Exploring the Genetics of Alzheimer's Disease in Humans and Drosophila

描述（由申请人提供）：基因分型技术和统计方法的进步已经汇聚在一起，使发现常见疾病的易感基因成为现实。全基因组关联研究（GWAS）正在进行阿尔茨海默病（AD），很可能会出现验证的基因座，因为遗传变异的识别障碍被克服。虽然一个主要的障碍是样本量，另一个是表型异质性。AD诊断的离散临床结果受到患者样本中的临床异质性和对照受试者中存在大量但亚临床AD相关病理的影响。使用定量中间表型是一种补充方法，可最大限度地减少这些混杂因素，并有可能提高统计功效。我们正在对人类基因组中与AD神经病理学定量测量相关的基因座进行分析，这些基因座存在于来自社区研究的两个大型尸检队列中，即宗教秩序研究（ROS）和拉什记忆和衰老项目（MAP）。将对多态性与认知能力下降的相关性进行二次评价，以确定其临床相关性。我们建议将这些人类遗传学研究与一个简单但功能强大的功能性筛选结合起来，在一个与黑腹果蝇AD相关的现有遗传模型中进行。这一策略将使我们能够有效地从GWAS结果列表转移到易感基因的验证和遗传精细定位的位点选择。具体而言，我们建议执行以下目标：目标1：AD神经病理学中间表型的GWAS。我们将使用来自1000多名受试者的合并尸检队列的906，600个单核苷酸多态性和946，000个拷贝数探针的数据进行全基因组关联分析。将基于淀粉样斑块和神经纤维缠结的计数来检查整体AD病理学的定量测量的关联。目的2：评估AD病理易感位点与认知功能下降的相关性。将在超过3，800名受试者的汇总队列中评估GWAS的得分最高的多态性，并进行纵向神经精神测量，以确定其临床相关性。该队列将包括ROS和MAP，以及来自基于人群的芝加哥健康与老龄化项目的受试者。目的3：在果蝇属模型系统中验证候选易感基因。我们将利用果蝇遗传学的高通量能力，以及果蝇基因组的近饱和功能获得和功能丧失试剂的可用性，筛选目标1和2中鉴定的候选基因与Tau神经毒性的功能相互作用。目的4：最有希望的基因座的遗传精细定位。 相关性：AD是最常见的神经退行性疾病，也是痴呆症的主要原因，预计到2050年，美国将有近1300万人受到影响。因此，确定风险因素和开发新疗法的努力是一个优先事项。发现与AD病理和认知能力下降相关的基因将突出疾病的新机制，确定候选药物靶点，并可能促进早期诊断和风险预测。

DESCRIPTION (provided by applicant): Advances in genotyping technology and statistical methods have converged to make the discovery of susceptibility genes for common diseases a reality. Genome-wide association studies (GWAS) are being performed for Alzheimer's disease (AD) and it is likely that validated loci will emerge, as impediments to the identification of genetic variants are overcome. While a major barrier is sample size, another is phenotypic heterogeneity. The discrete clinical outcome of AD diagnosis is burdened by clinical heterogeneity in the patient sample and the presence of substantial but sub-clinical AD-related pathology in control subjects. The use of quantitative intermediate phenotypes is a complementary approach that minimizes these confounders and has the potential to enhance statistical power. We are conducting an analysis of the human genome for loci associated with a quantitative measure of AD neuropathology present in two large autopsy cohorts from community-based studies, the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). Polymorphisms will be secondarily evaluated for associations with cognitive decline to establish their clinical relevance. We propose to couple these human genetic studies with a simple but powerful functional screen in an existing genetic model relevant to AD in Drosophila melanogaster. This strategy will enable us to move efficiently from a list of GWAS results to validation of susceptibility genes and selection of loci for genetic fine mapping. Specifically we propose to execute the following aims: Aim 1: A GWAS for an AD neuropathology intermediate phenotype. We will perform genome-wide association analysis using data on 906,600 single nucleotide polymorphisms and 946,000 copy number probes from a pooled autopsy cohort of more than 1000 subjects. Associations will be examined for a quantitative measure of global AD pathology based on counts of amyloid plaques and neurofibrillary tangles. Aim 2: Evaluation of AD pathology susceptibility loci for associations with cognitive decline. Top-scoring polymorphisms from the GWAS will be evaluated in a pooled cohort of more than 3,800 subjects with longitudinal neuropsychiatric measures to establish their clinical relevance. This cohort will include both ROS and MAP, as well as subjects from the population-based Chicago Health and Aging Project. Aim 3: Validation of candidate susceptibility genes in a Drosopiiila model system. We will leverage the high-throughput capabilities of fly genetics, and the availability of near-saturation gain- and loss-of-function reagents for the Drosopiiila genome, to screen candidate genes identified in Aims 1 & 2 for functional interactions with Tau neurotoxicity. Aim 4: Genetic fine mapping of the most promising locus. RELEVANCE: AD is the most common neurodegenerative disease and the leading cause of dementia, with nearly 13 million individuals projected to be affected in the US by 2050. Efforts to identify risk factors and develop new therapies are therefore a priority. The discovery of genes associated with AD pathology and cognitive decline will highlight novel mechanisms of disease, identify candidate drug targets, and may facilitate early diagnosis and risk prediction.