Illuminating the APOE Locus with Long-Read Sequencing and Targeted Genomics

通过长读长测序和靶向基因组学阐明 APOE 基因座

• 批准号: 10640191
• 负责人: Michael D Greicius
• 金额: $ 92.25万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10640191
• 关键词: Affect; African American; African American population; African ancestry; Alleles; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; American; Apolipoprotein E; Brain Diseases; DNA; DNA Sequence Alteration; Disease; Disease Progression; European; European ancestry; Fibroblasts; Gene Proteins; Genes; Genetic Diseases; Genomics; Individual; Leukocytes; Literature; Patients; Persons; Proteins; RNA; Structure; Technology; Variant; brain tissue; drug development; genetic risk factor; genetic variant; genome sequencing; new therapeutic target; patient subsets; whole genome

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a common, progressive, and ultimately fatal brain disease. Currently approved treatments provide only minimal symptomatic benefits and do not stop the disease from progressing. The field is in dire need of novel drug targets which could lead to disease-modifying therapies. The most common genetic risk factor for AD is the ε4 variant of the apolipoprotein E gene (APOE4). The effect of APOE4 varies greatly between people of African ancestry and people of European ancestry. The current study—Illuminating the APOE Locus with Long-Read Sequencing and Targeted Genomics—will apply a new genome sequencing technology (long-read sequencing) to the study of APOE and several other AD-relevant genes including ABCA7. Long-read sequencing will be performed on DNA from roughly 2000 African-Americans with AD and 2000 healthy older African-American control subjects as well as DNA from roughly 5000 European-American AD patients and 5000 European-American controls. A subset of these patients will also have long-read sequencing of these genes’ RNA derived from white blood cells, fibroblasts, or brain tissue. These analyses will help us understand how local genetic variants near the APOE4 variant can alter the type or amount of the APOE4 protein and how this affects risk of AD. Similar analyses will be done on ABCA7 and another 15-20 targeted genes that will be selected just before sequencing begins and following an up-to-date review of the AD genetics literature. In addition to understanding the local variants regulating a gene and the protein it produces, long-read sequencing will be useful in detecting large, damaging genetic mutations that are easily missed with standard whole-genome sequencing. The results will allow for more specific estimates of AD risk in individuals of diverse ancestral backgrounds and will provide novel targets for drug development.

项目总结/摘要 阿尔茨海默病（AD）是一种常见的、进行性的、最终致命的脑部疾病。目前批准 治疗仅提供最小的症状益处，并且不能阻止疾病的进展。领域 迫切需要新的药物靶点，这可能导致疾病改善疗法。最常见的 AD的遗传风险因素是载脂蛋白E基因（APOE 4）的ε4变体。APOE 4的作用各不相同 非洲血统的人和欧洲血统的人之间的差异很大。当前研究-照明 载脂蛋白E基因座与长读序和靶向基因组学-将应用一种新的基因组测序 技术（长读测序）的研究载脂蛋白E和其他几个AD相关基因，包括 ABCA7.将对大约2000名患有AD的非洲裔美国人的DNA进行长读测序， 2000名健康的老年非裔美国人对照组以及大约5000名欧洲裔美国人的DNA AD患者和5000名欧美对照。这些患者的一个子集也将有长期阅读 这些基因的RNA来源于白色血细胞、成纤维细胞或脑组织。这些分析 这将有助于我们了解APOE 4变异体附近的局部遗传变异如何改变细胞的类型或数量。 APOE 4蛋白及其如何影响AD风险将对ABCA 7和另外15-20进行类似的分析 靶向基因，将被选择之前测序开始，并遵循最新的审查， AD遗传学文献。除了了解调节基因和蛋白质的局部变异外， 长读测序将有助于检测大的、破坏性的基因突变， 标准的全基因组测序没有发现。这些结果将允许对AD风险进行更具体的估计 在不同祖先背景的个体中，并将为药物开发提供新的靶点。