Evidence for Genetic Linkage of Alzheimer's Disease to Chromosome 10q

Bertram, Lars; Blacker, Deborah; Mullin, Kristina; Keeney, Devon B.; Jones, Jennifer; Basu, Subhash; Yhu, Stephen; McInnis, Melvin G.; Go, Rodney C.P.; Vekrellis, Konstantinos; Selkoe, Dennis J.; Saunders, Aleister J.; Tanzi, Rudolph E.

doi:10.1126/science.290.5500.2302

Cited by 482 publications

(283 citation statements)

References 8 publications

(4 reference statements)

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“…In the total sample, Haplotype H2 carrying the intron 9/A allele suggested AD risk (p=0.06) and haplotype carrying the intron 9 /G allele suggested protection against AD risk (p=0.09) and these differences became significant among non-APOE*4 carriers (haplotype H2: p=0.0009; haplotype H3: p=0.0082). Recently a CHAT intron 10 SNP (rs2177369) was found to be associated with AD risk in a pilot sample of 202 cases and 295 controls, but not in a replication sample of 179 cases and 295 controls [2]. The intron 10 SNP is about 10 kb from the intron 9 SNP and it is likely that both SNP may be in LD, although their frequencies are different from each other.…”

Section: Discussionmentioning

confidence: 99%

“…Linkage studies have identified several promising chromosomal regions to harbor additional AD genes, including chromosomes 12, 10, 9 and 6 [reviewed in 7]. A broad linkage peak encompassing >60 cM region between chromosome 10q21 and 10q25 that influence both AD risk and AAO has been suggested [2,4,10,13]. There are more than 300 genes in this broad genomic region of chromosome 10 and thus the task of identifying the chromosome 10 candidate gene is daunting.…”

Section: Introductionmentioning

confidence: 99%

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Genetic variation in the choline acetyltransferase (CHAT) gene may be associated with the risk of Alzheimer's disease

Öztürk

DeKosky

Kamboh

2006

Neurobiology of Aging

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Several independent linkage studies have mapped a broad susceptibility region for Alzheimer's disease (AD) on the long arm of chromosome 10. There are several biological candidate genes in this region, including choline acetyltransferase (CHAT). A number of studies have examined the role of CHAT genetic variants with AD risk and age-at-onset (AAO), but the results are equivocal. We examined the association of three Single Nucleotide Polymorphisms (SNPs) in the CHAT gene in 1001 white sporadic late-onset AD (LOAD) cases and 708 white controls. We also examined the role of these three SNP with quantitative traits of AD including AAO, disease duration, and MiniMental State Examination (MMSE) score. We observed both allelic and genotypic associations of the intron 9 SNP with AD risk in the total sample (p=0.029 for genotype and p=0.028 for allele frequency differences) as well as among non-APOE*4 carriers (p=0.007 for genotype and p=0.006 for allele frequency differences). Three-site haplotype analysis confirmed that haplotypes determined by the intron 9 SNP were associated with either risk (p=0.0009) or protective (p=0.0082) effects among non-APOE*4 carriers. The three CHAT SNPs also showed a modest association with MMSE score. Our data suggest that genetic variation in the CHAT gene may be associated with AD risk and quantitative traits related to AD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic variation in the choline acetyltransferase (CHAT) gene may be associated with the risk of Alzheimer's disease

Öztürk

DeKosky

Kamboh

2006

Neurobiology of Aging

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“…[26][27][28][29][30][31][32] This is a problem because failure to identify causal variants within linkage regions may impede gene discovery. Part of the difficulty may be related to the analytical strategy using association-based methods to follow up linkage.…”

