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

摘要 25年来，我们研究了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海拉美裔中，为 阿尔茨海默病遗传学联合会和阿尔茨海默病测序项目。对于这个新的 建议，我们打算将加勒比海拉美裔AD的遗传分析与深层分子相结合 表观基因组学、转录组学、蛋白质组学和全血、血浆、代谢组学 尽可能使用脑脊液和脑组织。在这一少数群体中产生的多重组学数据将 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 并与在白人、非西班牙裔人群中进行的类似研究的结果进行比较 被称为加速药物伙伴关系-阿尔茨海默氏症。 与非拉美裔美国人相比，我们已经表明，加勒比拉美裔美国人患癌症的可能性是非拉美裔美国人的三倍 在75岁之前患上老年痴呆症。如果他们的家人患有AD，他们的风险会高出五倍。来自这项研究 题为《ESTUDIO熟悉的遗传学研究阿尔茨海默病》(EFIGA，RF1AG01543)，我们有临床信息 在701个受AD影响的家庭中，生物样本成倍增加，包括5932个个体，其中304个家庭 (43%)有三个或更多受影响的亲属，1874名散发性AD患者和2739名健康对照。 我们已经开始招募60岁及以上的加勒比拉美裔宗教教团成员 同意抽血检测DNA和血浆，腰椎穿刺术检测脑脊液，死亡时进行尸检。 我们对CH的系统遗传分析发现了ABCA7、BIN1、CD2AP、CLU、CR1、 EPHA1、MS4A4A/MS4A6A、PICALM、SORL1、PINX1和SRCAP，每一个都被复制。 为了将这些基因发现转化为对AD有意义的应用，我们现在想把我们的努力集中在 基因变异与表观基因组学、转录组学、蛋白质组学、代谢组学的关系。 从现有的具有基因特征的个体队列中，我们将组装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的系统级变化，并将提供洞察力 研究遗传变异的机制，帮助确定疾病途径，推测的蛋白质-蛋白质 相互作用和下游代谢产物，可用于指导临床前工作，开发生物标记物和 最终成为药物发现的治疗靶点。首要目标是使用一种以基因为中心的变异， 环境包容的多个组学层次的整合，以识别特定的致病基因并研究 它们如何扰乱导致疾病的途径。

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.