作项目，目的是验证先前GWAS中的关联，并通过对缺血性脑卒中和其亚型的GWAS数据集进行荟萃分析来确定新的基因关联。
我们对来自15个缺血性脑卒中队列的数据进行了荟萃分析，这些队列共有12389名缺血性脑卒中患者和62004名对照，均为欧洲血统。对于在METASTROKE中达到全基因组显著水平的关联，我们进行了进一步分析，以每个相关区域的首要单核苷酸多态性为条件。在13347例患者和29083名对照中对新的提示性信号进行了重复验证。
我们验证了先前在PITX2（p = 2.8×10⁻¹⁶）和ZFHX3（p = 2.28×10⁻⁸）附近与心源性栓塞性脑卒中的关联，以及在9p21位点（p = 3.32×10⁻⁵）和HDAC9（p = 2.03×10⁻¹²）与大血管性脑卒中的关联。此外，我们验证了所有关联都是亚型特异性的。在关联达到全基因组显著水平的三个区域（PITX2、ZFHX3和HDAC9）进行的条件分析表明，每个区域的所有信号都可归因于一种风险单倍型。我们还确定了12个p < 5×10⁻⁶的潜在新位点。然而，我们无法在重复验证队列中重复这些新的关联中的任何一个。
我们的结果表明，尽管与对照相比，在缺血性脑卒中患者中可以检测到基因变异，但我们能够确认的所有关联都是针对一种脑卒中亚型的。这一发现有两个含义。首先，为了使缺血性脑卒中的遗传学研究取得最大成功，需要详细的脑卒中亚型分类。其次，不同的遗传病理生理机制似乎与不同的脑卒中亚型相关。
英国惠康信托基金、英国医学研究理事会（MRC）、澳大利亚国家卫生与医学研究理事会、美国国立卫生研究院（NIH），包括美国国家心肺血液研究所（NHLBI）、美国国家衰老研究所（NIA）、美国国家人类基因组研究所（NHGRI）以及美国国家神经疾病和脑卒中研究所（NINDS）
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. 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. 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. 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. 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).