title: Fine mapping of the alpha-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees.
abstract: Using plasma amyloid beta protein (Abeta42) levels as an intermediate, quantitative phenotype for late onset Alzheimer's disease (LOAD), we previously obtained significant linkage at approximately 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 Abeta42. VR22 is a large (1.7 Mb) gene located at 80 cM that encodes alpha-T catenin, which is a binding partner of beta catenin. This makes VR22 an attractive candidate gene because beta catenin interacts with presenilin 1, which has many mutations that elevate Abeta42 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 Abeta42 in 10 extended LOAD families. This association clearly contributed to the linkage at approximately 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 Abeta42 and contribute to the previously reported linkage for plasma Abeta42 in LOAD families.
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.
authors.forename: Nilüfer
authors.initials: N
authors.lastname: Ertekin-Taner
authors.forename: James
authors.initials: J
authors.lastname: Ronald
authors.forename: Hideaki
authors.initials: H
authors.lastname: Asahara
authors.forename: Linda
authors.initials: L
authors.lastname: Younkin
authors.forename: Maria
authors.initials: M
authors.lastname: Hella
authors.forename: Shushant
authors.initials: S
authors.lastname: Jain
authors.forename: Eugene
authors.initials: E
authors.lastname: Gnida
authors.forename: Samuel
authors.initials: S
authors.lastname: Younkin
authors.forename: Daniel
authors.initials: D
authors.lastname: Fadale
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ohyagi
authors.forename: Adam
authors.initials: A
authors.lastname: Singleton
authors.forename: Leah
authors.initials: L
authors.lastname: Scanlin
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.forename: Ronald
authors.initials: R
authors.lastname: Petersen
authors.forename: Neill
authors.initials: N
authors.lastname: Graff-Radford
authors.forename: Michael
authors.initials: M
authors.lastname: Hutton
authors.forename: Steven
authors.initials: S
authors.lastname: Younkin
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000235:genetics; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D051178:alpha Catenin
chemical_list: D016229:Amyloid beta-Peptides; C441963:CTNNA3 protein, human; D003598:Cytoskeletal Proteins; D051178:alpha Catenin