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. 2004 Nov 2;101(44):15688-93.
doi: 10.1073/pnas.0403535101. Epub 2004 Oct 26.

Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family

Yonghong Li  1 , 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, Andrew Grupe
Affiliations

Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family

Yonghong Li et al. Proc Natl Acad Sci U S A. .

Erratum in

  • Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6411

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.

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Figures

Fig. 1.
Fig. 1.
Allelic P values of 223 markers are plotted for a 30-Mbp region of chromosome 12p. P values were for genotyping results of all exploratory markers tested in the WashU case-control set. (A) ALL stratum: analysis of all case and control samples in the set. (B) The APOE4 absent (APOE4-) stratum includes all samples without an APOE4 allele. (C) The APOE4 present (APOE4+) stratum includes all samples that have one or two APOE4 alleles. rs3741916 in GAPD is highlighted with a circle.
Fig. 2.
Fig. 2.
Allelic P values from 62 fine-mapping markers and rs3741916 in GAPD. P values are presented for the ALL stratum (A) and the APOE4 absent (APOE4-) stratum (B) of the WashU sample set, along with a gene map of the region based on Celera's R27 human genome assembly (C). rs758738 is located at 8,171,519 bp in the Celera genome assembly and is shown at relative genomic position 0.
Fig. 3.
Fig. 3.
LD metrics. The LD map was constructed from APOE4-negative subjects (cases and controls) in the WashU sample set with 63 markers, covering a 418-kbp region. D′ values are shown in the top left triangle, and r2 values are shown in the bottom right.
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