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

项目摘要 心血管疾病是全球和美国境内的主要死亡原因。这些 疾病是可遗传的，然而，这种遗传性的很大一部分仍然无法解释， 目前的协会研究。例如，最近一项关于冠状动脉疾病（CAD）的研究发现， SNP仅解释了CAD遗传性的一半。这种“缺失的遗传性”可以解释为， 专注于心血管疾病遗传结构中的单核苷酸多态性。我建议 研究拷贝数变异（CNVs）在心血管疾病中的作用。 首先，我将开发新的敏感方法，能够检测更小，更多，CNVs内 使用基因型阵列数据的个体，基因型阵列数据是最广泛使用的遗传数据形式之一。我会用这个 方法调用现有最大的生物库之一，英国生物库中的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CNVs与心血管疾病之间关联的能力。 其次，利用这个大型数据库，我将测试CNVs和心血管疾病之间的关联， 可能导致先前未知的CNV-疾病关联。最后，我将调查CNV的程度 遗传性心血管疾病病例的负担以及这种负担如何在缺失中分布 和重复，以及不同跨度和频率的CNV。探索和表征CNVs的作用 在心血管疾病中的应用将进一步加深我们对这些疾病的生物学机制的认识， 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.