Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family
- Yonghong Li*,
- Petra Nowotny†,
- Peter Holmans‡,
- Scott Smemo†,
- John S. K. Kauwe†,
- Anthony L. Hinrichs†,
- Kristina Tacey*,
- Lisa Doil*,
- Ryan van Luchene*,
- Veronica Garcia*,
- Charles Rowland*,
- Steve Schrodi*,
- Diane Leong*,
- Goran Gogic*,
- Joanne Chan*,
- Anibal Cravchik*,
- David Ross*,
- Kit Lau*,
- Shirley Kwok*,
- Sheng-Yung Chang*,
- Joe Catanese*,
- John Sninsky*,
- Thomas J. White*,
- John Hardy§,
- John Powell¶,
- Simon Lovestone¶,
- John C. Morris†,
- Leon Thal∥,
- Michael Owen**,
- Julie Williams‡,**,
- Alison Goate†, and
- Andrew Grupe*,††
- *Celera Diagnostics, Alameda, CA 94502; †Departments of Psychiatry and Neurology, Washington University School of Medicine, St. Louis, MO 63110; ‡Biostatistics and Bioinformatics Unit and **Department of Psychological Medicine, Cardiff University, Wales College of Medicine, Cardiff CF14 4XN, United Kingdom; §National Institute on Aging, Bethesda, MD 20892; ¶Department of Neuroscience, Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom; and ∥Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093
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Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD (received for review May 18, 2004)
Abstract
Although several genes have been implicated in the development of the early-onset autosomal dominant form of Alzheimer's disease (AD), the genetics of late-onset AD (LOAD) is complex. Loci on several chromosomes have been linked to the disease, but so far only the apolipoprotein E gene has been consistently shown to be a risk factor. We have performed a large-scale single-nucleotide polymorphism (SNP)-based association study, across the region of linkage on chromosome 12, in multiple case-control series totaling 1,089 LOAD patients and 1,196 control subjects and report association with SNPs in the glyceraldehyde-3-phosphate dehydrogenase (GAPD) gene. Subsequent analysis of GAPD paralogs on other chromosomes demonstrated association with two other paralogs. A significant association between LOAD and a compound genotype of the three GAPD genes was observed in all three sample sets. Individually, these SNPs make differential contributions to disease risk in each of the casecontrol series, suggesting that variants in functionally similar genes may account for series-to-series heterogeneity of disease risk. Our observations raise the possibility that GAPD genes are AD risk factors, a hypothesis that is consistent with the role of GAPD in neuronal apoptosis.
Footnotes
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↵ †† To whom correspondence should be addressed. E-mail: andrew.grupe{at}celeradiagnostics.com.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: AD, Alzheimer's disease; APOE, apolipoprotein E; GAPD, glyceraldehyde-3-phosphate dehydrogenase; LOAD, late-onset AD; SNP, single-nucleotide polymorphism; WashU, Washington University; UCSD, University of California at San Diego; UK, Wales College of Medicine and King's College London; LD, linkage disequilibrium; OR, odds ratio; Aβ, β-amyloid.
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↵ ‡‡ Roses, A., Devlin, B., Conneally, P. M., Small, G., Saunders, A. M., Pritchard, M., Locke, P. A., et al. (1995) Am. J. Hum. Genet. Suppl. 57, A202 (abstr.).
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Freely available online through the PNAS open access option.
- Copyright © 2004, The National Academy of Sciences
