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Human Molecular Genetics Advance Access originally published online on October 14, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 23 3133-3143
DOI: 10.1093/hmg/ddg343
© 2003 Oxford University Press

Fine mapping of the {alpha}-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees

Nilüfer Ertekin-Taner1,{dagger}, James Ronald1,{dagger}, Hideaki Asahara1, Linda Younkin1, Maria Hella1, Shushant Jain1, Eugene Gnida1, Samuel Younkin1, Daniel Fadale1, Yasumasa Ohyagi2, Adam Singleton1, Leah Scanlin1, Mariza de Andrade3, Ronald Petersen4, Neill Graff-Radford5, Michael Hutton1 and Steven Younkin1,*

1Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA, 2Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 3Department of Health Sciences Research, Division of Biostatistics, Mayo Clinic Rochester, Rochester, MN, USA, 4Department of Neurology, Mayo Clinic Rochester, Rochester, MN, USA and 5Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL, USA

Received July 29, 2003; Revised September 23, 2003; Accepted October 7, 2003

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 ~80 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 {alpha}-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.

* To whom correspondence should be addressed at: Mayo Clinic Jacksonville, 4500 San Pablo Road, Birdsall 2, Jacksonville, FL 32224, USA. Tel: +1 9049537356; Fax: +1 9049537370; Email: younkin.steven{at}mayo.edu

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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