Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression: an association study with mechanistic implications
1 Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, USA
2 Mayo Clinic Minnesota, Department of Biostatistics, Rochester, MN, USA
3 Mayo Clinic Florida, Biostatistics Unit, Jacksonville, FL, USA
4 Mayo Clinic Minnesota, Gene Expression Core, Advanced Genome Technology Center, Rochester, MN, USA
5 Department of Neurology, St.Olav's Hospital, Edvard Griegs Gate 8, 7006 Trondheim, Norway
6 Department of Neuroscience, Norwegian University of Science and Technology, NTNU, 7491 Trondheim, Norway
7 Department of Neurodegenerative Disorders, Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
8 Mayo Clinic Florida, Department of Neurology, Jacksonville, FL, USA
9 Mayo Clinic Minnesota, Department of Neurology, Rochester, MN, USA
Molecular Neurodegeneration 2012, 7:13 doi:10.1186/1750-1326-7-13Published: 11 April 2012
Glutathione S-transferase omega-1 and 2 genes (GSTO1, GSTO2), 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. GSTO 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, GSTO1 rs4925 and GSTO2 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).
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.