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.

项目摘要/摘要 阿尔茨海默氏病（AD）是一种常见的，进行的，最终的致命脑疾病 治疗只能提供最小的症状益处，不要阻止疾病的发展。 迫切需要新的药物靶标，这些靶标可以改善疗法 AD的遗传因子是载脂蛋白E基因的ε4变体（APOE4）。 在非洲血统和欧洲血统的人们之间很大程度上。 具有长阅读测序和靶向基因组学的APOE基因座 - 将应用新的基因组测序 研究APOE和Severevant基因的技术（长阅读测序） ABCA7。 2000年健康的年长的非裔美国人对照科目以及大约5000名欧美的DNA 广告患者和5000名欧美对照。 这些基因的RNA测序来自白细胞，成纤维细胞或脑组织 将帮助我们了解APOE4变体附近的局部遗传变异如何改变您的类型或数量 APOE4蛋白以及如何影响AD的风险。 在测序开始之前将选择的目标基因，并在对 AD遗传学文献除了了解调节基因的局部变体 产生长阅读测序将有助于检测大型，有害的基因杂种，以iSoy easile 错过了标准的全基因组测序。 在各种祖先背景的个体中，将为药物开发提供新的目标。