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

Nilufer Taner, James Ronald, Hideaki Asahara, Linda Younkin, Maria Hella, Shushant Jain, Eugene Gnida, Samuel Younkin, Daniel Fadale, Yasumasa Ohyagi, Adam Singleton, Leah Scanlin, Mariza De Andrade, Ronald Carl Petersen, Neill R Graff Radford, Michael Hutton, Steven G Younkin

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Abstract

Using plasma amyloid β protein (Aβ42) 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 Aβ42. VR22 is a large (1.7 Mb) gene located at 80 cM that encodes α-T catenin, which is a binding partner of β catenin. This makes VR22 an attractive candidate gene because β catenin interacts with presenilin 1, which has many mutations that elevate Aβ42 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 Aβ42 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 Aβ42 and contribute to the previously reported linkage for plasma Aβ42 in LOAD families.

Original languageEnglish (US)
Pages (from-to)3133-3143
Number of pages11
JournalHuman Molecular Genetics
Volume12
Issue number23
DOIs
StatePublished - Dec 1 2003

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Catenins
Chromosomes, Human, Pair 10
Quantitative Trait Loci
Pedigree
Alzheimer Disease
Genes
Single Nucleotide Polymorphism
Presenilin-1
Lod Score
Amyloidogenic Proteins
Linkage Disequilibrium
Blood Proteins
Phenotype
Mutation

ASJC Scopus subject areas

  • Genetics

Cite this

Fine mapping of the α-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. / Taner, Nilufer; Ronald, James; Asahara, Hideaki; Younkin, Linda; Hella, Maria; Jain, Shushant; Gnida, Eugene; Younkin, Samuel; Fadale, Daniel; Ohyagi, Yasumasa; Singleton, Adam; Scanlin, Leah; De Andrade, Mariza; Petersen, Ronald Carl; Graff Radford, Neill R; Hutton, Michael; Younkin, Steven G.

In: Human Molecular Genetics, Vol. 12, No. 23, 01.12.2003, p. 3133-3143.

Research output: Contribution to journalArticle

Taner, N, Ronald, J, Asahara, H, Younkin, L, Hella, M, Jain, S, Gnida, E, Younkin, S, Fadale, D, Ohyagi, Y, Singleton, A, Scanlin, L, De Andrade, M, Petersen, RC, Graff Radford, NR, Hutton, M & Younkin, SG 2003, 'Fine mapping of the α-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees', Human Molecular Genetics, vol. 12, no. 23, pp. 3133-3143. https://doi.org/10.1093/hmg/ddg343
Taner, Nilufer ; Ronald, James ; Asahara, Hideaki ; Younkin, Linda ; Hella, Maria ; Jain, Shushant ; Gnida, Eugene ; Younkin, Samuel ; Fadale, Daniel ; Ohyagi, Yasumasa ; Singleton, Adam ; Scanlin, Leah ; De Andrade, Mariza ; Petersen, Ronald Carl ; Graff Radford, Neill R ; Hutton, Michael ; Younkin, Steven G. / Fine mapping of the α-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. In: Human Molecular Genetics. 2003 ; Vol. 12, No. 23. pp. 3133-3143.
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AU - Taner, Nilufer

AU - Ronald, James

AU - Asahara, Hideaki

AU - Younkin, Linda

AU - Hella, Maria

AU - Jain, Shushant

AU - Gnida, Eugene

AU - Younkin, Samuel

AU - Fadale, Daniel

AU - Ohyagi, Yasumasa

AU - Singleton, Adam

AU - Scanlin, Leah

AU - De Andrade, Mariza

AU - Petersen, Ronald Carl

AU - Graff Radford, Neill R

AU - Hutton, Michael

AU - Younkin, Steven G

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N2 - Using plasma amyloid β protein (Aβ42) 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 Aβ42. VR22 is a large (1.7 Mb) gene located at 80 cM that encodes α-T catenin, which is a binding partner of β catenin. This makes VR22 an attractive candidate gene because β catenin interacts with presenilin 1, which has many mutations that elevate Aβ42 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 Aβ42 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 Aβ42 and contribute to the previously reported linkage for plasma Aβ42 in LOAD families.

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