A Scan of Chromosome 10 Identifies a Novel Locus Showing Strong Association with Late-Onset Alzheimer Disease

Department of Psychological Medicine and Neurology, Cardiff University, Cardiff, Wales, United Kingdom
The American Journal of Human Genetics (Impact Factor: 10.93). 01/2006; 78(1):78-88. DOI: 10.1086/498851
Source: PubMed


Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A (LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants (e.g., noncoding RNAs) in the pathogenesis of this disorder.

Download full-text


Available from: Amanda J Myers
  • Source
    • "There are many reported pleiotropic 25 effects of statins. For example, chronic statin treatment 26 can enhance memory (e.g., atorvastatin or simvastatin, 27 (Grupe et al., 2006; Li et al., 2006; Lu et al., 2007), 28 decrease inflammatory cytokine production (Balduini 29 et al., 2003), improve cerebral blood flow to a site of injury 30 (Chen et al., 2003) and reduce deficits in long-term poten- 31 tiation in a mouse model of Alzheimer's disease (AD) 32 (Metais et al., 2014). Moreover statins can enhance neuro- 33 genesis in the dentate gyrus (Chen et al., 2003; Lu et al., 34 2007) in addition to promoting angiogenesis and neurite 35 outgrowth (Pooler et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Simvastatin is an HMG-CoA reductase inhibitor commonly used in the clinic to treat hypercholesterolemia. In addition, simvastatin has been shown to cross the blood brain barrier and pleiotropic effects of simvastatin have been reported including anti-inflammatory properties, enhancement of neurite outgrowth, and memory enhancement properties. However, little has been reported on the effects of simvastatin on basal synaptic transmission and neuronal excitability. Here we report that simvastatin increases the fEPSP, the NMDA receptor-mediated fEPSP using extracellular recordings in the dendritic region of the CA1 of hippocampal slices taken from 8 week old C57Black6J mice. In addition, we found that simvastatin perfusion causes a change in the input/output curve and a decrease of the paired pulse facilitation ratio, indicating respectively an increase of the neuronal excitability and neurotransmitter release. We have also observed that acute application of simvastatin increased the amplitude of the compound action potential in the CA1 region. Notably, using LY294002, we have demonstrated that this effect was PI3K dependent and was occluded if the animals had previously received a diet supplemented with simvastatin. We have finally shown that the simvastatin mediated increase of the compound action potential amplitude was also present in hippocampal slices from aged mice. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Feb 2015 · Neuroscience
  • Source
    • "Our results are consistent with previous reports that genetic variations in SORCS1 are associated with AD and could affect APP processing [4], [5], [31]. Memory is the cognitive domain predominantly affected by AD, and is associated with changes in Aβ levels [32], [33], [34]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We previously reported that genetic variants in SORCS1 increase the risk of AD, that over-expression of SorCS1 reduces γ-secretase activity and Aβ levels, and that SorCS1 suppression increases γ-secretase processing of APP and Aβ levels. We now explored the effect of variation in SORCS1 on memory. We explored associations between SORCS1-SNPs and memory retention in the NIA-LOAD case control dataset (162 cases,670 controls) and a cohort of Caribbean Hispanics (549 cases,544 controls) using single marker and haplotype analyses. Three SNPs in intron 1, were associated with memory retention in the NIA-LOAD dataset or the Caribbean Hispanic dataset (rs10884402(A allele:β = -0.15,p = 0.008), rs7078098(C allele:β = 0.18,p = 0.007) and rs950809(C allele:β = 0.17,p = 0.008)) and all three SNPs were significant in a meta-analysis of both datasets (0.002<p<0.03). The corresponding A-T-T haplotype for these SNPs was associated with lower scores in both datasets (p = 0.02,p = 0.0009), and the complementary G-C-C haplotype was associated with higher scores in NIA-LOAD (p = 0.02). These associations were restricted to cases. Variation in intron 1 in SORCS1 is associated with memory changes in AD.
    Full-text · Article · Oct 2011 · PLoS ONE
  • Source
    • "Therefore, analyses were performed with and without the individuals harboring these variants. The estimated haplotype network was used for all Treescan [8,27,28] analyses. All treescanning analyses used genotypes as factors and only included genotypic classes with counts of five or more. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Genotype/phenotype association analyses (Treescan) with plasma lipid levels and functional site prediction methods (TreeSAAP and PolyPhen) were performed using sequence data for ANGPTL4 from 3,551 patients in the Dallas Heart Study. Biological assays of rare variants in phenotypic tails and results from a Treescan analysis were used as "known" variants to assess the site prediction abilities of PolyPhen and TreeSAAP. The E40K variant in European Americans and the R278Q variant in African Americans were significantly associated with multiple lipid phenotypes. Combining TreeSAAP and PolyPhen performed well to predict "known" functional variants while reducing noise from false positives.
    Full-text · Article · Jan 2010 · International Journal of Molecular Sciences
Show more

We use cookies to give you the best possible experience on ResearchGate. Read our cookies policy to learn more.