Common genetic variation within the low-density lipoprotein receptor-related protein 6 and late-onset Alzheimer's disease

De Ferrari, Giancarlo V. and Papassotiropoulos, Andreas and Biechele, Travis and Wavrant De-Vrieze, Fabienne and Avila, Miguel E. and Major, Michael B. and Myers, Amanda and Sáez, Katia and Henríquez, Juan P. and Zhao, Alice and Wollmer, M. Axel and Nitsch, Roger M. and Hock, Christoph and Morris, Chris M. and Hardy, John and Moon, Randall T.. (2007) Common genetic variation within the low-density lipoprotein receptor-related protein 6 and late-onset Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, H. 22. pp. 9434-9439.

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Official URL: http://edoc.unibas.ch/dok/A5257154

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Genome-wide linkage studies have defined a broad susceptibility region for late-onset Alzheimer's disease on chromosome 12, which contains the Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) gene, a coreceptor for Wnt signaling. Here, we report the association between common LRP6 variants and late-onset Alzheimer's disease in a multicenter case-control series as well as in a large family-based series ascertained by the National Institute of Mental Health-National Institute on Aging Genetics Initiative. As shown in the genome-wide linkage studies, our association depends mainly on apolipoprotein E-epsilon4 (APOE-epsilon4) carrier status. Haplotype tagging single-nucleotide polymorphisms (SNPs) with a set of seven allelic variants of LRP6 identified a putative risk haplotype, which includes a highly conserved coding sequence SNP: Ile-1062 --< Val. Functional analyses revealed that the associated allele Val-1062, an allele previously linked to low bone mass, has decreased beta-catenin signaling in HEK293T cells. Our study unveils a genetic relationship between LRP6 and APOE and supports the hypothesis that altered Wnt/beta-catenin signaling may be involved in this neurodegenerative disease.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Services Biozentrum > Life Sciences Training Facility (Papassotiropoulos)
07 Faculty of Psychology > Departement Psychologie > Ehemalige Einheiten Psychologie > Molecular Neuroscience (Papassotiropoulos)
UniBasel Contributors:Papassotiropoulos, Andreas
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:National Academy of Sciences
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:22 Mar 2012 14:19
Deposited On:22 Mar 2012 13:17

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