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: 10381723
• 负责人: RICHARD P MAYEUX
• 金额: $ 228.26万
• 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/10381723
• 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，我们研究了家庭和零星阿尔茨海默氏病的遗传基础（AD） 在美国和多米尼加共和国的加勒比西班牙裔美国人中，为样本和数据贡献了 阿尔茨海默氏病遗传学财团和阿尔茨海默氏病测序项目。对于这个新 提案，我们打算将加勒比西班牙裔AD的遗传分析与深层分子相结合 表型：使用全血，等离子体，表观基因组学，转录组学，蛋白质组学和代谢组学 尽可能的脑脊液和脑组织。该少数人口中产生的多摩斯数据将 用于了解基因变异对疾病的影响，澄清受影响的蛋白质和途径 AD的基础和与从白人非西班牙裔人群中的类似研究获得的结果进行了比较 作为加速药物伙伴关系 - 阿尔茨海默氏病。 与非西班牙裔人相比，我们表明加勒比西班牙裔的可能性是 根据75岁的年龄开发广告。如果他们的家庭成员患有AD风险，他们的风险将高出五倍。从研究 题为“ Estudio熟悉的研究者遗传学阿尔茨海默氏症”（Efiga，RF1AG01543），我们有临床信息 701个家庭中的生物样品繁殖受AD的影响，其中包括5,932个个人，其中304个家庭 （43％）有三个或更多受影响的亲戚和1,874名零星AD和2,739个健康对照的人。 我们已经开始招募60岁以上的加勒比西班牙裔宗教命令的成员 同意DNA和血浆的血液采样，死亡时脑脊液的腰椎穿刺和尸检。 我们在CH中的系统遗传分析在ABCA7，BIN1，CD2AP，CLU，CR1， EPHA1，MS4A4A/MS4A6A，PICALM，SORL1，PINX1和SRCAP，每种都已重复。 为了将这些遗传发现涵盖为有意义的广告应用，我们现在想将精力集中在 遗传变异与表观基因组学，转录组学，保护性，代谢组学之间的关系。 从现有的遗传表征个体的同类中，我们将组装一个新的多摩尼克人群。 这个由1,000个人组成的多派对人群将确定AD中的系统级变更，并将提供洞察力 进入遗传变异的基础机制，有助于鉴定疾病途径，推定的蛋白质蛋白 相互作用和下游代谢产物，可用于为临床前工作提供信息，发展生物标志物和 最终用于药物发现的治疗靶标。总体目标是使用以遗传变体为中心的， 多个OMIC层的环境包含在环境中，以识别特定的因果基因并研究 它们如何扰动导致疾病的途径。