Exploring the role of genomic repeats in cardiovascular disease heritability

项目摘要/摘要 这个项目的目的是探索心血管疾病的遗传成分由重复的 人类基因组。心血管疾病是美国的主要死亡原因，它有相当大的遗传因素 仍未被关联研究解释的成分。最近关于冠状动脉疾病的研究， 缺血性中风和房颤可以解释这些疾病中不到四分之一的遗传性 家庭研究。观察到的遗传力和解释的遗传力之间的差距仍然存在，尽管 全基因组关联研究中的样本量。这种“遗漏的遗传性”阻碍了人们对 心血管疾病的遗传基础，以及遗传信息疗法的发展。 缺失遗传性的一个潜在因素是基因组的结构变异，这种变异通常被省略。 来自联想研究。遗传关联研究通常集中于单核苷酸多态。 (SNPs)--即单碱基对变化--不考虑结构性变异--即影响 基因组的大范围。结构变异很难使用短读测序或阵列- 基于基因分型技术。虽然结构变异比SNPs更罕见，但它们造成的 由于长度较大，每个个体的碱基对都有变异。 拟议的研究计划将量化和表征变量对心血管的影响 串联重复序列(VNTRs)，是一类研究较少的结构变体，其中特定的核苷酸序列 在不同的个体中重复不同的次数。人类基因组包含数千个 VNTR区域，已知其中几个区域影响常见疾病。拟议的研究将 利用现有的由数十万人组成的基因分型队列进行系统性的 Vntr长度变异在心血管疾病中作用的研究。这些队列的基因分型使用 不直接分析VNTR长度的数组。PI将开发统计方法来归因于VNTR 并分析了VNTR变异对心血管疾病的影响。 此外，PI将完善脂蛋白(A)的遗传结构，脂蛋白(A)是一种由带有 VNTR的长度已知会影响心血管疾病的风险。

PROJECT SUMMARY/ABSTRACT This project aims to explore the genetic component of cardiovascular diseases contributed by repeats in human genomes. Cardiovascular diseases, the leading cause of death in the US, have sizeable genetic components which remain unexplained by association studies. Recent studies of coronary artery disease, ischemic stroke, and atrial fibrillation explain less than a quarter of the heritability in these diseases observed in family studies. The gap between observed and explained heritability has persisted despite large increases in the sample sizes in genome-wide association studies. This ‘missing heritability’ hinders the understanding of the genetic basis for cardiovascular disease, and the development of genetically-informed therapies. A potential contributor to the missing heritability is structural variation in genomes, which is usually omitted from association studies. Genetic association studies typically focus on single nucleotide polymorphisms (SNPs)—i.e., single base pair changes—and do not account for structural variants—i.e., mutations affecting large stretches of the genome. Structural variants are difficult to resolve using short-read sequencing or array- based genotyping technologies. While structural variants are rarer than SNPs, they are responsible for more base pairs of variation per individual due to their large length. The proposed research program will quantify and characterize the cardiovascular impact of variable number tandem repeats (VNTRs), an understudied class of structural variants in which a specific nucleotide sequence is repeated a varying number of times in different individuals. The human genome contains thousands of VNTR regions, a few of which are already known to influence common diseases. The proposed research will leverage existing genotyped cohorts consisting of hundreds of thousands of individuals to conduct a systematic study of the role of VNTR length variation in cardiovascular diseases. These cohorts are genotyped using arrays which do not directly assay VNTR lengths. The PI will develop statistical methods to impute VNTR lengths into large cohorts, and characterize the contribution of VNTR variation to cardiovascular disease. Additionally, the PI will refine the genetic architecture of Lipoprotein(a), a protein encoded by a gene with a VNTR whose length is known to influence cardiovascular disease risk.