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

Abstract

Background: 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).

Results: 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).

Conclusion: 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.

Figure 1

Meta-analysis of rs156697 in LOAD: a) Older LOAD series with ages > 80 years; b) Younger LOAD series with ages between 60-80 years. Combined series p value of association with LOAD risk is p = 0.018 in the older and p = 0.79 in the younger LOAD series. Breslow-Day test for series heterogeneity p value = 0.97 in the older and p = 0.004 in the younger series.

Figure 2

Box plots of brain GSTO2 expression levels by rs156697 genotype: a. Cerebellar measurements from combined autopsy series of 373 subjects (197 ADs, 176 controls) b. Temporal cortex measurements from combined autopsy series of 393 subjects (202 ADs, 191 controls). GSTO2 expression value residuals obtained after multivariate linear regression analysis are displayed in box plots according to the genotypes for rs156697. 0 = Homozygous Major (TT), 1 = Heterozygote (TC) and 2 = Homozygous Minor (CC). The number of subjects with each genotype is indicated above each box plot. The bottom and top of a box represent the lower and upper quartiles, respectively. The band near the middle of the box is the median. The ends of the whiskers depict the most extreme observations still within 1.5 inter quartile range of the corresponding quartile. Any data not included between the whiskers are plotted as dots.