Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression: an association study with mechanistic implications

We found that rs156697 minor allele associates with significantly increased risk (odds ratio = 1.14, p = 0.038) in the older ADs with age-at-diagnosis > 80 years. The minor allele of GSTO1 rs4925 associates with decreased risk in familial PD (odds ratio = 0.78, p = 0.034). There was no other association with disease risk or age-at-diagnosis. The minor alleles of both GSTO SNPs associate with lower brain levels of GSTO2 (p = 4.7 × 10-11-1.9 × 10-27), but not GSTO1. Pathway analysis of significant genes in our brain expression GWAS, identified significant enrichment for glutathione metabolism genes (p = 0.003).These results suggest that GSTO locus variants may lower brain GSTO2 levels and consequently confer AD risk in older age. Other glutathione metabolism genes should be assessed for their effects on AD and other chronic, neurologic diseases.Glutathione S-Transferase (GST) family of genes have been implicated in multiple neuropsychiatric [1-4] and neurodegenerative diseases [5-11]; where altered levels or function of these enzymes is thought to impact levels of oxidative stress and/or inflammation in a way that contributes to disease susceptibility. A linkage locus on chromosome 10q that has been implicated in both Alzheimer's (AD)[11-13] and Parkinson's disease (PD)[13] harbors two GST genes of the omega class: GSTO1 and GSTO2, which are approximately 75 kb apart.GSTOs have enzymatic activities as thioltransferases and dehydroascorbate reductases that promote antioxidant activity and can also function in metabolism of drugs and toxins[14]. Additionally, GSTO1 was shown to promote activation of the pro-inflammatory cytokine, interleukin-1β (IL-1β) by post-translational processing[15]. Given their location and function, they have been studied as candidate genes in AD and PD[5,6,9,11,14,16-18]. Li et al. compared hippocampal gene expression levels in 6 AD vs. 2 control brains and identified significantly lower GSTO1 levels in the AD hippocampi[5]. This group studied