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, Juliana Crook, V. 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 Carl Petersen, Neill R Graff Radford, Dennis W Dickson, Steven G Younkin, Nilufer Taner

Research output: Contribution to journalArticle

42 Citations (Scopus)

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 - 2012

Fingerprint

Glutathione Transferase
Parkinson Disease
Alzheimer Disease
Gene Expression
Brain
Genes
Alleles
Odds Ratio
Single Nucleotide Polymorphism
Glutathione
Genome-Wide Association Study
Nervous System Diseases
Age of Onset
Oxidative Stress
Chronic Disease

Keywords

  • Association
  • Disease risk
  • Gene expression
  • GSTO genes

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression : An association study with mechanistic implications. / Allen, Mariet; Zou, Fanggeng; Chai, High Seng; Younkin, Curtis S.; Miles, Richard; Nair, Asha A.; Crook, Juliana; Pankratz, V. Shane; Carrasquillo, Minerva M; Rowley, Christopher N.; Nguyen, Thuy; Ma, Li; Malphrus, Kimberly G.; Bisceglio, Gina; Ortolaza, Alexandra I.; Palusak, Ryan; Middha, Sumit; Maharjan, Sooraj; Georgescu, Constantin; Schultz, Debra; Rakhshan, Fariborz; Kolbert, Christopher P.; Jen, Jin; Sando, Sigrid B.; Aasly, Jan O.; Barcikowska, Maria; Uitti, Ryan J.; Wszolek, Zbigniew K; Ross, Owen A; Petersen, Ronald Carl; Graff Radford, Neill R; Dickson, Dennis W; Younkin, Steven G; Taner, Nilufer.

In: Molecular Neurodegeneration, Vol. 7, No. 1, 13, 2012.

Research output: Contribution to journalArticle

Allen, M, Zou, F, Chai, HS, Younkin, CS, Miles, R, Nair, AA, Crook, J, Pankratz, VS, Carrasquillo, MM, Rowley, CN, Nguyen, T, Ma, L, Malphrus, KG, Bisceglio, G, Ortolaza, AI, Palusak, R, Middha, S, Maharjan, S, Georgescu, C, Schultz, D, Rakhshan, F, Kolbert, CP, Jen, J, Sando, SB, Aasly, JO, Barcikowska, M, Uitti, RJ, Wszolek, ZK, Ross, OA, Petersen, RC, Graff Radford, NR, Dickson, DW, Younkin, SG & 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, vol. 7, no. 1, 13. https://doi.org/10.1186/1750-1326-7-13
Allen, Mariet ; Zou, Fanggeng ; Chai, High Seng ; Younkin, Curtis S. ; Miles, Richard ; Nair, Asha A. ; Crook, Juliana ; Pankratz, V. Shane ; Carrasquillo, Minerva M ; Rowley, Christopher N. ; Nguyen, Thuy ; Ma, Li ; Malphrus, Kimberly G. ; Bisceglio, Gina ; Ortolaza, Alexandra I. ; Palusak, Ryan ; Middha, Sumit ; Maharjan, Sooraj ; Georgescu, Constantin ; Schultz, Debra ; Rakhshan, Fariborz ; Kolbert, Christopher P. ; Jen, Jin ; Sando, Sigrid B. ; Aasly, Jan O. ; Barcikowska, Maria ; Uitti, Ryan J. ; Wszolek, Zbigniew K ; Ross, Owen A ; Petersen, Ronald Carl ; Graff Radford, Neill R ; Dickson, Dennis W ; Younkin, Steven G ; Taner, Nilufer. / Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression : An association study with mechanistic implications. In: Molecular Neurodegeneration. 2012 ; Vol. 7, No. 1.
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title = "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.",
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author = "Mariet Allen and Fanggeng Zou and Chai, {High Seng} and Younkin, {Curtis S.} and Richard Miles and Nair, {Asha A.} and Juliana Crook and Pankratz, {V. Shane} and Carrasquillo, {Minerva M} and Rowley, {Christopher N.} and Thuy Nguyen and Li Ma and Malphrus, {Kimberly G.} and Gina Bisceglio and Ortolaza, {Alexandra I.} and Ryan Palusak and Sumit Middha and Sooraj Maharjan and Constantin Georgescu and Debra Schultz and Fariborz Rakhshan and Kolbert, {Christopher P.} and Jin Jen and Sando, {Sigrid B.} and Aasly, {Jan O.} and Maria Barcikowska and Uitti, {Ryan J.} and Wszolek, {Zbigniew K} and Ross, {Owen A} and Petersen, {Ronald Carl} and {Graff Radford}, {Neill R} and Dickson, {Dennis W} and Younkin, {Steven G} and Nilufer Taner",
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T1 - Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression

T2 - An association study with mechanistic implications

AU - Allen, Mariet

AU - Zou, Fanggeng

AU - Chai, High Seng

AU - Younkin, Curtis S.

AU - Miles, Richard

AU - Nair, Asha A.

AU - Crook, Juliana

AU - Pankratz, V. Shane

AU - Carrasquillo, Minerva M

AU - Rowley, Christopher N.

AU - Nguyen, Thuy

AU - Ma, Li

AU - Malphrus, Kimberly G.

AU - Bisceglio, Gina

AU - Ortolaza, Alexandra I.

AU - Palusak, Ryan

AU - Middha, Sumit

AU - Maharjan, Sooraj

AU - Georgescu, Constantin

AU - Schultz, Debra

AU - Rakhshan, Fariborz

AU - Kolbert, Christopher P.

AU - Jen, Jin

AU - Sando, Sigrid B.

AU - Aasly, Jan O.

AU - Barcikowska, Maria

AU - Uitti, Ryan J.

AU - Wszolek, Zbigniew K

AU - Ross, Owen A

AU - Petersen, Ronald Carl

AU - Graff Radford, Neill R

AU - Dickson, Dennis W

AU - Younkin, Steven G

AU - Taner, Nilufer

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

KW - Association

KW - Disease risk

KW - Gene expression

KW - GSTO genes

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