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

Li, Yonghong, Nowotny, Petra, Holmans, Peter Alan, Smemo, Scott, Kauwe, John S. K., Hinrichs, Anthony L., Tacey, Kristina, Doil, Lisa, Luchene, Ryan van, Garcia, Veronica, Rowland, Charles, Schrodi, Steve, Leong, Diane, Gogic, Goran, Chan, Joanne, Cravchik, Anibal, Ross, David, Lau, Kit, Kwok, Shirley, Chang, Sheng-Yung, Catanese, Joseph, Sninsky, John, White, Thomas J., Hardy, John, Powell, John, Lovestone, Simon, Morris, John C., Thal, Leon, Owen, Michael John, Williams, Julie, Goate, Alison and Grupe, Andrew 2004. Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family. Proceedings of the National Academy of Sciences 101 (44) , pp. 15688-15693. 10.1073/pnas.0403535101

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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. Alzheimer's disease (AD), the most common form of dementia among the elderly, is a complex neurodegenerative disorder resulting from multiple genetic and nongenetic factors (1, 2, 3). A large body of evidence supports a central role for β-amyloid (Aβ) in AD pathogenesis. Mutations associated with familial AD in Aβ precursor protein and the γ-secretase subunits presenilin-1 and -2 all lead to increased production and/or deposition of Aβ42 (4). Because Aβ42 is known to be neurotoxic and/or neuroinflammatory in various experimental systems, it is believed that increased Aβ42 production leads to synaptic dysfunction and subsequent neuronal cell death, thereby contributing to memory loss and other symptoms (5). It follows that genetic mutations affecting various steps of the Aβ pathway, such as Aβ production, degradation/clearance, deposition, and neuronal apoptosis, could be associated with AD. Indeed, a number of such candidate genes have been reported to be risk factors for late-onset AD (LOAD), although so far only apolipoprotein E (APOE) has been confirmed by multiple independent studies (6). However, only ≈50% of AD cases carry an APOE4 allele,‡‡ and genetic studies have predicted that at least four other genes modify age of disease onset (7). Identification of other genetic risk factors is critical not only to further understanding of the disease mechanism but also to guide development of diagnostic reagents and disease-modifying treatments. The latter may be particularly sensitive to stratification by disease alleles. Genome-wide linkage screens in affected sibling pairs have identified several candidate gene regions, notably on chromosomes 9, 10, and 12 (8, 9, 10, 11, 12, 13, 14). Association studies have evaluated a small number of biological candidate genes from the linkage regions, but many of these studies have used samples of relatively small size, thus limiting their power to identify disease-risk genes (for review, see ref. 15). Previously, we and others have reported linkage on chromosome 12 in LOAD families (8, 11, 12, 14, 16). The linkage signal in these studies came predominantly from individuals with no APOE4 alleles. Subsequently, association with AD has been reported for polymorphisms in several candidate genes, but none have been consistently replicated (for review, see ref. 17). To follow up our linkage results on chromosome 12, we have genotyped 282 single-nucleotide polymorphisms (SNPs) under our linkage peak in multiple case-control series totaling 1,089 AD subjects and 1,196 nondemented controls. Strong association was observed in a small region that includes a gene encoding glyceraldehyde-3-phosphate dehydrogenase (GAPD), which led us to examine this gene and its paralogs on other chromosomes in more depth.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Publisher: National Acadey of Sciences
ISSN: 10916490
Last Modified: 02 May 2019 12:41
URI: http://orca.cf.ac.uk/id/eprint/586

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