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Genetic Variability in CLU and Its Association with Alzheimer's Disease

Guerreiro, RJ; Beck, J; Gibbs, JR; Santana, I; Rossor, MN; Schott, JM; Nalls, MA; ... Hardy, J; + view all (2010) Genetic Variability in CLU and Its Association with Alzheimer's Disease. PLOS ONE , 5 (3) , Article e9510. 10.1371/journal.pone.0009510. Green open access

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Abstract

Background: Recently, two large genome wide association studies in Alzheimer disease (AD) have identified variants in three different genes (CLU, PICALM and CR1) as being associated with the risk of developing AD. The strongest association was reported for an intronic single nucleotide polymorphism (SNP) in CLU.Methodology/Principal Findings: To further characterize this association we have sequenced the coding region of this gene in a total of 495 AD cases and 330 healthy controls. A total of twenty-four variants were found in both cases and controls. For the changes found in more than one individual, the genotypic frequencies were compared between cases and controls. Coding variants were found in both groups (including a nonsense mutation in a healthy subject), indicating that the pathogenicity of variants found in this gene must be carefully evaluated. We found no common coding variant associated with disease. In order to determine if common variants at the CLU locus effect expression of nearby (cis) mRNA transcripts, an expression quantitative loci (eQTL) analysis was performed. No significant eQTL associations were observed for the SNPs previously associated with AD.Conclusions/Significance: We conclude that common coding variability at this locus does not explain the association, and that there is no large effect of common genetic variability on expression in brain tissue. We surmise that the most likely mechanism underpinning the association is either small effects of genetic variability on resting gene expression, or effects on damage induced expression of the protein.

Type: Article
Title: Genetic Variability in CLU and Its Association with Alzheimer's Disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0009510
Publisher version: http://dx.doi.org/10.1371/journal.pone.0009510
Language: English
Additional information: This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services, project number Z01 AG000950-06; MRC Prion Unit and Fundacao para a Ciencia e Tecnologia, Portugal [grant SFRH/BD/29647/2006 and project PIC/IC/83206/2007]. The UK Medical Research Council funded the analysis of the UK cohort. Some of this work was done at University College London Hospitals/University College London which received a proportion of funding from the Department of Health National Institute for Health Research Biomedical Research Centres funding scheme. The Dementia Research Centre in the Department of Neurodegenerative Disease, UCL is an Alzheimer Research Trust Co-ordinating Centre. NCF is funded by the MRC; JMS is in receipt of a HEFCE/NHS Senior lecturership and JH of a MRC Returning Scientist Grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: MULTILOCUS GENOTYPE DATA, GENOME-WIDE ASSOCIATION, APOLIPOPROTEIN-J, AMYLOID-BETA, CEREBROSPINAL-FLUID, IDENTIFIES VARIANTS, SENILE PLAQUES, CLUSTERIN GENE, BRAIN, EXPRESSION
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/145939
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