Genetic dissection of glutathione S-transferase omega-1: identification of novel downstream targets and Alzheimer's disease pathways.

ABSTRACT

Alzheimer's disease (AD) is affected by genetic factors. Polymorphisms in the glutathione S-transferase omega-1 (Gsto1) gene have been shown by genetic correlation analyses performed in different ethnic populations to be genetic risk factors for AD. Gene expression profile data from BXD recombinant inbred mice were used in combination with genetic and bioinformatic analyses to characterize the mechanisms underlying regulation of Gsto1 variation regulation and to identify network members that may contribute to AD risk or progression. Allele-specific assays confirmed that variation in Gsto1 expression is controlled by cis-expression quantitative trait loci. We found that Gsto1 mRNA levels were related to several central nervous system traits, such as glial acidic fibrillary protein levels in the caudate putamen, cortical gray matter volume, and hippocampus mossy fiber pathway volume. We identified 2168 genes whose expression was highly correlated with that of Gsto1. Some genes were enriched for the most common neurodegenerative diseases. Some Gsto1-related genes identified in this study had previously been identified as susceptibility genes for AD, such as APP, Grin2b, Ide, and Psenen. To evaluate the relationships between Gsto1 and candidate network members, we transfected astrocytes with Gsto1 siRNA and assessed the effect on putative downstream effectors. We confirmed that knockdown of Gsto1 had a significant influence on Pa2g4 expression, suggesting that Pa2g4 may be a downstream effector of Gsto1, and that both genes interact with other genes in a network during AD pathogenesis.