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

Mariet Allen, Fanggeng Zou, High Seng Chai, Curtis S. Younkin, Richard Miles, Asha A. Nair, Julia E. Crook, Vernon Shane Pankratz, Minerva M. Carrasquillo, Christopher N. Rowley, Thuy Nguyen, Li Ma, Kimberly G. Malphrus, Gina Bisceglio, Alexandra I. Ortolaza, Ryan Palusak, Sumit Middha, Sooraj Maharjan, Constantin Georgescu, Debra SchultzFariborz Rakhshan, Christopher P. Kolbert, Jin Jen, Sigrid B. Sando, Jan O. Aasly, Maria Barcikowska, Ryan J. Uitti, Zbigniew K. Wszolek, Owen A. Ross, Ronald C. Petersen, Neill R. Graff-Radford, Dennis W. Dickson, Steven G. Younkin, Nilüfer Ertekin-Taner

Research output: Contribution to journalArticle

47 Scopus citations

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.

Original languageEnglish (US)
Article number13
JournalMolecular neurodegeneration
Volume7
Issue number1
DOIs
StatePublished - Apr 12 2012

Keywords

  • Association
  • Disease risk
  • GSTO genes
  • Gene expression

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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    Allen, M., Zou, F., Chai, H. S., Younkin, C. S., Miles, R., Nair, A. A., Crook, J. E., Pankratz, V. S., Carrasquillo, M. M., Rowley, C. N., Nguyen, T., Ma, L., Malphrus, K. G., Bisceglio, G., Ortolaza, A. I., Palusak, R., Middha, S., Maharjan, S., Georgescu, C., ... Ertekin-Taner, N. (2012). Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression: An association study with mechanistic implications. Molecular neurodegeneration, 7(1), [13]. https://doi.org/10.1186/1750-1326-7-13