SynthesisThe Lancet. Neurology2012
Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies.
Synthesis in The Lancet. Neurology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 274 papers, 15 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
274 citing papers in PubMed, 15 syntheses or guidelines pooled it, 484 citations in OpenAlex.
- The Role of Genetics in Stroke Risk and Outcome: A Review of Current Evidence.Brain and behavior · 2025Pooled it
- Pooled it
- Case-Control Study and Meta-Analysis of the Association Between LIPG rs9958947 SNP and Stroke Risk.Journal of molecular neuroscience : MN · 2021Pooled it
- Microbiome and ischemic stroke: A systematic review.PloS one · 2021Pooled it
- Pooled it
- Adherence to the Mediterranean diet and risk of stroke and stroke subtypes.European journal of epidemiology · 2019Pooled it
- Genetic susceptibility to cerebrovascular disease: A systematic review.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2018Pooled it
- The association between HDAC9 gene polymorphisms and stroke risk in the Chinese population: A meta-analysis.Scientific reports · 2017Pooled it
- Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension.Nature genetics · 2016Pooled it
- The association between vascular endothelial growth factor gene polymorphisms and stroke: a meta-analysis.Brain and behavior · 2016Pooled it
- Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies.The Lancet. Neurology · 2016Pooled it
- Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration.Neurology · 2016Pooled it
- Pooled it
- Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2.Stroke · 2016Pooled it
- Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans.Stroke · 2015Pooled it
- Trial
- Trial
- Epigenome-wide association of myocardial infarction with DNA methylation sites at loci related to cardiovascular disease.Clinical epigenetics · 2017Trial
- Cross-phenotype and cross-species integrative genomic prioritization of FOXF2 and FOXC1 at a cerebral small vessel disease locus.Functional & integrative genomics · 2026Article
- Single-nucleus analysis of the adult human olfactory epithelium uncovers shared neurogenesis programs with the brain.Nature communications · 2026Article
214 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
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- Erratum issuedCorrections.2015
Authors and funding
84 authors at 20 institutions in 17 countries.
Funding
Abstract
backgroundVarious 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.
methodsWe 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.
findingsWe 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.
interpretationOur 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.
fundingWellcome 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).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.