Project 1: Genetic Analysis

项目1：遗传分析

• 批准号: 10555696
• 负责人: Gyungah Jun
• 金额: $ 58.66万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555696
• 关键词: African; African ancestry; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; American; Amyloid beta-Protein; Asian; Asian Americans; Asian ancestry; Asian population; Biological Markers; Canada; Characteristics; Cognitive; Collaborations; Collection; Creatine; Data; Data Analyses; Data Set; Disease; East Asian; European; European ancestry; Frequencies; Genes; Genetic; Genetic Diseases; Genetic Risk; Genetic study; Genotype; Glial Fibrillary Acidic Protein; Goals; Heritability; Individual; Koreans; Late Onset Alzheimer Disease; Light; Maps; North America; Participant; Pathogenicity; Peptides; Performance; Phenotype; Plasma; Population; Positioning Attribute; Prevention trial; Process; Quantitative Trait Loci; Risk; Risk Reduction; Sample Size; Subgroup; Variant; causal variant; cohort; data management; ethnic difference; gene environment interaction; genetic analysis; genetic architecture; genetic profiling; genetic risk factor; genetic variant; genome wide association study; genome-wide; imaging biomarker; insight; multi-ethnic; neurofilament; novel; pleiotropism; polygenic risk score; prevent; protective allele; risk variant; sex; success; synergism; tau Proteins; tau-1; therapeutic target; treatment trial

SUMMARY Alzheimer’s disease (AD) is heritable with a large proportion of phenotypic variability explained by genetic components. Identifying these factors, particularly those that are modifiable in plasma biomarkers, could lead to effective AD treatments and risk reduction strategies. Multi-ethnic studies showed that population differences in genetic background can be leveraged to make novel discoveries that might require a sample sizes several orders of magnitude larger than existing subject collections to achieve similar success within a single sub- population. Genome-wide association study (GWAS) for AD has been focused on mostly Europeans ancestry, especially lacking a large-scale GWAS in Asian Americans and Canadians. Heritability of AD is currently unknown in Asians, and AD polygenic risk score applicable to Asians has not been established. The overarching goal of the Project 1 is to uncover risk and protective variants for AD and plasma biomarkers in the Asian Cohort for AD (ACAD). We propose a comprehensive approach in three specific aims. For Aim 1, we will identify risk and protective variants for AD in ACAD participants and compare the results to Asian and non-Asian populations. In collaboration with Data Management and Analysis Core (Core D), this is the first major AD genetics study of Asians in the US and Canada and will compare results with existing East Asians and multi-ethnic datasets obtained from the Alzheimer Disease Genetic Consortium (ADGC). For Aim 2, we will understand genetic architecture for plasma AD biomarkers in ACAD participants. We will identify quantitative trait loci (QTL) for plasma AD related biomarkers including Aβ peptides, total tau (t-tau), phosphorylated-tau (p-tau 181), and neurofilament light chain (NfL) in collaboration with Core D, Biosampe Core, and Project 2. For Aim 3, we will determine heritability of AD and establish AD polygenic risk score (ADPRS) in ACAD participants. Our study will provide insights on Asian ancestry specific (ASAC and/or Asians) and multi-ethnic targets in AD therapeutics. We anticipate that results from this study will facilitate potential novel, population-specific therapeutic targets for AD for treating and preventing AD. The results from this proposal will provide the important synergy to further investigate gene-environment interactions in Project 2.

概括 阿尔茨海默病 (AD) 具有遗传性，大部分表型变异可通过遗传来解释 成分。识别这些因素，特别是那些可在血浆生物标志物中修改的因素，可能会导致 有效的 AD 治疗和降低风险策略。多种族研究表明，人口差异 可以利用遗传背景来做出新的发现，这可能需要几个样本量 比现有主题集合大几个数量级，以在单个子项目中取得类似的成功 人口。 AD 的全基因组关联研究 (GWAS) 主要关注欧洲人的血统， 尤其缺乏针对亚裔美国人和加拿大人的大规模 GWAS。 AD的遗传力目前为 在亚洲人中未知，适用于亚洲人的 AD 多基因风险评分尚未建立。这 项目 1 的总体目标是发现 AD 和血浆的风险和保护性变异 亚洲 AD 队列 (ACAD) 中的生物标志物。我们提出了三个具体的综合方法 目标。对于目标 1，我们将确定 ACAD 参与者中 AD 的风险和保护性变异，并比较 对亚洲和非亚洲人群的结果。与数据管理和分析核心（Core D)，这是在美国和加拿大对亚洲人进行的第一项主要 AD 遗传学研究，并将结果与 从阿尔茨海默病遗传联盟获得的现有东亚人和多种族数据集 （ADGC）。对于目标 2，我们将了解 ACAD 参与者血浆 AD 生物标志物的遗传结构。 我们将鉴定血浆 AD 相关生物标志物的数量性状位点 (QTL)，包括 Aβ 肽、总 tau 蛋白 (t-tau)、磷酸化-tau (p-tau 181) 和神经丝轻链 (NfL) 与 Core D 合作， Biosampe 核心和项目 2。对于目标 3，我们将确定 AD 的遗传力并建立 AD 多基因风险 ACAD 参与者的得分 (ADPRS)。我们的研究将提供有关亚洲血统特定的见解（ASAC 和/或 AD 治疗中的亚洲人）和多种族目标。我们预计这项研究的结果将有助于 AD 治疗和预防 AD 的潜在新型、针对人群的治疗靶点。结果来自 该提案将为进一步研究项目中基因与环境的相互作用提供重要的协同作用 2.