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<p>Abstract</p> <p>Background</p> <p>Glutathione S-transferase omega-1 and 2 genes (<it>GSTO1</it>, <it>GSTO2</it>), residing within an Alzheimer and Parkinson disease (AD and PD) linkage region, have diverse functions including mitigation of oxidative stress and may underlie the pathophysiology of both diseases. <it>GSTO </it>polymorphisms were previously reported to associate with risk and age-at-onset of these diseases, although inconsistent follow-up study designs make interpretation of results difficult. We assessed two previously reported SNPs, <it>GSTO1 </it>rs4925 and <it>GSTO2 </it>rs156697, in AD (3,493 ADs vs. 4,617 controls) and PD (678 PDs vs. 712 controls) for association with disease risk (case-controls), age-at-diagnosis (cases) and brain gene expression levels (autopsied subjects).</p> <p>Results</p> <p>We found that rs156697 minor allele associates with significantly increased risk (odds ratio = 1.14, <it>p </it>= 0.038) in the older ADs with age-at-diagnosis > 80 years. The minor allele of <it>GSTO1 </it>rs4925 associates with decreased risk in familial PD (odds ratio = 0.78, <it>p </it>= 0.034). There was no other association with disease risk or age-at-diagnosis. The minor alleles of both <it>GSTO </it>SNPs associate with lower brain levels of <it>GSTO2 </it>(<it>p </it>= 4.7 × 10^-11-1.9 × 10^-27), but not <it>GSTO1</it>. Pathway analysis of significant genes in our brain expression GWAS, identified significant enrichment for glutathione metabolism genes (<it>p </it>= 0.003).</p> <p>Conclusion</p> <p>These results suggest that <it>GSTO </it>locus variants may lower brain <it>GSTO2 </it>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.</p>