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: 10208579
• 负责人: Michael D Greicius
• 金额: $ 94.42万
• 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/10208579
• 关键词: Affect; African; African American; 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; 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.

项目摘要/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。目前已批准 治疗只提供最小的症状益处，并不能阻止疾病的进展。田野 迫切需要新的药物靶点，从而可能导致疾病修改疗法。最常见的 阿尔茨海默病的遗传危险因素是载脂蛋白E基因的ε4变异体。载脂蛋白4的作用各不相同 非洲血统的人和欧洲血统的人之间有很大的区别。当前的研究-启迪 APOE基因座具有长阅读测序和靶向基因组学-将应用新的基因组测序 技术(长阅读测序)用于研究载脂蛋白E和其他几个与AD相关的基因，包括 ABCA7。将对大约2000名患有AD和AND的非裔美国人的DNA进行长读测序 2000名健康的老年非裔美国人作为对照，以及大约5000名欧洲裔美国人的DNA AD患者和5000名欧美对照。这些患者中的一部分也将长期阅读 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变异体附近的局部遗传变异体如何改变 ApoE4蛋白及其对AD风险的影响。将对ABCA7和另外15-20进行类似的分析 目标基因将在测序开始之前选择，并在最新的 广告遗传学文献。除了了解调控基因和蛋白质的局部变异外 生产，长读测序将有助于检测大的，破坏性的基因突变，很容易 错过了标准的全基因组测序。这一结果将允许对AD风险进行更具体的估计 在不同祖先背景的个人中使用，并将为药物开发提供新的靶点。