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.

摘要 阿尔茨海默病(AD)是可遗传的，有很大一部分表型变异是由基因解释的 组件。识别这些因素，特别是那些在血浆生物标记物中可改变的因素，可能会导致 有效的AD治疗和降低风险的策略。多种族研究表明，人口差异 可以利用遗传背景来进行新的发现，这可能需要几个大小的样本 比现有主题集合大几个数量级，以在单个子集内实现类似的成功 人口。阿尔茨海默病的全基因组关联研究主要集中在欧洲血统上， 尤其是在亚裔美国人和加拿大人中缺乏大规模的GWA。阿尔茨海默病的遗传性目前 在亚洲人中未知，并且适用于亚洲人的AD多基因风险评分尚未建立。这个 项目1的总体目标是发现AD和血浆的风险和保护性变体 AD亚洲队列中的生物标记物(ACAD)。我们在三个具体的方面提出了一个全面的方法 目标。对于目标1，我们将在ACAD参与者中识别AD的风险和保护性变异，并比较 对亚洲人和非亚洲人的结果。与数据管理和分析核心(核心)合作 D)，这是美国和加拿大对亚洲人进行的第一项重大AD遗传学研究，并将与 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。 我们将确定血浆AD相关生物标志物的数量性状基因座，包括Aβ肽、总tau (t-tau)、磷酸化tau(p-tau 181)和神经丝轻链(NFL)与核心D合作， Biosampe Core和项目2。对于目标3，我们将确定AD的遗传性并确定AD的多基因风险 ACAD参与者的评分(ADPR)。我们的研究将提供对特定亚洲血统(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 治疗和预防阿尔茨海默病的潜在新的、人群特异性的治疗靶点。结果来自于 这一建议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.