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Human Molecular Genetics Advance Access published online on October 21, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg357
© 2003 by Oxford University Press
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©2003 Oxford University Press

Article

Glutathione S-Transferase Omega 1 modifies age-at-onset of Alzheimer Disease and Parkinson Disease

Yi-Ju Li 1*, Sofia A. Oliveira 2, Puting Xu 2, Eden R. Martin 2, Judith E. Stenger 2, Clemens R. Scherzer 3, Michael A. Hauser 2, William K. Scott 2, Gary W. Small 4, Martha A. Nance 5, Ray L. Watts 6, Jean P. Hubble 7, William C. Koller 8, Rajesh Pahwa 9, Mathew B. Stern 10, Bradley C. Hiner 11, Joseph Jankovic 12, Christopher G. Goetz 13, Frank Mastaglia 14, Lefkos T. Middleton 15, Allen D. Roses 16, Ann M. Saunders 16, Donald E. Schmechel 17, Steven R. Gullans 3, Jonathan L. Haines 18, John R. Gilbert 2, Jeffery M. Vance 2, and Margaret A. Pericak-Vance 2

1 Department of Medicine and Center for Human Genetics, Institute for Genome Science and Policy, Duke University Medical Center Box 3445, Durham, North Carolina 27710
2 Department of Medicine and Center for Human Genetics, Duke University Medical Center, Durham, North Carolina 27710
3 Harvard University Medical School, Boston, Massachusetts 02115
4 Departments of Psychiatry & Biobehavioral Science and Neurology, University of California, Los Angeles, California 90024
5 Struthers Parkinson Center, Golden Valley, MN 55426
6 Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322
7 Department of Neurology, Ohio State University, Columbus, OH 43210
8 Department of Neurology, University of Miami School of Medicine, Miami, FL 33124
9 Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas 66045
10 Department of Neurology, University of Pennsylvania Health System, Philadelphia, PA 19104
11 Department of Neurology, Marshfield Clinic, Marshfield, WI 54449
12 Department of Neurology, Baylor College of Medicine, Houston, TX 77030
13 Department of Neurological Sciences, Rush-Presbyterian-St. Luke's Hospital, Chicago, IL 60612
14 Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Western Australia 6009
15 GlaxoSmithKline Research and Development, Greenford, Middlesex, UB60HE United Kingdom
16 GlaxoSmithKline Genetics Research Directorate, Research Triangle Park, NC
17 Department of Medicine and Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, North Carolina 27710
18 Program in Human Genetics, Vanderbilt University Medical Center, Nashville, Tennessee 37232

* To whom correspondence should be addressed. E-mail: yiju.li{at}duke.edu.


  Abstract

We previously reported genetic linkage of loci controlling age-at-onset in Alzheimer disease (AD) and Parkinson disease (PD) to a 15 cM region on chromosome 10q. Given the large number of genes in this initial starting region, we applied our 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 complex 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-1{beta}. This is provocative given reports of the possible role of inflammation in these two neurodegenerative disorders.


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