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

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.