Wang Xusheng, Chen Ying, Wang Xiaodong, Lu Lu
Institute of Bioinformatics, Zhejiang University, Hangzhou, P.R. China.
Exp Aging Res. 2010 Jan-Mar;36(1):79-93. doi: 10.1080/03610730903418729.
A number of studies have shown that amyloid precursor protein (App) plays a critical role in Alzheimer's disease (AD); however, little is known about the genetic regulatory network. In this study, the authors combined array analysis and quantitative trait loci (QTL) mapping to characterize the genetic variation and genetic regulatory network for App using hippocampus of BXD recombinant inbred (RI) mice. The variation in expression level of App is conspicuous across the 78 BXD RI strains. Moreover, the expression level of App is significantly higher in DBA/2J than the level in C57BL/6J (p < .001). Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis has further confirmed the significant difference between the two parental strains C57BL/6J and DBA/2J. The authors performed an interval mapping for App gene expression and found that it is cis regulated with highly significant likelihood-ratio statistic (LRS) score (LRS = 19; p < .05). Four SNPs and two InDels (insertions or deletions) were identified in the promoter, and one of the SNPs is located in the pax2 motif. Genetic regulatory network analysis showed that App coregulated with many AD-related genes, including Gsk3b, Falz, Mef2a, Tlk2, Rtn, and Prkca. The genetical genomics approach demonstrates the importance and the potential power of the expression quantitative trait loci (eQTL) studies in identifying regulatory network that contribute to complex traits, such as AD.
多项研究表明，淀粉样前体蛋白（App）在阿尔茨海默病（AD）中起关键作用；然而，对于其遗传调控网络却知之甚少。在本研究中，作者结合阵列分析和数量性状基因座（QTL）定位，利用BXD重组近交（RI）小鼠的海马体来表征App的遗传变异和遗传调控网络。在78个BXD RI品系中，App表达水平的变异十分显著。此外，DBA/2J中App的表达水平显著高于C57BL/6J中的水平（p <.001）。定量逆转录聚合酶链反应（qRT-PCR）分析进一步证实了两个亲本品系C57BL/6J和DBA/2J之间的显著差异。作者对App基因表达进行了区间定位，发现它受到顺式调控，具有高度显著的似然比统计（LRS）分数（LRS = 19；p <.05）。在启动子区域鉴定出4个单核苷酸多态性（SNP）和2个插入缺失（InDel，插入或缺失），其中一个SNP位于pax2基序中。遗传调控网络分析表明，App与许多AD相关基因共同调控，包括Gsk3b、Falz、Mef2a、Tlk2、Rtn和Prkca。遗传基因组学方法证明了表达数量性状基因座（eQTL）研究在识别促成复杂性状（如AD）的调控网络方面的重要性和潜在能力。
