Search for the Alzheimer's Gene on Chromosome 10

描述(由主要研究人员提供)：迟发性阿尔茨海默病(LOAD)是一种复杂的多因素疾病，可能涉及几个基因。载脂蛋白E(APOE)，特别是APOE*4等位基因，已被认为是一种强烈的易感标记，占负荷风险的20%-29%。除了疾病风险，阿尔茨海默病的发病年龄(AAO)也是由基因控制的，APOE基因解释了AAO变异的10%。这强调了其他遗传和/或环境因素的参与，这些因素单独或与载脂蛋白E*4结合可以改变AD的风险或AAO。最近，全基因组的LOAD连锁提供了证据，证明在几条染色体上存在多个AD的可能基因，其中9号、10号和12号染色体上的证据最强。随着人类基因组单核苷酸多态(SNPs)高密度图谱的构建，现在有可能使用基于群体的关联研究方法来识别可能的AD危险基因。在染色体10q11(位于50Mb)和10q25(位于116Mb)之间存在一个包含&gt；65Mb区域的宽广的连锁高峰，它同时影响AD风险和AAO。作为我们初步数据的一部分，我们在我们的大型病例对照队列中筛选了位于这个广泛的&>65Mb连锁区域下的13个已知生物候选基因中的21个SNPs，并发现与位于10q11的胆碱乙酰转移酶(ChAT)基因的50.5Mb和位于10q22的75.3Mb的尿激酶型纤溶酶原激活物(PLAU)基因的SNPs具有显著的相关性，因此我们的关联研究结果是对已报道的连锁研究的补充。这为通过高性能的关联研究来识别10号染色体AD基因来全面检查这一连锁区域提供了强有力的理论基础。此应用程序的主要目标是全面检查10q11和10q25之间的~65Mb区域，首先在第一阶段发现样本中筛选广泛的连锁不平衡(LD)标记SNPs小组，以确定重要的SNPs(目标1)，然后在第二阶段复制样本中确认重要的发现(目标2)。然后，作为目标3的一部分，将全面筛选在两个阶段的分析中含有被确认的显著SNPs的基因，以确定假定的功能性SNPs。

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.