Genetic Heritability of Ischemic Stroke and the Contribution of Previously Reported Candidate Gene and Genomewide Associations
Genetic Heritability of Ischemic Stroke and the Contribution of Previously Reported Candidate Gene and Genomewide Associations
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DOI：
10.1161/strokeaha.112.665760
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发表时间：
2012-12-01
期刊：
影响因子：
8.3
通讯作者：
Markus, Hugh S.
中科院分区：
文献类型：
--
作者：
Bevan, Steve;Traylor, Matthew;Markus, Hugh S.
背景和目的-遗传学对卒中风险的影响，以及不同卒中亚型的影响是否不同，仍然不确定。全基因组复杂性状分析允许从全基因组关联研究（GWAS）数据评估遗传力。以前的候选基因研究已经确定了许多与斯托克的关联，但这些是否重要需要在大型独立数据集中进行复制。GWAS数据集提供了一个强大的资源来执行replicationstudy. Methods，我们应用全基因组复杂性状分析的GWAS数据集的3752缺血性中风和5972控制和确定所有缺血性中风和最常见的亚型：大血管疾病，小血管疾病，心源性栓塞性中风的遗传性。通过系统回顾，我们确定了先前的候选基因和GWAS与卒中的相关性，以及先前的GWAS与相关心血管表型心肌梗死、房颤和颈动脉内膜中层厚度的相关性。结果：所有缺血性卒中的遗传率为37.9%。中风亚型的遗传性差异显著，大血管疾病为40.3%，心源性栓塞为32.6%，但小血管疾病的遗传性较低（16.1%）。经多重检验严格校正后，先前报道的候选基因均不显著。与此相反，来自相关的心血管GWAS研究的3个位点是显著的：PHACTR 1在大血管疾病中P=2.63e-6），PITX 2在心源性栓塞性卒中中P=4.78e-8），ZFHX 3在心源性栓塞性卒中中P=5.50e-7）。以前的候选基因关联对这种遗传性贡献很小，但GWAS在相关心血管表型中的研究正在确定强有力的关联。遗传性数据和GWAS的数据表明，检测其他相关性将取决于仔细的中风亚型分型。中风2012; 43：3161-3167）。
Background and Purpose-The contribution of genetics to stroke risk, and whether this differs for different stroke subtypes, remains uncertain. Genomewide complex trait analysis allows heritability to be assessed from genomewide association study GWAS) data. Previous candidate gene studies have identified many associations with stoke but whether these are important requires replication in large independent data sets. GWAS data sets provide a powerful resource to perform replication studies.Methods-We applied genomewide complex trait analysis to a GWAS data set of 3752 ischemic strokes and 5972 controls and determined heritability for all ischemic stroke and the most common subtypes: large-vessel disease, small-vessel disease, and cardioembolic stroke. By systematic review we identified previous candidate gene and GWAS associations with stroke and previous GWAS associations with related cardiovascular phenotypes myocardial infarction, atrial fibrillation, and carotid intima-media thickness). Fifty associations were identified.Results-For all ischemic stroke, heritability was 37.9%. Heritability varied markedly by stroke subtype being 40.3% for large-vessel disease and 32.6% for cardioembolic but lower for small-vessel disease 16.1%). No previously reported candidate gene was significant after rigorous correction for multiple testing. In contrast, 3 loci from related cardiovascular GWAS studies were significant: PHACTR1 in large-vessel disease P=2.63e-6), PITX2 in cardioembolic stroke P=4.78e(-8)), and ZFHX3 in cardioembolic stroke P=5.50e(-7)).Conclusions-There is substantial heritability for ischemic stroke, but this varies for different stroke subtypes. Previous candidate gene associations contribute little to this heritability, but GWAS studies in related cardiovascular phenotypes are identifying robust associations. The heritability data, and data from GWAS, suggest detecting additional associations will depend on careful stroke subtyping. Stroke. 2012; 43: 3161-3167.)