Section: Discussionmentioning

confidence: 99%

A novel method, the Variant Impact On Linkage Effect Test (VIOLET), leads to improved identification of causal variants in linkage regions

et al. 2013

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The Human Genome Project was expected to individualize medicine by rapidly advancing knowledge of common complex disease through discovery of disease-causing genetic variants. However, this has proved challenging. Although linkage analysis has identified replicated chromosomal regions, subsequent detection of causal variants for complex traits has been limited. One explanation for this difficulty is that utilization of association to follow up linkage is problematic given that linkage and association are not required to co-occur. Indeed, co-occurrence is likely to occur only in special circumstances, such as Mendelian inheritance, but cannot be universally expected. To overcome this problem, we propose a novel method, the Variant Impact On Linkage Effect Test (VIOLET), which differs from other quantitative methods in that it is designed to follow up linkage by identifying variants that influence the variance explained by a quantitative trait locus. VIOLET's performance was compared with measured genotype and combined linkage association in two data sets with quantitative traits. Using simulated data, VIOLET had high power to detect the causal variant and reduced false positives compared with standard methods. Using real data, VIOLET identified a single variant, which explained 24% of linkage; this variant exhibited only nominal association (P ¼ 0.04) using measured genotype and was not identified by combined linkage association. These results demonstrate that VIOLET is highly specific while retaining low false-negative results. In summary, VIOLET overcomes a barrier to gene discovery and thus may be broadly applicable to identify underlying genetic etiology for traits exhibiting linkage.

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“…Microglia cells degrade β-amyloid protein (Qiu et al 1998;Vekrellis et al 2000;Miners et al 2008), and this function is known to be altered in Alzheimer's disease (AD) (Bertram et al 2000) with the consequent noxious accumulation of the protein.…”

Section: Photoreceptor Nervous Cellsmentioning

confidence: 99%

“…Without the key example of AMD, it was previously hypothesized that AD was dependent upon the decline in function of these particular gliocytes determined by telomere shortening (Fossel 1996;Fossel 2004): "One function of the microglia ) is degradation of β-amyloid through insulindegrading enzyme (IDE), a function known to falter in Alzheimer disease (Bertram et al 2000)" (p. 233), and "telomere lengths of circulating monocytes can serve as an independent predictor in at least vascular dementia (von Zglinicki et al 2000)" (p. 235) (Fossel 2004).…”

Section: Photoreceptor Nervous Cellsmentioning

confidence: 99%

Aging of perennial cells and organ parts according to the programmed aging paradigm

Libertini

Ferrara

2016

AGE

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If aging is a physiological phenomenon-as maintained by the programmed aging paradigm-it must be caused by specific genetically determined and regulated mechanisms, which must be confirmed by evidence. Within the programmed aging paradigm, a complete proposal starts from the observation that cells, tissues, and organs show continuous turnover: As telomere shortening determines both limits to cell replication and a progressive impairment of cellular functions, a progressive decline in age-related fitness decline (i.e., aging) is a clear consequence. Against this hypothesis, a critic might argue that there are cells (most types of neurons) and organ parts (crystalline core and tooth enamel) that have no turnover and are subject to wear or manifest alterations similar to those of cells with turnover. In this review, it is shown how cell types without turnover appear to be strictly dependent on cells subjected to turnover. The loss or weakening of the functions fulfilled by these cells with turnover, due to telomere shortening and turnover slowing, compromises the vitality of the served cells without turnover. This determines well-known clinical manifestations, which in their early forms are described as distinct diseases (e.g., Alzheimer's disease, Parkinson's disease, age-related macular degeneration, etc.). Moreover, for the two organ parts (crystalline core and tooth enamel) without viable cells or any cell turnover, it is discussed how this is entirely compatible with the programmed aging paradigm.

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Evidence for Genetic Linkage of Alzheimer's Disease to Chromosome 10q

Cited by 482 publications

References 8 publications

Genetic variation in the choline acetyltransferase (CHAT) gene may be associated with the risk of Alzheimer's disease

Genetic variation in the choline acetyltransferase (CHAT) gene may be associated with the risk of Alzheimer's disease

A novel method, the Variant Impact On Linkage Effect Test (VIOLET), leads to improved identification of causal variants in linkage regions

Aging of perennial cells and organ parts according to the programmed aging paradigm

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