GENETIC ANALYSES OF GENES IN PRESENILIN RELATED PATHWAYS

早老素相关通路基因的遗传分析

• 批准号: 7483171
• 负责人: RUDOLPH Emile TANZI
• 金额: $ 47.11万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483171
• 关键词: 19q; Affect; Age; Allosteric Regulation; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Biological; Candidate Disease Gene; Catalysis; Categories; Chromosomes; Chromosomes, Human, Pair 19; Complex; Data; Evaluation; Family; Follow-Up Studies; Funding; Generations; Genes; Genetic; Genetic Transcription; Genome; Genomics; Haplotypes; Individual; Laboratories; Ligand Binding; Linkage Disequilibrium Mapping; Logistic Regressions; Methods; National Institute of Mental Health; Pathogenesis; Pathway interactions; Positioning Attribute; Post-Translational Protein Processing; Protein C; Proteins; RNA Splicing; Relative (related person); Resolution; Resources; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Survival Analysis; Testing; base; disorder risk; gamma secretase; genetic analysis; genetic linkage; genetic linkage analysis; novel; presenilin; secretase; signal peptide peptidase

In Project 2, we have shifted our focus to genetic analyses of positional candidate genes encoding proteins implicated in presenilin-related pathways. Over the past decade, our group has led the ascertainment, evaluation, and comprehensive genetic analyses of the NIMH Genetics Initiative Alzheimer's disease (AD) sample. This set of AD families, which currently includes 1527 individuals in 457 families, is the largest uniformly ascertained and evaluated sample ever assembled for the study of AD genetics. In separately funded studies, our laboratory recently completed the genetic analyses and preliminary follow-up studies of a comprehensive high-resolution genome screen for novel AD genes. The genome screen revealed that in addition to the expected highly significant linkage peak on chromosome 19q (APOE locus), several regions demonstrate evidence of 'suggestive' linkage to AD. In separately funded studies, we are further refining these linkage regions using additional markers. The immense data emanating from this screen constitute a powerful resource for research efforts aimed at identifying novel AD genes. To identify novel AD genes, we propose a positional candidate approach in which we test biologically compelling candidate genes from our AD genetic linkage peaks using family-based association, augmented by linkage disequilibrium mapping. Clusters of tightly spaced single nucleotide polymorphisms (SNPs) in positional candidate genes encoding proteins that are biologically implicated in presenilin-related pathways will be tested for association with AD. These genes have been divided into six categories: a. presenilin interactors, b. PS/gamma-secretase substrates, c. PS/gamma-secretase complex components and proteins that affect PS/gamma-secretase activity/Abeta generation, d. amyloid precursor protein (APP) C-terminus/APP intracellular domain (AICD) interactors, e. AICD transcriptional targets, and f. presenilin-like signal peptide peptidases. Testing of these genes will be prioritized according to their genomic position relative to the best-confirmed AD genetic linkage peaks, and their biological relevance to AD pathogenesis. Candidate genes for which positive signals are successfully found in the NIMH sample will be tested in an independent sample, the Consortium on Alzheimer's Genetics (CAG) sample. SNPs found to be strongly associated with AD in these samples will be phenotypically and functionally characterized including collaborative analyses with the six other PPG laboratories.

在项目2中，我们将重点转移到了编码与Presenilin相关途径有关的蛋白质的位置候选基因的遗传分析。在过去的十年中，我们的小组领导了NIMH遗传学倡议阿尔茨海默氏病（AD）样本的确定，评估和全面的遗传分析。目前包括457个家庭中的1527个个体的这组AD家族是有史以来最大的统一确定和评估样本，用于研究AD遗传学。在单独资助的研究中，我们的实验室最近完成了遗传分析和初步随访研究 新型广告基因的综合高分辨率基因组筛选。基因组筛查显示，除了预期的19q染色体上高度显着的连锁峰（APOE基因座）外，几个区域还证明了与AD的“暗示性”联系的证据。在单独资助的研究中，我们正在使用其他标记进一步完善这些联系区域。从该屏幕发出的巨大数据构成了旨在识别新型AD基因的研究工作的强大资源。为了识别新颖的广告基因，我们提出了一个位置 候选方法我们使用基于家庭的关联从我们的AD遗传连锁峰中测试了具有生物学吸引人的候选基因，并通过连锁不平衡映射增强。在生物学上与Presenililin相关途径有关的蛋白质的位置候选基因中紧密间隔的单核苷酸多态性（SNP）的簇将经过与AD相关的测试。这些基因已分为六个类别： Presenilin互动者，b。 PS/GAMMA-分泌酶底物，c。影响PS/GAMMA-分泌酶活性/ABETA生成的PS/GAMMA - 分泌酶复合成分和蛋白质，d。淀粉样蛋白前体蛋白（APP）C-末端/APP细胞内结构域（AICD）相互作用器，e。 AICD转录目标，f。老年蛋白样信号肽肽酶。这些基因的测试将根据其基因组位置相对于确认的AD遗传链接峰以及它们与AD发病机理的生物学相关性确定优先级。在NIMH样品中成功找到正信号的候选基因将在独立中测试 样本，阿尔茨海默氏症遗传学（CAG）样本的联盟。在这些样品中发现与AD密切相关的SNP将在表型和功能上表征，包括与其他六个PPG实验室的协作分析。