Common genetic variation within the low-density lipoprotein receptor-related protein 6 and late-onset Alzheimer's disease.
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.
De Ferrari
Giancarlo V
GV
Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA 98195, USA. gdeferrari@udec.cl
Papassotiropoulos
Andreas
A
Biechele
Travis
T
Wavrant De-Vrieze
Fabienne
F
Avila
Miguel E
ME
Major
Michael B
MB
Myers
Amanda
A
Sáez
Katia
K
Henríquez
Juan P
JP
Zhao
Alice
A
Wollmer
M Axel
MA
Nitsch
Roger M
RM
Hock
Christoph
C
Morris
Chris M
CM
Hardy
John
J
Moon
Randall T
RT
D017668:Age of Onset; D000375:Aging / Q000235:genetics*; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D017124:Conserved Sequence; D005786:Gene Expression Regulation; D017930:Genes, Reporter / Q000235:genetics; D006239:Haplotypes; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016415:Sequence Alignment; D014633:Valine / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051176:beta Catenin; D014633:Valine