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

基本信息

批准号：
8279293
负责人：
NICOLE SCHUPF
金额：
$ 22.72万
依托单位：
HUGO W. MOSER RES INST KENNEDY KRIEGER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8279293
关键词：
Adult Age Age-Years Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Amyloid beta-Protein Precursor Analysis of Variance Anemia 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 functional status genetic analysis genetic epidemiology genetic variant genome-wide linkage high risk mRNA Expression men neuropathology neuropsychological sex

项目摘要

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遗传变异对唐氏综合症 (DS) 成人的发病年龄和阿尔茨海默病 (AD) 风险的影响。连锁和关联研究提供了遗传因素对 AD 风险的显着影响的证据，但大多数遗传因素在 DS 成人中的作用尚未得到研究。患有 DS 的成人过度表达 p 淀粉样前体蛋白 (APP)，AD 神经病理学发病较早，痴呆风险较高。然而，AD 的发病年龄范围很广，而且并非所有患有 DS 的成年人都会患 AD，这表明其他风险决定因素的重要性。在之前的工作中，我们进行了几项关键观察，支持以下假设：遗传和环境因素可能会影响 DS 的发病年龄和 AD 风险。我们现在建议确定遗传变异的贡献，这些变异可能影响认知功能、AD 风险、AD 发病年龄，以及我们当前项目中一大群患有 DS 的成年人中 AB 肽水平的差异。我们将利用自本研究开始以来已完成的深度表型分析和重复评估。该队列已完成多达 6 项随访评估，我们拥有大量 AD 事件病例样本，其发病和进展都有详细记录。我们存储了 366 名患有 DS 的男性和女性的 DNA、神经心理学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 2 一起。因此，我们处于独特的地位，可以将遗传变异与一系列 AD 相关表型联系起来。我们将对患有 DS 的成人中 AD 的一系列候选基因进行分析。我们将使用 lllumina GoldenGate 定制阵列精细定位候选基因。分析将首先关注在之前的全基因组连锁或关联研究、荟萃分析中鉴定出的、与 AD 发病机制有关的变异，包括对筛选具有重要生物学意义的区域，以及 21 号染色体上的候选基因患有 DS 的成人中出现三次。我们将进行等位基因和基因型关联研究，以确定对 (1) AD 风险影响最大的多态性； (2)AD发病年龄； (3) 痴呆和非痴呆成人中 AB 肽的水平和变化率； (4)认知功能。然后，我们将使用与 AD 具有显着相关性的 SNP 来确认独立复制数据集中的关联，首先是在一大群特征明确的 DS 成人队列中，然后是在来自国家老龄化晚发性阿尔茨海默病研究所的非 DS 队列中研究（NIA-LOAD）。我们将把 Tycko 博士的表观遗传项目中发现的基因变异与血液相关表型联系起来。