Many an Alzheimer disease gene miner is busy looking for gold under the peaks of chromosome 12. In a study published the week of 18 October 2004 in the early online edition of PNAS, Andrew Grupe and Yonghong Li of Celera Diagnostics, leaders of a multinational team of researchers, report that a gene encoding glyceraldehyde-3-phosphate dehydrogenase (GAPD) on chromosome 12 is associated with increased risk of late-onset Alzheimer disease. Moreover, the researchers report risk associations with other GAPD isoforms, as well.

First author Li and colleagues combined three different AD case-control series—from Washington University in St. Louis, Missouri; the University of California, San Diego; and a combined set from the University of Wales in Cardiff and King's College, London. This brought them to a total of 1,089 cases and 1,196 controls. In these samples, the researchers genotyped 282 SNPs under the linkage peak they had identified in previous work on the Washington University group.

The researchers report a strong late-onset AD (LOAD) association with SNPs in the gene for GAPD in this region. Since a number of GAPD isoforms are found elsewhere in the genome, the researchers looked for associations between LOAD and GAPD family genes on chromosomes with some evidence of AD risk loci. In the combined sample, Li and colleagues found associations with a GAPD isoform elsewhere on chromosome 12 and one on chromosome 19. However, not all of the GAPD isoforms were found to be significantly associated with LOAD in each of the three case-control series.

On the possibility that some of the different GAPD genes produce proteins that merge into common pathways, the researchers examined whether combinations of the genes were associated with LOAD. "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 case-control series, suggesting that variants in functionally similar genes may account for series-to-series heterogeneity of disease risk," the authors write.

So what do we know about GAPD? It's clearly an important "housekeeping" enzyme in glucose metabolism, but a critical role in apoptosis has also been proposed. There are intriguing reports on GAPD in Alzheimer brain, including a report of increased enzymatic activity (Soucek et al., 2003). However, a recent study found no difference in GAPD expression between AD and control brain (Gutala and Reddy, 2004).

Some questions for our readers: How strong do you find this claim for a GAPD association? How can we explain the apparent discrepancies between GAPD activity and expression in AD brain? And what about GAPD in apoptosis—does that need to be confirmed?—Hakon Heimer

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  1. For a chromosome (chr 12) with only marginal genetic linkage signals, an unexpectedly large number of AD candidate genes have already been proposed over the past six years including A2M, LRP, OLR1, and LBP-1c. Now we need to add yet another, GAPD, which sits only 2.5 megabases from A2M. In this brute-force high-throughput genomics-style approach to genetics, over 200 SNPs were genotyped in a mixed set of case-control samples, and then tested for association with AD alone or taking into account gender and ApoE genotype status. In the end, this makes for a huge number of comparisons, thus raising the double-edged sword of testing hundreds of SNPs in a single linkage region; while this approach can be incredibly comprehensive, it also dramatically increases the probability of false positive results due to multiple comparisons, or as we sometimes call this in Boston, "The Curse of Bonferroni." Remember that 1 in 20 comparisons is likely to yield a false result. With over 200 SNPs genotyped and then tested for association with AD in multiple models, e.g., according to gender and/or ApoE, a "meaningful" result would have to be, statistically speaking, very strong. The authors report odds ratios that are relatively small.

  2. From the AlzGene team:
    In addition to the three AD samples listed, this study also tested a fourth AD sample comprising subjects originating from a sib-pair linkage study. However, since these linkage AD cases were not contrasted to an independent sample of controls, we decided to not include it into the database.

    View all comments by Lars Bertram

References

Paper Citations

  1. . The regulation of glucose metabolism by HIF-1 mediates a neuroprotective response to amyloid beta peptide. Neuron. 2003 Jul 3;39(1):43-56. PubMed.
  2. . The use of real-time PCR analysis in a gene expression study of Alzheimer's disease post-mortem brains. J Neurosci Methods. 2004 Jan 15;132(1):101-7. PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. . Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family. Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15688-93. PubMed.