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-ε4) 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.
| Original language | English |
|---|---|
| Pages (from-to) | 9434-9439 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 104 |
| Issue number | 22 |
| DOIs | |
| State | Published - May 29 2007 |
| Externally published | Yes |
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Keywords
- APOE
- LRP-6
- Neurodegenerative
- Single-nucleotide polymorphism
- Wnt
ASJC Scopus subject areas
- Genetics
- General
Cite this
Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease. / De Ferrari, Giancarlo V.; Papassotiropoulos, Andreas; Biechele, Travis; De-Vrieze, Fabienne Wavrant; Avila, Miguel E.; Major, Michael B.; Myers, Amanda J; Sáez, Katia; Henríquez, Juan P.; Zhao, Alice; Axel Wollmer, M.; Nitsch, Roger M.; Hock, Christoph; Morris, Chris M.; Hardy, John; Moon, Randall T.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 22, 29.05.2007, p. 9434-9439.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease
AU - De Ferrari, Giancarlo V.
AU - Papassotiropoulos, Andreas
AU - Biechele, Travis
AU - De-Vrieze, Fabienne Wavrant
AU - Avila, Miguel E.
AU - Major, Michael B.
AU - Myers, Amanda J
AU - Sáez, Katia
AU - Henríquez, Juan P.
AU - Zhao, Alice
AU - Axel Wollmer, M.
AU - Nitsch, Roger M.
AU - Hock, Christoph
AU - Morris, Chris M.
AU - Hardy, John
AU - Moon, Randall T.
PY - 2007/5/29
Y1 - 2007/5/29
N2 - 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-ε4) 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.
AB - 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-ε4) 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.
KW - APOE
KW - LRP-6
KW - Neurodegenerative
KW - Single-nucleotide polymorphism
KW - Wnt
UR - http://www.scopus.com/inward/record.url?scp=34547191230&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34547191230&partnerID=8YFLogxK
U2 - 10.1073/pnas.0603523104
DO - 10.1073/pnas.0603523104
M3 - Article
C2 - 17517621
AN - SCOPUS:34547191230
VL - 104
SP - 9434
EP - 9439
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 22
ER -