Exploring the role of genomic repeats in cardiovascular disease heritability

探索基因组重复在心血管疾病遗传性中的作用

• 批准号: 10337196
• 负责人: Ronen Mukamel
• 金额: $ 15.66万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337196
• 关键词: Affect; All of Us Research Program; Alleles; Atrial Fibrillation; Attention Deficit Disorder; Base Pairing; Base Sequence; Biological Assay; Blood; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Cataloging; Cause of Death; Cessation of life; Cholesterol; Computer software; Coronary Arteriosclerosis; DNA Microarray Chip; DRD4 gene; Data; Development; Diploidy; Disease; Family Study; Fragile X Syndrome; Future; Genes; Genetic; Genome; Genomics; Genotype; Goals; Health; Heritability; Human; Human Genome; Huntington Disease; Hypertension; Individual; Ischemic Stroke; Length; Light; Link; Lipids; Lipoprotein (a); Maps; Measures; Methodology; Methods; Minisatellite Repeats; Modeling; Mutation; Outcome; Phase; Phenotype; Play; Population; Procedures; Proteins; Repetitive Sequence; Research; Resolution; Role; Sample Size; Single Nucleotide Polymorphism; Statistical Algorithm; Statistical Methods; Stretching; Testing; Time; United States National Institutes of Health; Variant; Work; base; biobank; cardiovascular disorder risk; cardiovascular risk factor; cohort; genetic architecture; genetic association; genome sequencing; genome wide association study; genome-wide; genotyping technology; illness length; interest; open source; programs; rare variant; risk variant; trait; whole genome

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.

项目摘要/摘要 该项目旨在探索由重复作用的心血管疾病的遗传成分 人基因组。心血管疾病是美国的主要死亡原因，具有相当大的通用 通过关联研究仍然未知的组件。最近关于冠状动脉疾病的研究， 缺血性中风，心房颤动解释了这些疾病中观察到的遗传力的四分之一 家庭研究。观察到的遗传力之间的差距持续了目的地，大幅增加 全基因组关联研究中的样本大小。这种“缺少遗传力”阻碍了对 心血管疾病的遗传基础以及遗传信息疗法的发展。 导致缺失遗传力的潜在贡献是基因组的结构变化，通常省略 来自协会研究。遗传关联研究通常关注单核苷酸多态性 （SNP） - 即，单基对变化 - 并且不考虑结构变体 - 即影响的突变 基因组的大伸展。结构变体很难使用短阅读测序或数组 - 基于基因分型技术。尽管结构变体比SNP稀有，但它们负责更多 由于其长度较大，每个人的基本对变化。 拟议的研究计划将量化和表征可变数字的心血管影响 串联重复（VNTR），这是一种理解的一类结构变体，其中特定的核苷酸序列 在不同个体中重复多次重复次数。人类基因组包含数千个 VNTR地区，其中一些已经众所周知会影响常见疾病。拟议的研究将 利用由数十万个个人组成的现有基因分型队列进行系统的 研究VNTR长度变化在心血管疾病中的作用。这些队列是使用基因分型的 不直接测定VNTR长度的阵列。 PI将开发统计方法来估算VNTR 长度为大型队列，并表征了VNTR变异对心血管疾病的贡献。 此外，PI将完善脂蛋白（a）的遗传结构，一种由具有A的基因编码的蛋白 已知长度会影响心血管疾病风险的VNTR。