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: 10667461
• 负责人: Gary Wayne Beecham
• 金额: $ 112.39万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667461
• 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; Disparate; Early Onset Alzheimer Disease; Early identification; Elderly; Ethnic Population; Etiology; Failure; Family; Frequencies; Genes; Genetic; Genetic Diseases; Genetic Variation; Genome; Genomic approach; Genomics; Genotype; Heritability; Impairment; Individual; Infrastructure; Inheritance Patterns; Investigation; Joints; Language; 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; cognitive control; cohort; comorbidity; early onset; endophenotype; experimental study; genetic architecture; genetic linkage analysis; genetic risk factor; genetic variant; genome resource; genome sequencing; genomic data; improved; member; neuropsychiatry; new therapeutic target; novel; novel therapeutics; phenome; polygenic risk score; presenilin-1; presenilin-2; racial population; 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 阿尔茨海默病（AD）的基因组研究主要集中在非西班牙裔白色（NHW）参与者 受疾病的晚发形式（LOAD;发病年龄：>65）影响，或早发性AD（EOAD; 发病年龄<=65岁），来自表现出孟德尔遗传模式的家庭的病例与基因突变相关 APP、PSEN 1和PSEN 2基因。然而，这三个基因的突变解释了约10%的EOAD病例。那里 没有大规模的努力来收集和研究这些基因不能解释的EOAD病例，尽管事实上， 这种无法解释的EOAD类别约占病例的90%。已经进行的为数不多的小型研究 表明EOAD的遗传结构与迟发性形式仅部分重叠。因此，学习 无APP、PSEN 1和PSEN 2突变的受试者的EOAD是一个关键差距，提供了一个独特的机会 用于发现新的治疗靶点和分子途径。 为了解决这个问题，我们的目标是通过一个大规模的整体， 基因组测序（WGS）研究不明原因的EOAD。我们将包括来自几个成熟的案例 AD队列，包括早发性阿尔茨海默病研究资源（READR）， 华盛顿大学、阿尔茨海默病遗传学联盟（ADGC）等。生成和 协调200个非西班牙裔白色（NHW）和加勒比西班牙裔（CH）多重EOAD家族的数据集， 超过4，000名EOAD单例患者和超过13，000名不相关的认知对照患者，所有患者均使用WGS，该项目将产生 迄今为止最大的EOAD基因组学数据集，提高了变异识别的统计能力， 评估特定因素的影响，如APOE基因型、血管危险因素和神经精神因素。 合并症。纳入大量CH家族和单胎患者将允许检查EOAD风险 在一个研究严重不足但快速增长的少数民族人口中。分析将包括联系和 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、神经精神和心血管内表型。我们希望当成功的时候 完成后，这项研究将指出EOAD的新遗传因素，阐明AD的机制， 促进新疗法的发展。 采样、表型分析和测序分析方案将与 现有的LOAD基因组学资源，如阿尔茨海默病测序项目（ADSP）和相关的 问题研究这种表型和基因组的一致性，以及使用现有的AD基础设施， （NIAGADS），允许立即与LOAD上的主要工作集成，从而实现快速的大规模 研究了各种其他关键的AD基因组学假设。