Genetic Regulatory Network Analysis for App Based on Genetical Genomics Approach

Institute of Bioinformatics, Zhejiang University, Hangzhou, P.R. China.
Experimental Aging Research (Impact Factor: 0.92). 12/2009; 36(1):79-93. DOI: 10.1080/03610730903418729
Source: PubMed


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.

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    • "Computational and Mathematical Methods in Medicine gene modules, each of which represented a biological process perturbed in AD [5]. By combining array analysis and quantitative trait loci (QTL) mapping to characterize the genetic variation and genetic regulatory network, Wang et al. identified many AD-related genes coregulating with App including Gsk3b, Falz, Mef2a, Tlk2, Rtn, and Prkca [6]. Zhang et al. found regulators of tmem59 and reconstructed gene regulatory networks of mouse neural stem cells. "
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    • "Phenotypes are often very different between mouse strains with diverse genetic backgrounds and the strain characteristics of DBA/2J are often contrasted with other genetically distinct inbred strains such as C57BL/6J. These defined genetic backgrounds provide an excellent system for mapping modifier genes [20], [21], [22]. To study these differences a number of DBA/2J-relevant resources have been generated. "
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