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

Abstract

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.

• Authors: Giancarlo V De Ferrari, Andreas Papassotiropoulos, Travis Biechele, Fabienne Wavrant De-Vrieze, Miguel E Avila, Michael B Major, Amanda Myers, Katia Sáez, Juan P Henríquez, Alice Zhao, M Axel Wollmer, Roger M Nitsch, Christoph Hock, Chris M Morris, John Hardy, Randall T Moon
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 22 Pg. 9434-9 (May 29 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17517621 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• LDL-Receptor Related Proteins
• LRP6 protein, human
• Low Density Lipoprotein Receptor-Related Protein-6
• beta Catenin
• Valine

Topics

• Age of Onset
• Aging (genetics)
• Alleles
• Alzheimer Disease (genetics, metabolism)
• Amino Acid Sequence
• Animals
• Cell Line
• Cells, Cultured
• Chromosomes, Human, Pair 12 (genetics)
• Conserved Sequence
• Gene Expression Regulation
• Genes, Reporter (genetics)
• Haplotypes
• Hippocampus (metabolism)
• Humans
• LDL-Receptor Related Proteins (chemistry, genetics, metabolism)
• Low Density Lipoprotein Receptor-Related Protein-6
• Molecular Sequence Data
• Polymorphism, Single Nucleotide (genetics)
• Sequence Alignment
• Valine (genetics, metabolism)
• beta Catenin (genetics, metabolism)