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.

Figure 1

Dose-dependent effect of VR22 4360 SNP on plasma Aβ42 levels in extended LOAD families. Box plots depicting the median (middle part of the box), 25th percentile (lower limit of box), 75th percentile (upper limit of box), 10th percentile (lower end of line) and 90th percentile (upper end of line) for the 10*logAβ42 levels of the 20–65-year-old family members in the 22 LOAD families. The plots are depicted separately for VR22 4360 genotypes TT (red), CT (green) and CC (blue).

Figure 2

Boundaries of VR22 4360/4783 association. (A) Marker–marker linkage disequilibrium in which all SNPs are analyzed with respect to the 4360 SNP. Horizontal line shows the position of the 1.7Mb VR22 gene. Dashed line shows D = 0.75. (B) Marker–phenotype (plasma Aβ42) association. Horizontal line shows the position of the 1.7Mb VR22 gene. Dashed line shows P = 0.05.

Figure 3

Effect of the VR22 SNP 4360 on the multipoint lod scores (MLS) in the LOAD families. Effect of VR22 4360 on the linkage of plasma Aβ42 in 10 LOAD families. Black line: linkage; gray line: linkage conditional upon association with the VR22 4360 SNP. The multipoint IBDs used in these analyses are generated using the 31 markers as described in the text.