GENETIC MAPPING OF LATE-ONSET ALZHEIMER'S DISEASE GENES

迟发性阿尔茨海默病基因的基因图谱

• 批准号: 7415093
• 负责人: ELLEN M WIJSMAN
• 金额: $ 18.92万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7415093
• 关键词: 19p; Abbreviations; Address; Affect; Age; Age of Onset; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Apolipoprotein E; Candidate Disease Gene; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 19; Chromosomes, Human, Pair 21; Clinical dementia rating scale; Complex; Coupled; Data; Data Set; Defect; Dementia; Diagnostic Procedure; Disease; Educational workshop; Elderly; Equipment and supply inventories; Etiology; FTD with parkinsonism; Family; Frontotemporal Dementia; Genes; Genetic; Genetic Databases; Genome Scan; Genotype; German population; Goals; Induced Mutation; Inherited; Joints; LDL-Receptor Related Protein 1; Late Onset Alzheimer Disease; Lead; Link; Linkage Disequilibrium; Localized; Location; Lod Score; Macroglobulins; Maintenance; Markov Chains; Measures; Methods; Mutation; National Institute of Mental Health; Neurodegenerative Disorders; Neurofibrillary Tangles; Parkinson Disease; Parkinsonian Disorders; Phenotype; Platelet Factor 4; Presenile Alzheimer Dementia; Principal Investigator; Quantitative Trait Loci; Questionnaires; Range; Rate; Recombination Fraction; Research; Research Personnel; Resources; Risk Factors; Sampling; Scoring Method; Sequence Analysis; Severities; Short Tandem Repeat Polymorphism; Signal Transduction; Susceptibility Gene; TNFRSF5 gene; Therapeutic; Time; Universities; Washington; autosomal dominant trait; base; density; early onset; familial Alzheimer disease; follow-up; genetic analysis; genetic linkage analysis; genetic pedigree; genetic risk factor; geriatric depression; improved; interest; kindred; neuropsychiatry; positional cloning; presenilin-1; presenilin-2; programs; segregation; simulation; size; trait

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. The causes of this debilitating neurodegenerative disease are unknown. A large body of evidence indicates that AD has a genetic basis. This evidence includes the identification of three genes in which mutations cause early-onset familial AD (FAD): the amyloid precursor protein (APP) gene, and presenilin 1 (PSEN1) and presenilin 2 (PSEN2) on chromosomes 14 and 1, respectively. Late onset (LO) AD is a more complex, multifactorial disease, with only APOE identified is a risk factor. APOE also affects age-at-onset of LO AD, with recent evidence also showing that there are effects of APOE on age-at-onset of AD induced by mutations in PSEN1 and PSEN2. This evidence for genetic basis of age-at-onset across a wide range of onset of AD, coupled with information supporting the existence of additional such genes, indicates that elucidation of the genetic basis of age-at-onset orf AD would contribute to understanding of the general etiology of AD. The long-range goal of this project is to identify the underlying causes of AD by identifying genes that contribute to the disease. The goal of the current project is to focus on the genetic basis of age-at-onset. The specific aims are (1) To identify chromosomal regions containing LO-FAD age-at-onset loci in the UW ADRC data set; (2) To identify chromosomal regions containing LO-FAD age-at-onset loci in the NIMH LO-FAD dataset; and (3) To more accurately resolve the size of the regions of interest detected in the analysis of both of these data sets including more accuractly localizing such QTLs, determining whether linkage disequlibrium can be detected, and evaluating candidate genes in the regions of interest. Identifcation of genes affecting AD age-at-onset will facilitate an understanding of the etiology of AD, lead to better diagnostic methods, and potentally also to improved therapeutic and preventative measures.

阿尔茨海默氏病（AD）是老年痴呆症的最常见原因。这种衰弱的神经退行性疾病的原因尚不清楚。大量证据表明AD具有遗传基础。该证据包括鉴定三个基因，其中突变引起早发家族性AD（FAD）：淀粉样蛋白前体蛋白（APP）基因，以及染色体14和1上的Presenilin 1（PSEN1）和Presenilin 2（PSEN1）和Presenilin 2（PSEN2）。晚发（LO）AD是一种更复杂的多因素疾病，仅确定APOE是一个危险因素。 ApoE还影响了LO AD的年龄，最近的证据还表明，ApoE对PSEN1和PSEN2突变引起的AD年龄at的影响。这一证据是广泛的AD发作的年龄增长的遗传基础，并与 支持存在此类基因的信息，表明阐明了年龄符合年龄的ORF AD的遗传基础将有助于理解AD的一般病因。该项目的远程目标是通过识别有助于该疾病的基因来识别AD的根本原因。当前项目的目的是专注于年龄增长的遗传基础。具体目的是（1）识别在UW ADRC数据集中包含lo fad年龄的基因座的染色体区域； （2）识别NIMH LO-FAD数据集中包含lo fad年龄基因座的染色体区域； （3）更准确地解决分析中检测到的感兴趣区域的大小 这两个数据集包括更精确地定位此类QTL，确定是否可以检测到连锁障碍，并评估感兴趣区域中的候选基因。鉴定影响AD年龄发病的基因将有助于了解AD的病因，从而获得更好的诊断方法，并有效地改善治疗和预防措施。