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: 10477987
• 负责人: Michael D Greicius
• 金额: $ 93.24万
• 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/10477987
• 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; European; Fibroblasts; Gene Proteins; Genes; Genetic Diseases; Genomics; Individual; Lead; Leukocytes; Literature; Patients; Persons; 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.

项目概要/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。目前已获批准 治疗只能提供最小的症状益处，并且不能阻止疾病的进展。领域 迫切需要能够导致疾病缓解疗法的新药物靶点。最常见的 AD 的遗传风险因素是载脂蛋白 E 基因 (APOE4) 的 ε4 变体。 APOE4 的效果各不相同 非洲血统的人和欧洲血统的人之间的关系非常密切。目前的研究——启发 具有长读长测序和靶向基因组学的 APOE 位点——将应用新的基因组测序 技术（长读长测序）用于研究 APOE 和其他几个 AD 相关基因，包括 ABCA7。将对大约 2000 名患有 AD 和 AD 的非裔美国人的 DNA 进行长读长测序 2000 名健康老年非裔美国人对照受试者以及约 5000 名欧洲裔美国人的 DNA AD 患者和 5000 名欧美对照。这些患者中的一部分也会有长篇阅读 对来自白细胞、成纤维细胞或脑组织的这些基因的 RNA 进行测序。这些分析 将帮助我们了解 APOE4 变体附近的局部遗传变体如何改变 APOE4 变体的类型或数量 APOE4 蛋白及其如何影响 AD 风险。类似的分析将对 ABCA7 和另外 15-20 个进行 将在测序开始之前并在对基因组进行最新审查后选择目标基因 AD遗传学文献。除了了解调节基因及其蛋白质的局部变异之外 产生的长读长测序将有助于检测容易检测到的大的、破坏性的基因突变 标准全基因组测序遗漏了。结果将有助于对 AD 风险进行更具体的估计 在不同祖先背景的个体中，将为药物开发提供新的靶点。