Dissecting the Genomic Etiology of non-Mendelian Early-Onset Alzheimer Disease and Related Phenotypes

剖析非孟德尔早发性阿尔茨海默病的基因组病因学及相关表型

• 批准号: 10412088
• 负责人: Gary Wayne Beecham
• 金额: $ 118.89万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10412088
• 关键词: Accounting; Address; Affect; Age; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease risk; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Caribbean Hispanic; Categories; Cognitive; Collection; Data; Data Set; Dementia; Development; Disease; Early Onset Alzheimer Disease; Elderly; Ethnic group; Etiology; Failure; Family; Frequencies; Genes; Genetic; Genetic Diseases; Genetic Variation; Genome; Genomic approach; Genomics; Genotype; Heritability; Impairment; Individual; Infrastructure; Inheritance Patterns; Investigation; Joints; Language; Light; Link; Memory; Mental Depression; Methods; Minority Groups; Molecular; Mutation; Neurocognitive; Neuropsychology; Not Hispanic or Latino; Participant; Pathway Analysis; Pathway interactions; Phenotype; Protocols documentation; Race; Research; Resources; Risk; Role; Sampling; Symptoms; Technology; Universities; Variant; Visuospatial; Washington; admixture mapping; advanced analytics; analytical method; base; cognitive control; cohort; comorbidity; early onset; endophenotype; experimental study; genetic architecture; genetic linkage analysis; genetic risk factor; genetic variant; genome sequencing; genomic data; improved; member; neuropsychiatry; new therapeutic target; novel; novel therapeutics; phenome; polygenic risk score; presenilin-1; presenilin-2; risk variant; segregation; sex; trait; vascular risk factor; whole genome

PROJECT SUMMARY Genomic studies of Alzheimer's disease (AD) have primarily focused on non-Hispanic White (NHW) participants affected by the late-onset form of the disease (LOAD; onset age: >65), or the study of early onset AD (EOAD; onset age <=65) cases from families showing Mendelian inheritance patterns associated with mutations in the APP, PSEN1 and PSEN2 genes. However, mutations in these three genes explain ~10% of EOAD cases. There are no large-scale efforts to collect and study EOAD cases not explained by these genes, despite the fact that this unexplained EOAD category accounts for ~90% of cases. The few smaller studies that have been conducted suggest that the genetic architecture of EOAD overlaps with the late-onset form only partially. Thus, studying EOAD in subjects without APP, PSEN1 and PSEN2 mutations is a critical gap that provides a unique opportunity for discovering novel therapeutic targets and molecular pathways. To address this issue we aim to identify additional EOAD-associated variants through a large-scale whole- genome sequencing (WGS) study of unexplained EOAD. We will include cases from several well-established AD cohorts including the Resource for Early-onset Alzheimer Disease Research (READR), the Knight-ADRC at Washington University, the Alzheimer's Disease Genetics Consortium (ADGC), and others. Generating and harmonizing a dataset of 200 non-Hispanic White (NHW) and Caribbean Hispanic (CH) multiplex EOAD families, over 4,000 EOAD singletons and over 13,000 unrelated, cognitive controls, all with WGS, this project will yield the largest EOAD genomics dataset to-date, improving statistical power for variant identification and allowing us to assess the impact of specific factors such as APOE genotype, vascular risk factors, and neuropsychiatric comorbidities. The inclusion of a large set of CH families and singletons will allow the examination of EOAD risk in a significantly understudied but fast-growing minority population. Analyses will comprise both linkage and association-based approaches, analyses of polygenic and ancestry effects, and a thorough examination of neurocognitive, neuropsychiatric and cardiovascular endophenotypes. We expect that when successfully completed, this study will point to novel genetic contributors to EOAD, shed light on the mechanisms of AD and facilitate the development of novel therapeutics. Sampling, phenotyping and sequencing analysis protocols will be complementary to and compatible with the existing LOAD genomics resources, such as the Alzheimer Disease Sequencing Project (ADSP) and related studies. This phenotypic and genomic consistency, together with the use of existing AD infrastructure (NIAGADS), allows for immediate integration with the leading efforts on LOAD, enabling rapid large-scale investigation of a variety of additional critical AD genomics hypotheses.

项目摘要 阿尔茨海默氏病（AD）的基因组研究主要集中于非西班牙裔白人（NHW）参与者 受疾病晚期形式的影响（负载；发病年龄：> 65），或研究早期发作AD（EOAD； 发病年龄<= 65）来自家庭的家庭病例，显示了与突变相关的孟德尔遗传模式 APP，PSEN1和PSEN2基因。但是，这三个基因的突变解释了约10％的EOAD病例。那里 尽管事实是 该无法解释的EOAD类别占案件的〜90％。进行的少数较小的研究 表明EOAD的遗传结构仅部分与晚发形式重叠。因此，学习 在没有应用程序，PSEN1和PSEN2突变的主题中，EOAD是一个关键差距，可提供独特的机会 用于发现新型的治疗靶标和分子途径。 为了解决这个问题，我们旨在通过大规模的整个整体来确定其他EOAD相关的变体 基因组测序（WGS）研究无法解释的EOAD。我们将包括几个已建立的案件 广告群包括包括早期发作的阿尔茨海默氏病研究资源（ReadR），骑士ADRC 华盛顿大学，阿尔茨海默氏病遗传学财团（ADGC）等。生成和 协调200个非西班牙裔白人（NHW）和加勒比海西班牙裔（CH）多重eoad家庭的数据集， 超过4,000个EOAD单例和超过13,000多个无关的认知控制与WGS，该项目将产生 最大的EOAD基因组学数据集迄今 评估特定因素的影响，例如APOE基因型，血管危险因素和神经精神病学 合并症。包含大量的CH家族和单人将允许检查EOAD风险 在大量研究但增长迅速的少数群体中。分析将既包括联系，又包括 基于关联的方法，多基因和祖先效应的分析以及对 神经认知，神经精神病学和心血管内表型。我们期望成功 该研究完成后，将指出EOAD的新遗传因素，阐明AD和 促进新型治疗学的发展。 抽样，表型和测序分析方案将与 现有的负载基因组资源，例如阿尔茨海默氏病测序项目（ADSP）及相关 研究。这种表型和基因组一致性，以及现有的AD基础架构的使用 （Niagads），允许立即与负载的主要努力进行整合，从而快速大规模 研究各种其他关键AD基因组学假设。