Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease.
We previously reported genetic linkage of loci controlling age-at-onset in Alzheimer disease (AD) and Parkinson's disease (PD) to a 15 cM region on chromosome 10q. Given the large number of genes in this initial starting region, we applied the process of 'genomic convergence' to prioritize and reduce the number of candidate genes for further analysis. As our second convergence factor we performed gene expression studies on hippocampus obtained from AD patients and controls. Analysis revealed that four of the genes [stearoyl-CoA desaturase; NADH-ubiquinone oxidoreductase 1 beta subcomplex 8; protease, serine 11; and glutathione S-transferase, omega-1 (GSTO1)] were significantly different in their expression between AD and controls and mapped to the 10q age-at-onset linkage region, the first convergence factor. Using 2814 samples from our AD dataset (1773 AD patients) and 1362 samples from our PD dataset (635 PD patients), allelic association studies for age-at-onset effects in AD and PD revealed no association for three of the candidates, but a significant association was found for GSTO1 (P=0.007) and a second transcribed member of the GST omega class, GSTO2 (P=0.005), located next to GSTO1. The functions of GSTO1 and GSTO2 are not well understood, but recent data suggest that GSTO1 maybe involved in the post-translational modification of the inflammatory cytokine interleukin-1beta. This is provocative given reports of the possible role of inflammation in these two neurodegenerative disorders.
Department of Medicine, Center for Human Genetics, Institute for Genome Science and Policy, Duke University Medical Center, Box 3445, Durham, NC 27710, USA. yiju.li@duke.edu
Yi-Ju
YJ
Li
Sofia A
SA
Oliveira
Puting
P
Xu
Eden R
ER
Martin
Judith E
JE
Stenger
Clemens R
CR
Scherzer
Michael A
MA
Hauser
William K
WK
Scott
Gary W
GW
Small
Martha A
MA
Nance
Ray L
RL
Watts
Jean P
JP
Hubble
William C
WC
Koller
Rajesh
R
Pahwa
Mathew B
MB
Stern
Bradley C
BC
Hiner
Joseph
J
Jankovic
Christopher G
CG
Goetz
Frank
F
Mastaglia
Lefkos T
LT
Middleton
Allen D
AD
Roses
Ann M
AM
Saunders
Donald E
DE
Schmechel
Steven R
SR
Gullans
Jonathan L
JL
Haines
John R
JR
Gilbert
Jeffery M
JM
Vance
Margaret A
MA
Pericak-Vance
Christine
C
Hulette
Kathleen A
KA
Welsh-Bohmer
D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015810:Linkage Disequilibrium; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
C490476:GSTO1 protein, human; D005982:Glutathione Transferase