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: 9975379
• 负责人: RICHARD P MAYEUX
• 金额: $ 229.97万
• 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/9975379
• 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; Multiomic Data; Not Hispanic or Latino; Pathway interactions; Patients; Plasma; Population; 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.

摘要