Exploring the role of genomic repeats in cardiovascular disease heritability

项目概要/摘要 本项目旨在探索心血管疾病中重复序列的遗传成分， 人类基因组心血管疾病是美国人死亡的主要原因， 相关研究仍然无法解释的成分。冠状动脉疾病的最新研究， 缺血性中风和心房颤动解释了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持续存在，尽管大幅度增加， 全基因组关联研究的样本量。这种“缺失的遗传性”阻碍了对 心血管疾病的遗传基础，以及基因疗法的发展。 遗传力缺失的一个潜在因素是基因组中的结构变异，这通常被忽略 从协会研究。遗传关联研究通常集中在单核苷酸多态性 （SNP）-即，单碱基对变化-并且不考虑结构变异-即，突变影响 基因组的大片段。结构变异很难使用短读测序或阵列来解析， 基于基因分型技术。虽然结构变异比SNPs更罕见，但它们对更多的生物多样性负责。 每个个体的变异碱基对，因为它们的长度很长。 拟议的研究计划将量化和表征变量数量的心血管影响 串联重复序列（VNTR），一种未充分研究的结构变体，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，其中一些已知会影响常见疾病。拟议的研究将 利用现有的基因分型队列，包括数十万人进行系统的 研究VNTR长度变异在心血管疾病中的作用。这些队列的基因分型使用 不直接测定VNTR长度的阵列。PI将开发统计方法来插补VNTR 长度到大队列，并表征VNTR变异对心血管疾病的贡献。 此外，PI将改善脂蛋白（a）的遗传结构，脂蛋白（a）是一种由基因编码的蛋白， 已知VNTR的长度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.