Human Molecular Genetics Advance Access published online on October 14, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg343
© 2003 by Oxford University Press
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1 Mayo Clinic Jacksonville, Department of Neuroscience, Jacksonville, FL, USA
* To whom correspondence should be addressed. E-mail: younkin.steven{at}mayo.edu.
Using plasma amyloid ß protein (Aß42) levels as an intermediate, quantitative phenotype for late onset Alzheimer's disease (LOAD), we previously obtained significant linkage at
Article
Fine Mapping of the
-T Catenin Gene to a Quantitative Trait Locus on Chromosome 10 in Late-Onset Alzheimer's Disease Pedigrees
2 Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
3 Mayo Clinic Rochester, Department of Health Sciences Research, Division of Biostatistics, Rochester, MN, USA
4 Mayo Clinic Rochester, Department of Neurology, Rochester, MN, USA
5 Mayo Clinic Jacksonville, Department of Neurology, Jacksonville, FL, USA.
6 Mayo Clinic Jacksonville, Department of Neuroscience, 4500 San Pablo Road, Birdsall #2, Jacksonville, FL 32224, USA
Abstract 
80 centimorgans (cM) on chromosome 10. Linkage to the same region was obtained independently in a study of affected LOAD sib-pairs. Together, these two studies provide strong evidence for a novel LOAD locus on chromosome 10 that acts to increase Aß42. VR22 is a large (1.7 Mb) gene located at 80 cM that encodes 
-T catenin, which is a binding partner of ß catenin. This makes VR22 an attractive candidate gene because ß catenin interacts with presenilin 1, which has many mutations that elevate Aß42 and cause early onset familial AD. We identified two intronic VR22 SNPs (4360 and 4783) in strong linkage disequilibrium (LD) that showed highly significant association (p = 0.0001 and 0.0006) with plasma Aß42 in 10 extended LOAD families. This association clearly contributed to the linkage at 80 cM because the lod scores decreased when linkage analysis was performed conditional upon the VR22 association. This association replicated in another independent set of 12 LOAD families (p = 0.04 for 4783 and p = 0.08 for 4360). Bounding of the association region using multiple SNPs showed VR22 to be the only confirmed gene within the region of association. These findings indicate that VR22 has variant(s) which influence Aß42 and contribute to the previously reported linkage for plasma Aß42 in LOAD families.
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