Plasma AB as a Surrogate Genetic Marker for LOAD

描述（由申请人提供）：为了努力理解和克服阻碍遗传关联研究复制的因素，我们最近相当详细地研究了编码胰岛素/AB降解酶基因的基因保守区域（IDE）的变异。当在我们的大型病例/对照系列中分析时，这些变体中相当高的百分比具有适度的影响，显示出可复制的关联。基于这些结果，我们目前的工作假设是，鉴定新的LOAD基因的进展缓慢，因为大多数LOAD基因类似于IDE；他们有多个易感等位基因，效应大小适中。apoe4等位基因等具有强大变异的基因的影响很容易在小病例/对照系列中检测和复制。但是，具有多个易感等位基因的净影响虽然不大，但却很重要，除非采用大型病例/对照系列来评估一组因其可能的功能影响而选择的变异，否则无法很好地检测和复制。利用上一个周期中开发的科学基础设施，我们建议通过靶向AB加工途径中的基因来追求这一假设。我们将对AB加工途径中可能含有新的LOAD基因的AB qtl进行无偏倚的全基因组搜索。此外，我们将在已知的AB加工途径的主要基因中彻底搜索和检查其他易感等位基因的功能。我们的具体目标是：(1)进行全基因组扫描，以鉴定与血浆AB水平相关的新型数量性状位点（qtl）；(2)通过使用多个大病例对照序列，分析AB加工途径中主要基因保守区域（SORL1、APP、IDE、MME、ECE1、PLAU、BACE1、PSEN1、PSEN2和VR22）的变异，鉴定新的LOAD易感等位基因；(3)评估特异性目标2中鉴定的易感等位基因的功能效应。根据所鉴定的每个易感等位基因的具体位置，将通过评估变异对(i)血浆AB和/或（ii）脑mRNA的影响来分析其功能。我们最近的研究结果表明，许多易感等位基因可能通过改变基因表达或剪接起作用。

DESCRIPTION (provided by applicant): In an effort to understand and to overcome the factors that thwart replication of genetic association studies, we recently studied variants in the conserved regions of the gene (IDE) that encodes the insulin/AB degrading enzyme gene in considerable detail. A remarkably high percentage of these variants had modest effects that showed replicable association when analyzed in our large case/control series. Based on these results, our current working hypothesis is that progress in identifying novel LOAD genes has been slow because most LOAD genes are like IDE; they have multiple susceptibility alleles with modest effect size. The effect of genes with powerful variants like the ApoE 4 allele is easily detected and replicated in small case/control series. But the net effect of genes with multiple susceptibility alleles that have modest effects, though substantial, cannot be detected and replicated well unless large case/control series are employed to evaluate a set of variants selected for their likely functional effect. Using the scientific infrastructure developed in the last cycle we propose to pursue this hypothesis by targeting genes in the AB processing pathway. We will perform an unbiased, genome-wide search for AB QTLs likely to harbor novel LOAD genes in the AB processing pathway. In addition, we will search thoroughly for and examine the function of additional susceptibility alleles in the known, major genes of the AB processing pathway. Our specific aims are to (1) perform whole genome scans to identify novel quantitative trait loci (QTLs) linked to plasma AB levels, (2) identify novel LOAD susceptibility alleles by using multiple, large case control series to analyze the variants in conserved regions of major genes in the AB processing pathway (SORL1, APP, IDE, MME, ECE1, PLAU, BACE1, PSEN1, PSEN2, and VR22), and (3) evaluate the functional effects of the susceptibility alleles identified in specific aim 2. Depending on the specific location of each susceptibility allele identified, function will be analyzed by evaluating the effect of the variant on (i) plasma AB and/or (ii) brain mRNA. Our recent results suggest that many susceptibility alleles may act by altering gene expression or splicing. There is strong evidence that reducing the AB42 peptide in normal elderly subjects could prevent Alzheimer's disease (AD), a disorder that inflicts enormous suffering and financial loss on our society. To perform affordable prevention trials and administer drugs to normal elderly people with an acceptable risk/benefit ratio, methods must be developed for identifying those elderly individuals who are at increased risk for AD. In this application, we propose experimentation to identify many genes with variants that alter AB42 thereby influencing risk for AD; we do so because each new AD gene identified opens new therapeutic possibilities and improves our ability to identify the at risk population.