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Human Molecular Genetics Advance Access originally published online on October 21, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 24 3259-3267
DOI: 10.1093/hmg/ddg357
© 2003 Oxford University Press

Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease

Yi-Ju Li1,*,{dagger}, Sofia A. Oliveira1,{dagger}, Puting Xu1, Eden R. Martin1, Judith E. Stenger1, Clemens R. Scherzer2, Michael A. Hauser1, William K. Scott1, Gary W. Small3, Martha A. Nance4, Ray L. Watts5, Jean P. Hubble6, William C. Koller7, Rajesh Pahwa8, Mathew B. Stern9, Bradley C. Hiner10, Joseph Jankovic11, Christopher G. Goetz12, Frank Mastaglia13, Lefkos T. Middleton14, Allen D. Roses15, Ann M. Saunders15, Donald E. Schmechel16, Steven R. Gullans2, Jonathan L. Haines17,{ddagger}, John R. Gilbert1,{ddagger}, Jeffery M. Vance1,{ddagger} and Margaret A. Pericak-Vance1,{ddagger}

1Department of Medicine and Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA, 2Harvard University Medical School, Boston, MA 02115, USA, 3Departments of Psychiatry and Biobehavioral Science and Neurology, University of California, Los Angeles, CA 90024, USA, 4Struthers Parkinson Center, Golden Valley, MN 55426, USA, 5Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA, 6Department of Neurology, Ohio State University, Columbus, OH 43210, USA, 7Department of Neurology, University of Miami School of Medicine, Miami, FL 33124, USA, 8Department of Neurology, University of Kansas Medical Center, Kansas City, KS 66045, USA, 9Department of Neurology, University of Pennsylvania Health System, Philadelphia, PA 19104, USA, 10Department of Neurology, Marshfield Clinic, Marshfield, WI 54449, USA, 11Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA, 12Department of Neurological Sciences, Rush-Presbyterian–St Luke's Hospital, Chicago, IL 60612, USA, 13Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Western Australia 6009, Australia, 14GlaxoSmithKline Research and Development, Greenford, Middlesex UB6 0HE, UK, 15GlaxoSmithKline Genetics Research Directorate, Research Triangle Park, NC, USA, 16Department of Medicine and Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC 27710, USA and 17Program in Human Genetics, Vanderbilt University Medical Center, Nashville, TN 37232, USA

Received July 7, 2003; Revised September 22, 2003; Accepted September 29, 2003

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-1ß. This is provocative given reports of the possible role of inflammation in these two neurodegenerative disorders.

* To whom correspondence should be addressed at: Center for Human Genetics, Institute for Genome Science and Policy, Duke University Medical Center Box 3445, Durham, NC 27710, USA. Tel: +1 9196840604; Fax: +1 9196840921; Email: yiju.li{at}duke.edu

{dagger} These authors contributed equally to the manuscript.

{ddagger} These authors contributed equally to the manuscript.


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