Pleiotropic and Interaction Effects on Alzheimer's disease Risk and Progression

对阿尔茨海默病风险和进展的多效性和相互作用影响

• 批准号: 8344487
• 负责人: John Sai Keong Kauwe
• 金额: $ 23.77万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8344487
• 关键词: Address; Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Architecture; Biological; Biological Markers; Brain; Brain Pathology; Cerebrospinal Fluid; Clinical; Complex; Data; Diagnosis; Disease; Disease Progression; Elderly; Foundations; Gene-Modified; Genes; Genetic; Genetic Risk; Genetic Variation; Genome; Genotype; Goals; Immune response; Individual; Inflammatory Response; Knowledge; Lead; Light; Measurement; Methods; Modeling; Neurodegenerative Disorders; Other Genetics; Pathology; Pathway interactions; Play; Prevention; Process; Quantitative Trait Loci; Research; Risk; Role; Sampling; Screening procedure; Series; Symptoms; Testing; Variant; Work; case control; clinical Diagnosis; gene environment interaction; gene interaction; genetic risk factor; genetic variant; genome wide association study; genome-wide; insight; novel strategies; pleiotropism; programs; protein aggregation; protein misfolding; research clinical testing; tau Proteins; trait; treatment strategy

DESCRIPTION (provided by applicant): Recent observations in Alzheimer's disease suggest that factors, which influence the relationship between pathological features in the brain and clinical symptoms, play a significant role in the disease process. First, more than 25% of non-demented, elderly individuals have brain pathology that is indistinguishable from known Alzheimer's disease individuals. Second, among those with a clinical diagnosis of disease there are clearly "fast progressors" and "slow progressors". We will perform a genome-wide screen for relationship loci (rQTL) that modify the known relationship (correlation) between cerebrospinal fluid A¿42 levels and case/control status, thus screening for loci that explain the observation of non-demented individuals with Alzheimer's disease pathology. With slight adjustments to our models we can also screen for loci, which modify the known relationship between cerebrospinal fluid A¿42 levels and tau levels, and may explain the variation in the rate of progression of disease. For these analyses we have assembled over 2,000 samples with cerebrospinal fluid biomarker measurements, clinical evaluations, and whole-genome marker data for discovery and nearly 1000 samples with cerebrospinal fluid biomarker measurements and clinical evaluations for replication (genotyping to be completed as part of this proposal). We will then test the replicated variants for association with risk and rate of progression of Alzheimer's disease in approximately 20,000 cases and 30,000 controls (over 1900 of which have longitudinal measurements of disease progression). As demonstrated by our preliminary analyses, this promising approach will leverage the largest sample of its kind to identify genetic variation that is associated with Alzheimer's disease and Alzheimer's disease biomarkers via pleiotropic and interaction effects. This will provide insight into variation in important disease related processes such as protein aggregation and inflammatory and immune response. These findings are likely to be important for other protein aggregation and/or protein misfolding diseases. PUBLIC HEALTH RELEVANCE: The broad, long-term goal of our research is to solve the complex genetic architecture of Alzheimer's Disease, which will lead to better strategies for treatment and prevention of this devastating disease. In this proposal we will test hypotheses that genetic factors influence important clinical observations, such as the observation of Pleiotropic effects of APOE e4 on cerebrospinal fluid A¿ and tau levels, non-demented individuals with Alzheimer's disease pathology and variation in the rate of progression in clinically diagnosed Alzheimer's disease cases. We will use genome-wide marker data to detect loci that simultaneously affect cerebrospinal fluid amyloid beta and tau levels (pleiotropy), the relationships between Alzheimer's disease biomarkers (cerebrospinal fluid amyloid beta and tau) and Alzheimer's disease (referred to as rQTL), and gene-by-gene interactions. Identified loci are likely to affect both risk and/or progression of AD and will shed light on pathways connecting cerebrospinal fluid amyloid beta, tau, and Alzheimer's Disease.

描述（由申请人提供）：最近对阿尔茨海默病的观察表明，影响大脑病理特征和临床症状之间关系的因素在疾病过程中发挥着重要作用。首先，超过 25% 的非痴呆老年人的大脑病变与已知的阿尔茨海默病患者没有区别。其次，在临床诊断出疾病的患者中，明显存在“快速进展者”和“缓慢进展者”。我们将对关系位点 (rQTL) 进行全基因组筛选，该位点修改脑脊液 A¿42 水平与病例/对照状态之间的已知关系（相关性），从而筛选能够解释对患有阿尔茨海默氏病病理学的非痴呆个体的观察结果的位点。通过对我们的模型进行轻微调整，我们还可以筛选基因座，这些基因座改变了脑脊液 A¿42 水平和 tau 水平之间的已知关系，并可能解释疾病进展速度的变化。对于这些分析，我们收集了超过 2,000 个具有脑脊液生物标志物测量、临床评估和全基因组标志物数据的样本以进行发现，并收集了近 1000 个具有脑脊液生物标志物测量和临床评估的样本以进行复制（基因分型将作为本提案的一部分完成）。然后，我们将在大约 20,000 例病例和 30,000 名对照者（其中超过 1900 名对照者对疾病进展进行纵向测量）中测试复制的变异与阿尔茨海默病进展的风险和速率的关联。正如我们的初步分析所证明的，这种有希望的方法将利用同类中最大的样本，通过多效性和相互作用效应来识别与阿尔茨海默病和阿尔茨海默病生物标志物相关的遗传变异。这将有助于深入了解重要疾病相关过程的变化，例如蛋白质聚集以及炎症和免疫反应。这些发现可能对其他蛋白质聚集和/或蛋白质错误折叠疾病很重要。 公共健康相关性：我们研究的广泛、长期目标是解决阿尔茨海默病的复杂遗传结构，这将为治疗和预防这种破坏性疾病提供更好的策略。在本提案中，我们将测试遗传因素影响重要临床观察的假设，例如观察 APOE e4 对脑脊液 A 和 tau 水平的多效性影响、患有阿尔茨海默病病理学的非痴呆个体以及临床诊断的阿尔茨海默病病例进展速度的变化。我们将使用全基因组标记数据来检测同时影响脑脊液淀粉样蛋白 β 和 tau 水平（多效性）的基因座、阿尔茨海默病生物标记物（脑脊液淀粉样蛋白 β 和 tau）与阿尔茨海默病（称为 rQTL）之间的关系，以及基因与基因之间的相互作用。已确定的位点可能会影响 AD 的风险和/或进展，并将揭示脑脊液 β 淀粉样蛋白、tau 蛋白和阿尔茨海默氏病之间的联系途径。