Genetic Epidemiology of Alzheimer's Disease in Down Syndrome

唐氏综合症中阿尔茨海默病的遗传流行病学

• 批准号: 7976430
• 负责人: NICOLE SCHUPF
• 金额: $ 21.8万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7976430
• 关键词: Adult; Age; Age-Years; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Analysis of Variance; Anemia; Apolipoprotein E; Autoimmunity; Bioinformatics; Biological; Blood; Blood Cells; Candidate Disease Gene; Chromosome Mapping; Chromosomes, Human, Pair 21; Cognitive; Cox Proportional Hazards Models; Custom; DNA; Data; Data Set; Dementia; Disease; Down Syndrome; Environmental Risk Factor; Epigenetic Process; Ethnic Origin; Genes; Genetic; Genetic Polymorphism; Genotype; Individual; Individual Differences; Infection; Inflammatory; Intellectual functioning disability; Late Onset Alzheimer Disease; Maps; Medical History; Memory; Menopausal Status; Mental Retardation; Meta-Analysis; Methylation; Modeling; Modification; Multivariate Analysis; National Institute on Aging; Participant; Pathogenesis; Pathway interactions; Peptides; Performance; Phenotype; Plasma; Positioning Attribute; Predisposition; Presenile Alzheimer Dementia; Recruitment Activity; Recurrence; Resistance; Risk; Risk Factors; Role; SNP genotyping; Sampling; Survival Analysis; Testing; Time; Variant; Woman; Work; base; cognitive function; cohort; follow up assessment; functional status; genetic analysis; genetic epidemiology; genetic variant; genome-wide linkage; high risk; mRNA Expression; men; neuropathology; neuropsychological; sex

The overall aim of this project is to determine the contribution of genetic variants to age at onset and risk of Alzheimer's disease (AD) in adults with Down syndrome (DS). Linkage and association studies have provided evidence for significant genetic influences on risk for AD, but the role for most of these genetic factors has not been investigated in adults with DS. Adults with DS over-express the p amyloid precursor protein (APP), have early onset of AD neuropathology and high risk for dementia. However, there is a wide range of age at onset of AD and not all adults with DS develop AD, suggesting the importance of additional determinants of risk. In previous work, we made several key observations that support the hypothesis that genetic and environmental factors can contribute to age at onset and risk of AD in DS. We propose now to determine the contribution of genetic variants that may influence cognitive function, risk for AD, age at onset of AD, and differences in AB peptide levels in a large cohort of adults with DS from our current project. We will take advantage of the deep phenotyping and repeated assessments that have been accomplished since the inception of this study. The cohort has completed up to 6 follow-up assessments and we have a large sample of incident AD cases whose onset and progression has been well documented. We have stored DNA, neuropsychological and functional status test scores, medical history, AP peptide levels, and dementia status on 366 men and women with DS and will recruit and follow an additional 150 nondemented participants in conjunction with Subprojects 1 and 2. Thus, we are in a unique position to relate genetic variants to a range of AD-related phenotypes. We will conduct an analysis of a broad panel of candidate genes for AD in adults with DS. We will fine map candidate genes using the lllumina GoldenGate custom array. Analyses will focus first on variants which have been identified in prior genome wide linkage or association studies, in meta-analyses, and that have been implicated in AD pathogenesis, including regions that are biologically important to screen, as well as candidate genes on chromosome 21 which are triplicated in adults with DS. We will perform allelic and genotypic association studies to identify polymorphisms that confer the strongest influence on (1) risk for AD; (2) age at onset of AD; (3) levels and rate of change in AB peptides in demented and nondemented adults; and (4) cognitive function. Then we will use the SNPs with robust significant associations with AD to confirm the associations in independent replication datasets, first in a large well characterized cohort of adults with DS and then in non-DS cohorts from the National Institute on Aging- Late Onset Alzheimer's Disease Study (NIA-LOAD). We will relate variants in genes identified in Dr. Tycko's epigenetic project to blood-related phenotypes.

该项目的总体目标是确定基因变异对唐氏综合征(DS)成人阿尔茨海默病(AD)发病年龄和风险的影响。连锁和关联研究已经为AD风险的显著遗传影响提供了证据，但这些遗传因素中的大多数在患有DS的成年人中的作用还没有被调查。成年DS患者过度表达β-淀粉样前体蛋白(APP)，具有较早的AD神经病理发病和痴呆的高风险。然而，AD的发病年龄范围很广，并不是所有患有DS的成年人都会患上AD，这表明其他风险决定因素的重要性。在之前的工作中，我们做了几个关键的观察，支持这样的假设，即遗传和环境因素可以影响DS患者的发病年龄和AD的风险。我们现在建议从我们目前的项目中确定可能影响认知功能、AD风险、AD发病年龄以及AB肽水平差异的遗传变异的贡献。我们将利用自这项研究开始以来所完成的深入表型和重复评估。该队列已经完成了多达6次后续评估，我们有大量的AD事件病例样本，这些病例的发病和进展都有很好的记录。我们已经存储了366名患有DS的男性和女性的DNA、神经心理和功能状态测试分数、病史、AP肽水平和痴呆状态，并将招募和跟踪 另外150名非痴呆参与者与子项目1和子项目2结合。因此，我们处于一个独特的位置，可以将遗传变异与一系列AD相关表型联系起来。我们将对成年DS患者的AD候选基因进行广泛的分析。我们将使用llLumina GoldenGate定制阵列对候选基因进行精细定位。分析将首先集中在先前的全基因组连锁或关联研究中发现的变异，在荟萃分析中，以及与AD发病机制有关的变异，包括对筛选具有生物学意义的区域，以及21号染色体上的候选基因，这些基因在患有DS的成年人中是三重的。我们将进行等位基因和基因关联研究，以确定对(1)AD风险；(2)AD发病年龄；(3)痴呆症和非痴呆症成年人AB肽水平和变化率影响最大的多态；以及(4)认知功能。然后，我们将使用与AD有显著相关性的SNP来确认独立复制数据集中的相关性，首先是在大量具有良好特征的成年DS患者队列中，然后是来自国家老龄化-晚发性阿尔茨海默病研究(NIA-LOAD)的非DS队列。我们将把Tycko博士的表观遗传学项目中发现的基因变异与血液相关的表型联系起来。