Disproportionate Contributions of Select Genomic Compartments and Cell Types to Genetic Risk for Coronary Artery Disease.
Disproportionate Contributions of Select Genomic Compartments and Cell Types to Genetic Risk for Coronary Artery Disease.
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DOI：
10.1371/journal.pgen.1005622
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发表时间：
2015-10
期刊：
影响因子：
4.5
通讯作者：
Do R
中科院分区：
文献类型：
--
作者：
Won HH;Natarajan P;Dobbyn A;Jordan DM;Roussos P;Lage K;Raychaudhuri S;Stahl E;Do R
大型全基因组关联研究已经确定了许多与心肌梗死(MI)和冠状动脉疾病(CAD)风险相关的遗传位点。与此同时，国家卫生研究院(NIH)路线图表观基因组学项目和DNA元素百科全书(ENCODE)联盟等努力提供了关于人类基因组功能元素的前所未有的数据。在本研究中，我们系统地研究了与这种复杂疾病相关的遗传变异和它们对基因功能的影响之间的生物学联系。首先，我们根据基因组区段来检验MI/CAD的遗传度。我们观察到，位于邻近调控区域的单核苷酸多态(SNPs)表现出显著的多源性，并贡献了MI/CAD遗传力的59%-71%。其次，我们发现这些SNPs所解释的多基因和遗传性在特定细胞类型中富含组蛋白修饰标记。第三，我们发现从大规模GWAS研究中发现的45个与MI/CAD相关的SNPs存在于基因组的某些功能元件中，特别是在活性增强子和启动子区域。最后，我们观察到这种信号在不同细胞类型之间的显著异质性，在脂肪核以及脑和脾细胞类型中观察到强烈的信号。这些结果表明，MI/CAD的遗传病因在很大程度上是由人类基因组中组织特异性的调节扰动所解释的。冠状动脉疾病(CAD)及其亚组分心肌梗死(MI)是全球范围内导致疾病和死亡的主要原因。大规模的遗传关联研究已经确定了许多与冠心病和心肌梗死相关的遗传标记。然而，很难确定这些标记物的确切功能效应。此外，尚不清楚哪些细胞类型在MI/CAD的发展中具有重要的生物学意义。通过将大规模遗传关联研究的结果与功能基因组注释相交叉，我们发现位于基因组区域的调控基因表达的遗传标记构成了MI/CAD遗传风险的很大比例。此外，我们发现这种影响在某些组织中尤其强烈，包括脂肪组织、脑组织和脾组织。这些结果强调了组织特异性调控机制在心肌梗死/冠心病的遗传病因中的作用。
Large genome-wide association studies (GWAS) have identified many genetic loci associated with risk for myocardial infarction (MI) and coronary artery disease (CAD). Concurrently, efforts such as the National Institutes of Health (NIH) Roadmap Epigenomics Project and the Encyclopedia of DNA Elements (ENCODE) Consortium have provided unprecedented data on functional elements of the human genome. In the present study, we systematically investigate the biological link between genetic variants associated with this complex disease and their impacts on gene function. First, we examined the heritability of MI/CAD according to genomic compartments. We observed that single nucleotide polymorphisms (SNPs) residing within nearby regulatory regions show significant polygenicity and contribute between 59–71% of the heritability for MI/CAD. Second, we showed that the polygenicity and heritability explained by these SNPs are enriched in histone modification marks in specific cell types. Third, we found that a statistically higher number of 45 MI/CAD-associated SNPs that have been identified from large-scale GWAS studies reside within certain functional elements of the genome, particularly in active enhancer and promoter regions. Finally, we observed significant heterogeneity of this signal across cell types, with strong signals observed within adipose nuclei, as well as brain and spleen cell types. These results suggest that the genetic etiology of MI/CAD is largely explained by tissue-specific regulatory perturbation within the human genome. Coronary artery disease (CAD) and its subcomponent, myocardial infarction (MI), are the leading causes of infirmity and death worldwide. Large-scale genetic association studies have identified many genetic markers associated with CAD and MI. However, it has been difficult to determine the precise functional effects of these markers. Furthermore, it is unknown which cell types are biologically important in the development of MI/CAD. By intersecting findings from large-scale genetic association studies with functional genomic annotations, we show that genetic markers located in genomic regions that regulate expression of genes make up a large proportion of the genetic risk of MI/CAD. Furthermore, we show that this effect is particularly strong in certain tissues, including adipose, brain and spleen tissue. These results highlight the role of tissue-specific regulatory mechanisms in the genetic etiology of MI/CAD.