Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls.
Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls.
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16-664 例病例和 32-792 例对照中与中风相关的基因位点的亚型特异性。
DOI：
10.1161/circgen.118.002338
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发表时间：
2019
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作者：
Traylor,Matthew;Anderson,ChristopherD;Rutten-Jacobs,LoesCA;Falcone,GuidoJ;Comeau,MaryE;Ay,Hakan;Sudlow,CathieLM;Xu,Huichun;Mitchell,BraxtonD;Cole,JohnW;Rexrode,Kathryn;Jimenez-Conde,Jordi;Schmidt,Reinhold;Grewal,RajiP;
背景全基因组关联研究已经确定了与中风相关的多个位点。然而，受影响的具体中风亚型以及基因座是否影响缺血性和出血性中风仍然未知。对于与中风相关的基因座，我们的目的是推断可能受影响的中风亚型组合，并在此过程中评估这些基因座对中风亚型的同质影响程度。方法我们使用模型选择，对 16~664 名中风病例和 32~792 名欧洲血统对照进行贝叶斯多项回归，以确定最有可能受已发表的全基因组中风关联的基因座影响的中风亚型组合。根据 2 个常用的中风分类系统 TOAST（Org 10172 急性中风治疗试验）和中风病因分类对病例进行亚型分类。所有个体的基因型均归于单倍型参考联盟 1.1 小组。结果考虑了 16 个基因座进行分析。 7 个位点同时影响出血性和缺血性中风，其中 3 个位点影响 TOAST 和中风病因分类下的缺血性和出血性亚型。根据中风的病因分类，有 4 个基因座影响小血管中风和脑出血。 EDNRA基因座对缺血性和出血性中风表现出相反的作用。没有预测基因座会在同一方向上影响所有中风亚型，只有一个基因座 (12q24) 预计会影响所有缺血性中风亚型。 结论 中风相关基因座对中风亚型的影响普遍存在异质性，反映了不同的因果路径。然而，出血性卒中和缺血性卒中之间存在重叠，这可能反映了易患小血管动脉病的共同病理生物学。中风是一种复杂的异质性疾病，需要量身定制的分析策略来破译遗传机制。
BackgroundGenome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes.MethodsWe performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel.ResultsSixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. AnEDNRAlocus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes.ConclusionsHeterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.