Genetic Studies of Alzheimer Disease in Koreans

韩国人阿尔茨海默病的遗传学研究

• 批准号: 10242783
• 负责人: Lindsay A. Farrer
• 金额: $ 131.59万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242783
• 关键词: Affect; Age; Alzheimer' s Disease; Asians; Bioinformatics; Blood specimen; Brain; Brain imaging; Caucasians; Chinese People; Cities; Clinical Trials; Cognitive; Coupled; DNA; DNA sequencing; Data; Data Set; Dementia; Development; Dideoxy Chain Termination DNA Sequencing; Drug Targeting; Elderly; Environmental Risk Factor; Ethnic Origin; Ethnic group; European; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Diseases; Genetic Drift; Genetic Transcription; Genetic Variation; Genetic study; Genomics; Genotype; Goals; High Prevalence; Incidence; Individual; Japanese Population; Koreans; Lead; Life Style; MRI Scans; Magnetic Resonance Imaging; Measures; Medical History; Methods; Modeling; Modification; Mutation; Neuropsychological Tests; Nucleotides; Participant; Pathogenicity; Pathway Analysis; Persons; Population; Population Heterogeneity; Prevalence; Process; Proteins; Quantitative Trait Loci; Research; Risk; Risk Assessment; Sampling; Sequence Alignment; South Korea; Specimen; Structure; Survival Analysis; Symptoms; Tissues; Universities; Variant; analytical method; base; case control; clinical examination; cognitive function; cognitive testing; cohort; design; drug development; endophenotype; genetic analysis; genetic architecture; genetic association; genetic testing; genetic variant; genome sequencing; genome wide association study; insertion/deletion mutation; next generation sequencing; novel; novel therapeutics; patient registry; phenotypic data; positional cloning; prospective; protein structure; rare variant; risk variant; sex; trait; whole genome

ABSTRACT Most discoveries of the genetic basis of Alzheimer disease (AD) were made in Caucasians of European ancestry (EAs) and required samples between 10,000 and 75,000 subjects to detect them. We and others have demonstrated that risk variants for AD can be identified in ethnic groups of a more homogeneous genetic background using samples comprising several thousand or fewer subjects. Studies of non-EA populations also afford the opportunity to discover variants that are rare or display a smaller effect size in EAs due to modification by other genes and environmental factors. We will direct our efforts to Koreans, a population which has a high prevalence of AD, but, like other East Asian populations, have not been included in large DNA sequencing studies and for whom little is known about the genetic basis of AD other than association with APOE. They have maintained a distinct genetic profile that reflects a unique component resulting from genetic drift and new mutations during the last two millennia. We will leverage the genetic architecture of Koreans to promote discovery of AD-related genes and variants by studying rare and common genetic variation, and the impact of AD- associated variants on gene expression. To accomplish our scientific goals, we will study AD cases and controls who are ascertained and followed longitudinally at the National Center for Research on Dementia at Chosun University located in the southwestern city of Gwangju, Republic of Korea, and obtain from each participant a blood specimen and phenotypic data including clinical exam, demographic, medical history and lifestyle information. In addition, most subjects will undergo an extensive neuropsychological test battery developed specifically for Koreans and a brain MRI scan. The cohort will comprise an unrelated group of 2,000 AD cases and 2,000 elderly controls ascertained from existing patient registries and prospectively identified subjects all of whom will have GWAS data available generated using a microarray designed for Koreans. DNA specimens from all subjects will be whole genome sequenced (WGS). WGS data will be processed using pipelines established by the Alzheimer Disease Sequencing Project. We will conduct a genome-wide association study for AD using methods for single variant and gene-based tests based on models that adjust for age, sex and population substructure. Top-findings will be replicated in datasets of other ethnicities assembled by the Genomics Center for Alzheimer Disease for the Alzheimer Disease Sequencing Project using trans-ethnic analysis and approaches that focus on variants affecting protein structure, transcription, and gene expression. Next we will perform a GWAS for age at onset and brain imaging and cognitive endophenotypes. Finally, we will identify gene targets of the top-ranked SNPs by performing expression quantitative trait locus analysis using public datasets containing genotype and gene expression data in brain and other tissues, and establish functional connections among the top-ranked SNPs and genes using pathway analysis and co-expression network analysis. We expect this project will identify novel targets for development of new drugs to treat or retard mechanisms leading to AD.

抽象的 大多数阿尔茨海默病 (AD) 遗传基础的发现都是在欧洲血统的白种人中发现的 （EA）并需要 10,000 至 75,000 名受试者的样本来检测它们。我们和其他人有 证明 AD 的风险变异可以在遗传更同质的种族群体中识别出来 使用包含数千或更少受试者的样本进行背景分析。对非 EA 人群的研究也 有机会发现罕见的变体或由于修改而在 EA 中显示较小的效应量 受其他基因和环境因素影响。我们将把努力的重点放在韩国人身上，因为韩国人的人口密度很高。 AD 的患病率，但与其他东亚人群一样，尚未被纳入大型 DNA 测序中 对他们来说，除了与 APOE 的相关性之外，对 AD 的遗传基础知之甚少。他们有 保持了独特的遗传特征，反映了遗传漂变和新发现所产生的独特成分 过去两千年的突变。我们将利用韩国人的基因结构来促进发现 通过研究罕见和常见的遗传变异以及 AD 的影响，研究与 AD 相关的基因和变异 基因表达的相关变异。为了实现我们的科学目标，我们将研究 AD 案例和对照 在朝鲜国家痴呆症研究中心确定并进行纵向跟踪的人 位于大韩民国西南部城市光州的大学，并从每位参与者处获得 血液样本和表型数据，包括临床检查、人口统计、病史和生活方式 信息。此外，大多数受试者将接受一系列广泛的神经心理学测试 专门针对韩国人的脑部核磁共振扫描。该队列将由 2,000 个不相关的 AD 病例组成 以及从现有患者登记和前瞻性确定的受试者中确定的 2,000 名老年对照 他们将获得使用专为韩国人设计的微阵列生成的 GWAS 数据。 DNA 样本来自 所有受试者都将进行全基因组测序（WGS）。 WGS 数据将使用已建立的管道进行处理 由阿尔茨海默病测序项目。我们将使用 AD 进行全基因组关联研究 基于年龄、性别和人口调整模型的单变体和基于基因的测试方法 子结构。顶尖发现将在基因组中心收集的其他种族的数据集中得到复制 使用跨种族分析和方法的阿尔茨海默病测序项目 重点关注影响蛋白质结构、转录和基因表达的变异。接下来我们将执行一个 GWAS 针对发病年龄、脑成像和认知内表型。最后，我们将确定基因目标 通过使用公共数据集进行表达数量性状基因座分析，获得排名靠前的 SNP 包含大脑和其他组织的基因型和基因表达数据，并建立功能连接 使用通路分析和共表达网络分析排名最高的 SNP 和基因。我们期望 该项目将确定开发新药的新靶标，以治疗或延缓导致 AD 的机制。