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.

该项目的总体目的是确定唐氏综合症成年人（DS）在发病时期和阿尔茨海默氏病风险（AD）时对年龄的贡献。连锁和关联研究提供了证据表明对AD风险的遗传影响很大，但是在DS成年人中，尚未研究大多数这些遗传因素的作用。 DS过表达的成年人P淀粉样蛋白前体蛋白（APP）具有早期的AD神经病理学和痴呆症的高风险。但是，AD发作时的年龄很广，而不是所有具有DS的成年人发展AD，这表明额外的风险决定因素的重要性。在先前的工作中，我们做出了几个关键的观察结果，以支持以下假设：遗传和环境因素可以在发病时会导致年龄以及DS中的AD风险。现在，我们建议确定可能影响认知功能，AD风险，AD发作时的风险，AB肽水平的差异的遗传变异的贡献，这些成年人与我们当前项目的DS有差异。我们将利用自本研究成立以来已经完成的深层表型和重复评估。该队列最多完成了6项随访评估，我们有大量的事件AD病例样本，其发作和进展已得到充分记录。我们已经存储了366名DS的DNA，神经心理学和功能状态测试评分，病史，AP肽水平和痴呆状态，并将招募并遵循 另外150名无需参与者与亚第2和2号的参与者一起。因此，我们处于独特的位置，将遗传变异与一系列与AD相关的表型相关联。我们将对DS成人成人的广泛候选基因进行分析。我们将使用Lllumina Goldengate自定义阵列罚款候选基因。分析将首先集中在荟萃分析中已经在先前的基因组广泛的链接或关联研究中鉴定出的变体，并且与AD发病机理有关，其中包括对筛查具有生物学重要性的区域以及21号染色体上的候选基因，这些区域在成人中与DS在成人中二次三倍。我们将进行等位基因和基因型关联研究，以确定对（1）AD风险产生最大影响的多态性； （2）AD发作时的年龄； （3）痴呆症和非痴呆成年人中AB肽的变化水平和变化率； （4）认知功能。然后，我们将使用与AD有牢固显着关联的SNP来确认独立复制数据集中的关联，首先是在大型成年人中与DS的大量表征，然后在美国国家衰老研究所的非DS同类中 - 在衰老的衰老研究所 - 晚期开始时期的阿尔茨海默氏病研究（NIA-LOAD）。我们将将Tycko博士表观遗传项目中鉴定的基因的变体与与血液相关的表型联系起来。