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.

项目概要/摘要 该项目旨在探索由重复序列引起的心血管疾病的遗传成分。 人类基因组。心血管疾病是美国的首要死因，与相当大的遗传因素有关 关联研究仍未解释的成分。冠状动脉疾病的最新研究， 缺血性中风和心房颤动解释了在这些疾病中观察到的不到四分之一的遗传性 家庭研究。尽管遗传力大幅增加，观察到的遗传力和解释的遗传力之间的差距仍然存在 全基因组关联研究中的样本量。这种“遗传性缺失”阻碍了对 心血管疾病的遗传基础，以及遗传信息疗法的开发。 遗传性缺失的一个潜在因素是基因组的结构变异，而这种变异通常被忽略 来自关联研究。遗传关联研究通常关注单核苷酸多态性 （SNP）——即单碱基对变化——并且不考虑结构变异——即影响基因的突变 基因组的大片区域。使用短读长测序或阵列很难解决结构变异 基于基因分型技术。虽然结构变异比 SNP 更罕见，但它们造成的影响更大 由于长度较长，每个个体的碱基对都有变异。 拟议的研究计划将量化和描述变量对心血管的影响 串联重复序列（VNTR），一类正在研究的结构变体，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，其中一些区域已知会影响常见疾病。拟议的研究将 利用现有的由数十万个体组成的基因分型队列来进行系统的研究 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 将开发统计方法来估算 VNTR 深入研究大型队列，并描述 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，脂蛋白（a）是一种由带有 a 基因的基因编码的蛋白质。 VNTR 的长度已知会影响心血管疾病的风险。