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: 6932670
• 负责人: ELLEN M WIJSMAN
• 金额: $ 12.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6932670
• 关键词: Alzheimer' s disease; apolipoprotein E; bioinformatics; clinical research; disease /disorder onset; gene mutation; genetic disorder; genetic mapping; genetic registry /resource /referral center; human genetic material tag; human tissue; presenilin; quantitative trait loci

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.

阿尔茨海默病（AD）是老年痴呆症的最常见原因。这种使人衰弱的神经退行性疾病的原因尚不清楚。大量证据表明AD有遗传基础。这些证据包括鉴定出三个基因，其中突变导致早发性家族性AD（FAD）：淀粉样前体蛋白（APP）基因，以及分别位于14号和1号染色体上的早老素1（PSEN 1）和早老素2（PSEN 2）。晚发性（LO）AD是一种更复杂的多因素疾病，只有APOE被确定为风险因素。APOE也影响LO AD的发病年龄，最近的证据也表明APOE对PSEN 1和PSEN 2突变诱导的AD发病年龄有影响。这一证据表明，在AD发病的广泛范围内，发病年龄具有遗传基础， 支持存在其他此类基因的信息表明，阐明AD发病年龄的遗传基础将有助于理解AD的一般病因。该项目的长期目标是通过识别导致该疾病的基因来确定AD的根本原因。目前项目的目标是集中研究发病年龄的遗传基础。具体目的是：（1）鉴定UW ADRC数据集中含有LO-FAD发病年龄基因座的染色体区域;（2）鉴定NIMH LO-FAD数据集中含有LO-FAD发病年龄基因座的染色体区域;以及（3）更准确地解析在对LO-FAD数据集的分析中检测到的感兴趣区域的大小。 这两个数据集包括更准确地定位这样的QTL，确定是否可以检测到连锁不平衡，并评估候选基因在感兴趣的区域。识别影响AD发病年龄的基因将有助于了解AD的病因，导致更好的诊断方法，并可能改善治疗和预防措施。