Exploring the role of genomic copy number variation in cardiovascular disease risk

项目摘要 心血管疾病是世界范围内和美国国内的主要死亡原因。这些 疾病是可以遗传的，然而，这种遗传性中有很大一部分仍然无法解释 目前的关联研究。例如，最近一项关于冠心病(CAD)的研究发现，常见的 SNPs只能解释一半的冠心病遗传性。这种“遗漏的遗传性”可以解释为当前的 关注心血管疾病遗传结构中的单核苷酸多态。我提议 研究拷贝数变异(CNV)在心血管疾病中的作用。 首先，我将开发新的敏感方法，以便能够检测到更小、更多的CNV 使用基因阵列数据的个体，这是可获得最广泛的遗传数据形式之一。我要用这个 方法调用现有最大的生物库之一UK Biobank中的CNV。这将生成一个大型数据库 它的独特之处在于它为研究人员提供了检测CNV和心血管疾病之间的联系的能力。 第二，使用这个大型数据库，我将测试CNV和心血管疾病之间的联系， 可能导致CNV-以前未知的疾病关联。最后，我将调查CNV的范围 遗传性心血管疾病患者之间的负担以及这种负担是如何在缺失之间分配的 和复制，以及不同跨度和频率的CNV。探索和刻画CNV的作用 将进一步加深我们对这些疾病的生物学机制的了解，并 可以指导药物开发，并产生预防或治疗这些疾病的潜在途径。

Project Summary Cardiovascular diseases are the leading cause of death both worldwide and within the United States. These diseases are heritable, however there is a large component of this heritability that remains unexplained with current association studies. For example, a recent study on coronary artery disease (CAD) found that common SNPs explained only half of CAD heritability. This “missing heritability” could be explained due to the current focus on single nucleotide polymorphisms in the genetic architecture of cardiovascular diseases. I propose to investigate the role copy number variants (CNVs) play in cardiovascular diseases. First, I will develop novel sensitive methods to be able to detect smaller, and many more, CNVs within individuals using genotype array data, one of the most widely available forms of genetic data. I will use this method to call CNVs in one of the largest existing biobanks, UK Biobank. This will generate a large database unique in the ability it provides researchers to detect associations between CNVs and cardiovascular diseases. Second, using this large database, I will test for associations between CNVs and cardiovascular diseases, likely leading to CNV-disease associations not previously known. Lastly, I will investigate the extent of CNV burden among cases of heritable cardiovascular disease and how this burden is distributed across deletions and duplications, and CNVs of varying spans and frequencies. Exploring and characterizing the role of CNVs in cardiovascular diseases would further our knowledge of the biological mechanisms of these diseases and could guide drug development and generate potential paths to preventing or treating these diseases.