Research Supplements to Promote Diversity in Health-Related Research

描述(申请人提供)：最近对阿尔茨海默病的观察表明，影响大脑病理特征与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%的非痴呆症老年人的大脑病理与已知的阿尔茨海默病患者难以区分。其次，在那些被临床诊断为疾病的人中，有明显的“快速进展者”和“缓慢进步者”。我们将进行全基因组范围的关系基因座(RQTL)筛选，以修正脑脊液A�42水平和病例/对照状态之间的已知关系(相关性)，从而筛选出解释阿尔茨海默病病理的非痴呆个体观察到的基因座。对我们的模型稍作调整，我们还可以筛选出改变脑脊液A�42水平和tau水平之间已知关系的基因座，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2000多个样本，其中包括用于发现的脑脊液生物标记物测量、临床评估和全基因组标记数据，以及近1000个样本和脑脊液生物标记物测量和临床评估以供复制(基因分型将作为该提案的一部分完成)。然后，我们将在大约20,000个病例和30,000个对照组(其中超过1900个有疾病进展的纵向测量)中测试复制的变异与阿尔茨海默病的风险和进展速度的相关性。正如我们的初步分析所表明的那样，这一有希望的方法将利用同类样本中最大的样本，通过多效性和相互作用效应识别与阿尔茨海默病和阿尔茨海默病生物标记物相关的基因变异。这将提供对蛋白质聚集、炎症和免疫反应等与疾病相关的重要过程的变化的洞察。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具有重要意义。

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.