Genetic Variability in CLU and Its Association with Alzheimer's Disease
Autor(a) principal: | |
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Data de Publicação: | 2010 |
Outros Autores: | , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/12861 https://doi.org/10.1371/journal.pone.0009510 |
Resumo: | 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. 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. 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 |
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Genetic Variability in CLU and Its Association with Alzheimer's DiseaseRecently, 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. 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. 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 proteinPublic Library of Science2010-03-03info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/12861http://hdl.handle.net/10316/12861https://doi.org/10.1371/journal.pone.0009510engPLoS ONE. 5:3 (2010) e95101932-6203Guerreiro, Rita J.Beck, JohnGibbs, J. RaphaelSantana, IsabelRossor, Martin N.Schott, Jonathan M.Nalls, Michael A.Ribeiro, HelenaSantiago, BeatrizFox, Nick C.Oliveira, CatarinaCollinge, JohnMead, SimonSingleton, AndrewHardy, Johninfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2020-11-06T17:00:14Zoai:estudogeral.uc.pt:10316/12861Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:55:42.189335Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Genetic Variability in CLU and Its Association with Alzheimer's Disease |
title |
Genetic Variability in CLU and Its Association with Alzheimer's Disease |
spellingShingle |
Genetic Variability in CLU and Its Association with Alzheimer's Disease Guerreiro, Rita J. |
title_short |
Genetic Variability in CLU and Its Association with Alzheimer's Disease |
title_full |
Genetic Variability in CLU and Its Association with Alzheimer's Disease |
title_fullStr |
Genetic Variability in CLU and Its Association with Alzheimer's Disease |
title_full_unstemmed |
Genetic Variability in CLU and Its Association with Alzheimer's Disease |
title_sort |
Genetic Variability in CLU and Its Association with Alzheimer's Disease |
author |
Guerreiro, Rita J. |
author_facet |
Guerreiro, Rita J. Beck, John Gibbs, J. Raphael Santana, Isabel Rossor, Martin N. Schott, Jonathan M. Nalls, Michael A. Ribeiro, Helena Santiago, Beatriz Fox, Nick C. Oliveira, Catarina Collinge, John Mead, Simon Singleton, Andrew Hardy, John |
author_role |
author |
author2 |
Beck, John Gibbs, J. Raphael Santana, Isabel Rossor, Martin N. Schott, Jonathan M. Nalls, Michael A. Ribeiro, Helena Santiago, Beatriz Fox, Nick C. Oliveira, Catarina Collinge, John Mead, Simon Singleton, Andrew Hardy, John |
author2_role |
author author author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Guerreiro, Rita J. Beck, John Gibbs, J. Raphael Santana, Isabel Rossor, Martin N. Schott, Jonathan M. Nalls, Michael A. Ribeiro, Helena Santiago, Beatriz Fox, Nick C. Oliveira, Catarina Collinge, John Mead, Simon Singleton, Andrew Hardy, John |
description |
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. 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. 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 |
publishDate |
2010 |
dc.date.none.fl_str_mv |
2010-03-03 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/12861 http://hdl.handle.net/10316/12861 https://doi.org/10.1371/journal.pone.0009510 |
url |
http://hdl.handle.net/10316/12861 https://doi.org/10.1371/journal.pone.0009510 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
PLoS ONE. 5:3 (2010) e9510 1932-6203 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Public Library of Science |
publisher.none.fl_str_mv |
Public Library of Science |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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