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

描述(申请人提供)：基因分型技术和统计方法的进步汇聚在一起，使发现常见疾病的易感基因成为现实。目前正在对阿尔茨海默病(AD)进行全基因组关联研究，随着遗传变异识别的障碍被克服，有效的基因座很可能会出现。虽然一个主要障碍是样本大小，但另一个障碍是表型异质性。AD诊断的离散临床结果受累于患者样本中的临床异质性和对照组中实质性但亚临床AD相关病理的存在。量化中间表型的使用是一种补充方法，它最大限度地减少了这些混杂因素，并有可能增强统计能力。我们正在对人类基因组进行分析，以寻找与AD神经病理的定量测量相关的基因座，该基因座存在于两个来自社区研究的大型尸检队列中，即宗教秩序研究(ROS)和快速记忆和衰老项目(MAP)。将对多态与认知功能下降的相关性进行二次评估，以确定它们的临床相关性。我们建议将这些人类基因研究与现有的与果蝇阿尔茨海默病相关的遗传模型中的一个简单但强大的功能筛选结合起来。这一策略将使我们能够有效地从GWAS结果列表转移到验证易感基因和选择用于遗传精细定位的基因座。具体地说，我们建议执行以下目标：目标1：AD神经病理中间表型的GWA型。我们将使用来自1000多名受试者的集合尸检队列中的906,600个单核苷酸多态和946,000个拷贝数探针的数据进行全基因组关联分析。将根据淀粉样斑块和神经原纤维缠结的计数，对全球AD病理的定量测量的相关性进行检查。目的2：评价AD病理易感基因与认知功能减退的关系。来自GWAS的得分最高的多态性将通过纵向神经精神病学测量在3800多名受试者中进行评估，以确定它们的临床相关性。这一队列将包括ROS和MAP，以及以人口为基础的芝加哥健康和老龄化项目的受试者。目的3：在Drosopiila模型系统中验证候选易感基因。我们将利用苍蝇遗传学的高通量能力，以及Drosopiiila基因组接近饱和的功能增减试剂的可用性，筛选AIMS 1和2中确定的与Tau神经毒性功能相互作用的候选基因。目的4：最有希望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，也是导致痴呆症的主要原因，预计到2050年，美国将有近1300万人受到影响。因此，努力确定风险因素和开发新的治疗方法是当务之急。AD病理和认知功能下降相关基因的发现将突出疾病的新机制，确定候选药物靶点，并可能有助于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.