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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Mayo Clinic Florida, Department of Neuroscience, Jacksonville, FL, USA.
authors.forename: Mariet
authors.initials: M
authors.lastname: Allen
authors.forename: Fanggeng
authors.initials: F
authors.lastname: Zou
authors.forename: High Seng
authors.initials: HS
authors.lastname: Chai
authors.forename: Curtis S
authors.initials: CS
authors.lastname: Younkin
authors.forename: Richard
authors.initials: R
authors.lastname: Miles
authors.forename: Asha A
authors.initials: AA
authors.lastname: Nair
authors.forename: Julia E
authors.initials: JE
authors.lastname: Crook
authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
authors.forename: Minerva M
authors.initials: MM
authors.lastname: Carrasquillo
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Rowley
authors.forename: Thuy
authors.initials: T
authors.lastname: Nguyen
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Kimberly G
authors.initials: KG
authors.lastname: Malphrus
authors.forename: Gina
authors.initials: G
authors.lastname: Bisceglio
authors.forename: Alexandra I
authors.initials: AI
authors.lastname: Ortolaza
authors.forename: Ryan
authors.initials: R
authors.lastname: Palusak
authors.forename: Sumit
authors.initials: S
authors.lastname: Middha
authors.forename: Sooraj
authors.initials: S
authors.lastname: Maharjan
authors.forename: Constantin
authors.initials: C
authors.lastname: Georgescu
authors.forename: Debra
authors.initials: D
authors.lastname: Schultz
authors.forename: Fariborz
authors.initials: F
authors.lastname: Rakhshan
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Kolbert
authors.forename: Jin
authors.initials: J
authors.lastname: Jen
authors.forename: Sigrid B
authors.initials: SB
authors.lastname: Sando
authors.forename: Jan O
authors.initials: JO
authors.lastname: Aasly
authors.forename: Maria
authors.initials: M
authors.lastname: Barcikowska
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Uitti
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.forename: Nilüfer
authors.initials: N
authors.lastname: Ertekin-Taner
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics*; D005500:Follow-Up Studies; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors
chemical_list: C490476:GSTO1 protein, human; C492569:GSTO2 protein, human; D005982:Glutathione Transferase