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，我们将重点转移到编码与早老素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，我们的团队领导了 NIMH 遗传学计划阿尔茨海默病 (AD) 样本的确定、评估和全面遗传分析。这组 AD 家族目前包括 457 个家族的 1527 名个体，是迄今为止为 AD 遗传学研究收集的最大的统一确定和评估样本。在单独资助的研究中，我们的实验室最近完成了一个基因分析和初步的后续研究。 全面的高分辨率基因组筛选新型 AD 基因。基因组筛选显示，除了 19q 染色体（APOE 位点）上预期的高度显着连锁峰外，几个区域还显示出与 AD 存在“暗示”连锁的证据。在单独资助的研究中，我们正在使用额外的标记进一步细化这些连锁区域。该屏幕产生的大量数据构成了旨在识别新型 AD 基因的研究工作的强大资源。为了识别新的 AD 基因，我们提出了一个位置 候选方法，我们使用基于家族的关联来测试来自 AD 遗传连锁峰的生物学上引人注目的候选基因，并通过连锁不平衡图谱进行增强。将测试位置候选基因中编码生物学上与早老素相关途径有关的蛋白质的紧密间隔的单核苷酸多态性 (SNP) 簇与 AD 的关联。这些基因被分为六类：早老素相互作用物，b。 PS/γ-分泌酶底物，c．影响PS/γ-分泌酶活性/Abeta生成的PS/γ-分泌酶复合物成分和蛋白质，d．淀粉样前体蛋白 (APP) C 末端/APP 胞内结构域 (AICD) 相互作用因子，例如AICD 转录靶标，以及 f．早老素样信号肽肽酶。这些基因的测试将根据它们相对于最佳确认的 AD 遗传连锁峰的基因组位置以及它们与 AD 发病机制的生物学相关性来确定优先顺序。在 NIMH 样本中成功发现阳性信号的候选基因将在独立的实验室中进行测试 样本，阿尔茨海默氏症遗传学联盟 (CAG) 样本。这些样本中被发现与 AD 密切相关的 SNP 将进行表型和功能表征，包括与其他六个 PPG 实验室进行合作分析。