Genetic Epidemiology and Multi-Omics Analyses in Familial and Sporadic Alzheimer's Disease Among Secular Caribbean Hispanics and Religious Order

世俗加勒比西班牙裔和宗教秩序中家族性和散发性阿尔茨海默病的遗传流行病学和多组学分析

• 批准号: 10171755
• 负责人: RICHARD P MAYEUX
• 金额: $ 229.35万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10171755
• 关键词: Affect; Age; Alzheimer' s Disease; Autopsy; Biological; Biological Assay; Biological Factors; Biological Markers; Blood; Blood specimen; Brain; Caribbean Hispanic; Cerebrospinal Fluid; Cessation of life; Chemicals; Clinical; Consent; DNA; DNA Methylation; Data; Dementia; Disease; Disease Pathway; Dominican Republic; EPHA1 gene; Elderly; Elderly man; Elderly woman; Environmental Risk Factor; Epidemiology; Evaluation of Risk Factors; Family; Family member; Frequencies; Gene Expression; Genes; Genetic; Genetic Diseases; Genetic Risk; Genetic study; Genome; Genomics; Goals; Individual; Investigation; Lead; Medicine; Metabolism; Methylation; Minority Groups; Multiomic Data; Not Hispanic or Latino; Pathway interactions; Patients; Plasma; Proteins; Proteomics; Quantitative Trait Loci; Regulatory Element; Religion and Spirituality; Resolution; Risk; Risk Factors; SNP genotyping; Sampling; Site; Spinal Puncture; System; Time; Tissue-Specific Gene Expression; Tissues; Transcript; Variant; Whole Blood; Work; aged; base; biomarker development; brain tissue; case control; causal variant; cohort; differential expression; drug discovery; epigenomics; genetic analysis; genetic epidemiology; genetic risk factor; genetic variant; genome wide association study; genome-wide; insight; member; metabolomics; methylation pattern; molecular phenotype; multiple omics; pre-clinical; protein metabolite; protein protein interaction; proteomic signature; recruit; research clinical testing; targeted biomarker; therapeutic development; therapeutic target; transcriptome sequencing; transcriptomics; whole genome

ABSTRACT For 25 years, we have investigated the genetic bases of familial and sporadic Alzheimer’s disease (AD) among Caribbean Hispanics in the US and in the Dominican Republic, contributing samples and data to the Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Sequencing Project. For this new proposal, we intend to integrate the genetic analyses of AD in Caribbean Hispanics with deep molecular phenotyping: epigenomics, transcriptomics, proteomics and metabolomics using whole blood, plasma, cerebrospinal fluid and brain tissue where possible. Multi-omics data generated in this minority population will be used to understand the effects of gene variants on disease, clarify the affected proteins and pathways that underlie AD and for comparison to results obtained from similar studies in white, non-Hispanic populations such as Accelerated Medicines Partnership – Alzheimer’s Disease. Compared with non-Hispanics, we have shown that Caribbean Hispanics are three times more likely to develop AD by age 75 years. If they have family members with AD their risk is five times higher. From the study entitled, “Estudio Familiar Investigar Genetica de Alzheimer” (EFIGA, RF1AG01543) we have clinical information and biological samples in 701 families multiply affected by AD, including 5,932 individuals of which 304 families (43%) have three or more affected relatives and 1,874 individuals with sporadic AD and 2,739 healthy controls. We have begun recruiting members of the Caribbean Hispanic Religious Orders aged 60 years and older who consent to blood sampling for DNA and plasma, lumbar puncture for cerebrospinal fluid and autopsy at death. Our systematic genetic analyses in CH have yielded putative variants in ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, PICALM, SORL1, PINX1 and SRCAP, each of which has been replicated. To covert these genetic findings into meaningful applications to AD we now want to focus our efforts on the relationships between the genetic variants and epigenomics, transcriptomics, proteomics, metabolomics. From the existing cohorts of genetically characterized individuals we will assemble a new multi-omics cohort. This multi-omics cohort of 1,000 individuals will identify systems-level alterations in AD and will provide insight into the mechanisms underlying genetic variants, assist in identifying disease pathways, putative protein-protein interactions and downstream metabolites that can be used to inform preclinical work, develop biomarkers and eventually therapeutic targets for drug discovery. The overarching goal is to use a genetic variant-centered, environmentally inclusive integration of multiple omics layers to identify specific causal genes and investigate how they may perturb pathways leading to disease.

抽象的 25 年来，我们一直在研究家族性和散发性阿尔茨海默病 (AD) 的遗传基础 在美国和多米尼加共和国的加勒比西班牙裔中，向 阿尔茨海默病遗传学联盟和阿尔茨海默病测序项目。对于这个新 提案中，我们打算将加勒比西班牙裔 AD 的遗传分析与深层分子分析相结合 表型分析：使用全血、血浆、 尽可能采集脑脊液和脑组织。在这个少数群体中产生的多组学数据将 用于了解基因变异对疾病的影响，阐明受影响的蛋白质和途径 AD 的基础，并与在白人、非西班牙裔人群中进行的类似研究获得的结果进行比较，例如 作为加速药物合作伙伴关系——阿尔茨海默病。 与非西班牙裔人相比，我们发现加勒比地区的西班牙裔人的可能性是非西班牙裔人的三倍 75 岁时患上 AD。如果他们的家庭成员患有AD，他们的风险会高出五倍。来自研究 标题为“Estudio Familiar Investigar Genetica de Alzheimer”（EFIGA，RF1AG01543），我们有临床信息 701个家庭的生物样本和生物样本受到AD的多重影响，其中包括5,932人，其中304个家庭 (43%) 有 3 名或以上受影响的亲属、1,874 名散发性 AD 患者和 2,739 名健康对照者。 我们已开始招募 60 岁及以上的加勒比西班牙裔宗教团体成员 同意在死亡时进行血液采样以获取 DNA 和血浆、腰椎穿刺以获取脑脊液并进行尸检。 我们对 CH 的系统遗传分析得出了 ABCA7、BIN1、CD2AP、CLU、CR1、 EPHA1、MS4A4A/MS4A6A、PICALM、SORL1、PINX1 和 SRCAP，每个都已被复制。 为了将这些遗传发现转化为对 AD 有意义的应用，我们现在希望集中精力 遗传变异与表观基因组学、转录组学、蛋白质组学、代谢组学之间的关系。 从现有的具有遗传特征的个体队列中，我们将组建一个新的多组学队列。 这个由 1,000 人组成的多组学队列将识别 AD 中的系统级改变，并提供见解 深入了解遗传变异的机制，协助识别疾病途径、推定的蛋白质-蛋白质 相互作用和下游代谢物，可用于指导临床前工作、开发生物标志物和 最终药物发现的治疗靶点。总体目标是使用以遗传变异为中心的、 多个组学层的环境包容性整合，以确定特定的因果基因并进行研究 它们如何干扰导致疾病的途径。