Cloning of Late-onset Alzheimer's Disease Genes

描述（由申请人提供）：阿尔茨海默病（AD）是最常见的 老年痴呆症的常见原因。在美国，这种疾病影响 约3-4百万人，美国经济损失超过50美元 每年10亿。这种使人衰弱的神经退行性疾病的原因 目前未知。然而，大量证据表明， 至少一些（如果不是全部的话）AD病例是由于遗传因素。遗传分析 有多个早发性AD病例的家庭的研究表明，3 常染色体显性基因负责至少一些发生的 疾病在这些家庭中，受影响者的后代至少占50%。 遗传家族性AD（FAD）基因和发展AD的风险。晚发型FAD LOFAD似乎涉及其他基因，是一种更复杂的疾病。使用 连锁分析，其他复杂的统计遗传学方法， 定位克隆方法，该项目的长期目标是 通过识别负责AD的基因， 迟发性AD的遗传形式使用遗传连锁分析，基于Monte Carlo马尔可夫链方法，我们确定了一个数量性状位点， 染色体-19p13.2影响AD风险。该位点被鉴定为 影响发病年龄的数量性状。19 p基因座的靶向， 该项目不同于ApoE，另一个LOFAD基因位于19 q13。以识别 通过定位克隆这种新的LOFAD基因，以下步骤将是 执行。首先，19p13.2的物理、序列和基因图谱跨越了 将生成由连锁分析指示的区域。第二，基因在这 将通过数据库分析和DNA测序筛选一个区域的多态性位点。 序列分析第三，跨区域的多态性将用于 测试该地区的连锁不平衡。检测的多态位点将 包括短串联重复多态性位点和单核苷酸 多态性（SNP）位点。第四，将测试该地区基因中的SNP 作为多个家族性和病例对照样本中的致病位点， 真正的致病等位基因第五，当基因和致病等位基因 发现，将设计功能测定来确定 导致AD的发病机制。其他LOFAD基因的鉴定应 大大提高了我们对AD的理解，并可能导致新类型的 治疗

DESCRIPTION (provided by the applicant): Alzheimer's disease (AD) is the most common cause of dementia in the elderly. In the U.S., this disease affects approximately 3-4 million persons, costing the U.S. economy more than $50 billion per year. The cause(s) of this debilitating neurodegenerative disease is/are presently unknown. However, a large body of evidence indicates that at least some, if not all, AD cases are due to genetic factors. Genetic analysis of families with multiple cases of early-onset AD has shown that 3 autosomal-dominant genes are responsible for at least some occurrences of the disease. In these families, offspring of affected persons are at least at 50% risk of inheriting a Familial AD (FAD) gene and developing AD. Late-Onset FAD (LOFAD) appears to involve other genes, and is a more complex disease. Using linkage analysis, other sophisticated statistical genetic methods and positional cloning approaches, the long-range goal of this project is to identify the underlying causes of AD by identifying the genes responsible for genetic forms of late-onset AD. Using genetic-linkage analysis, based on Monte Carlo Markov Chain methods, we identified a quantitative trait locus on chromosome-19p 13.2 that affects AD risk. This locus was identified as a quantitative trait that affects age-of-onset. The 19p locus targeted by this project is distinct from ApoE, another LOFAD gene located at 19q13. To identify this new LOFAD gene by positional cloning, the following steps will be performed. First, a physical, sequence, and gene-map of 19p13.2 spanning the region, indicated by linkage analysis, will be generated. Second, genes in this region will be screened for polymorphic sites by database analysis and DNA sequence analysis. Third, polymorphisms spanning the region will be used to test for linkage disequilibrium in the region. Polymorphic sites tested will include short tandem repeat polymorphic sites and single nucleotide polymorphism (SNP) sites. Fourth, SNP's in genes in the region will be tested as pathogenic sites in multiple familial and case-control samples to identify the true pathogenic allele. Fifth, when the gene and pathogenic alleles are found, functional assays will be devised to determine the mechanism of pathogenesis leading to AD. Identification of additional LOFAD genes should greatly enhance our understanding of AD, and potentially lead to new types of therapies.