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PMID: 17517621 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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 ·No. 22 ·2007-05-29 ·Pages 9434-9

De Ferrari GV, Papassotiropoulos A, Biechele T, Wavrant De-Vrieze F, Avila ME, Major MB, Myers A, Sáez K, Henríquez JP, Zhao A, Wollmer MA, Nitsch RM, Hock C, Morris CM, Hardy J, Moon RT

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.

MeSH Terms
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
Chemicals
LDL-Receptor Related Proteins LRP6 protein, human Low Density Lipoprotein Receptor-Related Protein-6 beta Catenin Valine
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
De Ferrari Giancarlo V
Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA 98195, USA. [email protected]
Papassotiropoulos Andreas
Biechele Travis
Wavrant De-Vrieze Fabienne
Avila Miguel E
Major Michael B
Myers Amanda
Sáez Katia
Henríquez Juan P
Zhao Alice
Wollmer M Axel
Nitsch Roger M
Hock Christoph
Morris Chris M
Hardy John
Moon Randall T
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0603523104
Email
[email protected]
Published
2007-05-29
Epub
2007-00-21
Pages
9434-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1890512
Subset
IM
Grants
NIMH NIH HHS · U01 MH 46281 · United States
NIA NIH HHS · U24 AG021886 · United States
Medical Research Council · G0701075 · United Kingdom
NIMH NIH HHS · U01 MH 46290 · United States
NIMH NIH HHS · U01 MH 46372 · United States
NIMH NIH HHS · U01 MH046290 · United States
NIMH NIH HHS · U01 MH046281 · United States
External Links
PubMed source DOI: 10.1073/pnas.0603523104 PMC Full Text View journal details
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