201. Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression: an association study with mechanistic implications
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Thuy Nguyen, Fanggeng Zou, V. Shane Pankratz, Ryan J. Uitti, Constantin Georgescu, Asha Nair, Fariborz Rakhshan, Sigrid Botne Sando, Christopher P. Kolbert, Julia E. Crook, Maria Barcikowska, Mariet Allen, Owen A. Ross, Ronald C. Petersen, High Seng Chai, Christopher Rowley, Jin Jen, Dennis W. Dickson, Jan O. Aasly, Sooraj Maharjan, Neill R. Graff-Radford, Gina Bisceglio, Richard Miles, Curtis S. Younkin, Zbigniew K. Wszolek, Debra A. Schultz, Alexandra I. Ortolaza, Ryan Palusak, Li Ma, Sumit Middha, Minerva M. Carrasquillo, Nilufer Ertekin-Taner, Steven G. Younkin, and Kimberly G. Malphrus
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Disease risk ,Clinical Neurology ,Gene Expression ,Genome-wide association study ,Single-nucleotide polymorphism ,Disease ,lcsh:Geriatrics ,Biology ,Polymorphism, Single Nucleotide ,lcsh:RC346-429 ,Association ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Alzheimer Disease ,Risk Factors ,medicine ,Humans ,Genetic Predisposition to Disease ,Age of Onset ,Allele ,Molecular Biology ,lcsh:Neurology. Diseases of the nervous system ,Alleles ,Aged ,Glutathione Transferase ,030304 developmental biology ,Aged, 80 and over ,Genetics ,GSTO genes ,0303 health sciences ,Parkinson Disease ,Odds ratio ,Middle Aged ,medicine.disease ,Minor allele frequency ,lcsh:RC952-954.6 ,Immunology ,Neurology (clinical) ,Age of onset ,Alzheimer's disease ,030217 neurology & neurosurgery ,Follow-Up Studies ,Research Article - 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.
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