In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 104, No. 22 ( 2007-05-29), p. 9434-9439
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-ε4 ( APOE -ε 4 ) 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 β-catenin signaling in HEK293T cells. Our study unveils a genetic relationship between LRP6 and APOE and supports the hypothesis that altered Wnt/β-catenin signaling may be involved in this neurodegenerative disease.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0603523104
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2007
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
Permalink