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.

总结 阿尔茨海默病（AD）是一种可遗传的疾病，其表型变异的很大一部分可以通过遗传因素来解释。 件.识别这些因素，特别是那些在血浆生物标志物中可改变的因素，可能会导致 有效的AD治疗和风险降低策略。多种族研究表明， 在遗传学背景中，可以利用新的发现，这可能需要几个样本大小， 数量级大于现有的主题集合，以实现类似的成功，在一个单一的子， 人口AD的全基因组关联研究（GWAS）主要集中在欧洲血统， 尤其是在亚裔美国人和加拿大人中缺乏大规模的GWAS。AD的遗传性目前 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。的 项目1的首要目标是揭示AD和血浆的风险和保护性变体 亚洲AD队列（ACAD）中的生物标志物。我们建议在三个具体方面采取综合办法 目标。对于目标1，我们将确定ACAD参与者中AD的风险和保护性变体，并比较 亚洲人和非亚洲人。数据管理和分析核心（Data Management and Analysis Core） D），这是美国和加拿大首次对亚洲人进行的主要AD遗传学研究，并将结果与 现有的东亚人和从阿尔茨海默病遗传联盟获得的多种族数据集 （ADGC）。对于目标2，我们将了解ACAD参与者中血浆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基因座（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）， Biosampe Core和项目2。对于目标3，我们将确定AD的遗传度并建立AD多基因风险 ACAD参与者的ADPRS评分。我们的研究将提供关于亚洲血统特定（ASAC和/或 亚洲人）和AD治疗中的多种族靶点。我们预计，这项研究的结果将有助于 用于治疗和预防AD的潜在的新的、人群特异性的AD治疗靶点。的结果 这一建议将为进一步研究基因与环境的相互作用提供重要的协同作用， 2.