Search for the Alzheimer's Gene on Chromosome 10

描述（由主要研究者提供）：晚发性阿尔茨海默病 (LOAD) 是一种复杂的多因素疾病，可能涉及多个基因。载脂蛋白 E (APOE)，尤其是 APOE*4 等位基因，已被确定为强易感性标记，占 LOAD 风险的 20-29%。除了疾病风险外，AD 的发病年龄 (AAO) 也受到基因控制，APOE 基因对 AAO 变异的影响小于 10%。这强调了其他遗传和/或环境因素的参与，这些因素单独或与 APOE*4 结合，可以改变 AD 的风险或 AAO。最近，LOAD 上的全基因组连锁为多条染色体上存在多个 AD 假定基因提供了证据，其中在 9、10 和 12 号染色体上的证据最为有力。随着人类基因组中单核苷酸多态性 (SNP) 高密度图谱的构建，现在可以使用基于群体的关联研究方法来识别假定的 AD 风险基因。有人提出，染色体 10q11（50 Mb）和 10q25（116 Mb）之间存在一个涵盖 >65 Mb 区域的宽连锁峰，该连锁峰影响 AD 风险和 AAO。作为我们初步数据的一部分，我们在大型病例对照队列中筛选了位于这个广泛的 >65 Mb 连锁区域下的 13 个已知生物候选基因中的 21 个 SNP，并确定了与位于 10q11 上 50.5 Mb 的胆碱乙酰转移酶 (CHAT) 基因和 10q22 上 75.3 Mb 的尿激酶型纤溶酶原激活剂 (PLAU) 基因中的 SNP 之间的显着关联。因此，我们的关联研究结果是对报告的关联研究的补充。这为通过高效关联研究全面检查该连锁区域以鉴定 10 号染色体 AD 基因提供了强有力的理由。此应用的主要目标是全面检查 10q11 和 10q25 之间的约 65 Mb 区域，首先筛选第一阶段发现样本中连锁不平衡 (LD) 标记 SNP 的广泛面板，以识别显着的 SNP（目标 1），然后确认第二阶段复制样本中的显着发现（目标 2）。然后，作为目标 3 的一部分，将全面筛选在两个阶段分析中均确认具有显着 SNP 的基因，以确定假定的功能性 SNP。公共卫生相关性阿尔茨海默病（AD）是美国的一个主要公共卫生问题，因为它的临床病程很长，但无法治愈。尽管 AD 具有强大的遗传基础，但仅发现了一小部分遗传贡献。全基因组连锁研究表明，几个染色体区域可能含有多个 AD 基因。本研究的重点是通过使用发现样本中的大型病例对照样本和复制样本中的基于家族的样本来识别 10 号染色体上的 AD 基因。

DESCRIPTION (provided by principal investigator): Late-onset Alzheimer's disease (LOAD) is a complex and multifactorial disease with the possible involvement of several genes. Apolipoprotein E (APOE), especially the APOE*4 allele, has been established as a strong susceptibility marker that accounts for 20-29 percent of the risk in LOAD. In addition to the disease risk, age-at-onset (AAO) of AD is also genetically controlled and the APOE gene accounts for <10 percent of the variation in AAO. This emphasizes the involvement of other genetic and/or environmental factors, which alone or in conjunction with APOE*4, can modify the risk or AAO of AD. Recently, genomewide linkage on LOAD have provided evidence for the existence of multiple putative genes for AD on several chromosomes with the strongest evidence on chromosomes 9, 10 and 12. With the construction of a high-density map of single nucleotide polymorphisms (SNPs) in the human genome, it is now possible to use the population-based association studies approach to identify the putative AD risk genes. A broad linkage peak encompassing >65 Mb region between chromosome 10q11 (at 50 Mb) and 10q25 (at 116 Mb) that influences both AD risk and AAO has been suggested. As part of our preliminary data we have screened 21 SNPs in 13 known biological candidate genes located under this broad >65 Mb linkage region in our large case-control cohort and identified suggestive significant associations with SNPs located in the choline acetyltransferase (CHAT) gene at 50.5 Mb on 10q11 and urokinase-type plasminogen activator (PLAU) gene at 75.3 Mb on 10q22 and thus our association findings are compliment to the reported linkage studies. This provides a strong rationale to comprehensively examine this linkage region by high-powered association studies to identify the chromosome 10 AD gene. The primary goal of this application is to comprehensively examine the ~65 Mb region between 10q11 and 10q25 first screening extensive panels of linkage disequilibrium (LD)-tagging SNPs in a first stage discovery sample to identify significant SNPs (Aim 1) and then confirm the significant findings in a second stage replication sample (Aim 2). The genes harboring confirmed significant SNPs in both stage analyses will then be comprehensively screened as part of Aim 3 to identify the putative functional SNPs. PUBLIC HEALTH RELEVANCE Alzheimer's disease (AD) is a major public health problem in the U.S. because it has a long clinical course, but there is no cure. Although AD has a strong genetic basis, only a small fraction of the genetic contribution has been discovered. Genome-wide linkage studies have implicated several chromosomal regions that might harbor multiple genes for AD. This study is focused on identifying the AD gene on chromosome 10 by using a large case-control sample in the discovery sample and a family-based sample in the replication sample.