Numerous studies have shown that the microtubule-associated protein tau (Mapt) gene plays an important role in tauopathies. However, little is known about the genetic regulatory network. In this study, we combined array analysis and quantitative trait loci (QTL) mapping approaches (genetical genomics) to characterize the expression variation and the regulatory network of Mapt in mouse. Through examining the probe sets for overlapping single nucleotide polymorphysms (SNPs), two probe sets without overlapping SNPs were selected for QTL mapping. Interval mapping results showed that expression quantitative trait loci (eQTL) mapping for Mapt had a significant linkage score (LRS) of 27.2. Moreover, the QTL was mapped to within 3 Mb of the location of the gene itself (Mapt) as a cis-acting QTL. Through mapping the joint modulation of Mapt, we identified 22 transcripts/genes with trans-regulated QTLs close to the location of Mapt. By further excluding the correlated transcripts due to linkage disequilibrium, the result highlighted three genes as potential downstream genes of Mapt. Expression correlation and genetic network analysis demonstrated that Mapt co-varies with many tauopathies-related genes, including Gsk3b, Falz, Apbb2, Slc1a3, Ntrk2, Pik3ca, and Ikbkap. These results demonstrate that the genetical genomics approach provides a powerful tool for constructing pathways that contribute to complex traits, such as neurodegenerative disorders.