Haplotype-based association analysis of the MAPT locus in late onset Alzheimer's disease

Abstract

Background: Late onset Alzheimer's disease (LOAD) is a common sporadic form of the illness, affecting individuals above the age of 65 yrs. A prominent hypothesis for the aetiopathology of Alzheimer's disease is that in the presence of a beta-amyloid load, individuals expressing a pathogenic form of tau protein (MAPT) are at increased risk for developing the disease. Genetic studies in this pursuit have, however, yielded conflicting results. A recent study showed a significant haplotype association (H1c) with AD. The current study is an attempt to replicate this association in an independently ascertained cohort.

Results: In this report we present the findings of a haplotype analysis at the MAPT locus. We failed to detect evidence of association of the H1c haplotype at the MAPT locus with LOAD. None of the six SNPs forming the H1c haplotype showed evidence of association with disease. In addition, nested clade analysis suggested the presence of independent mutations at multiple points in the haplotype network or homoplasy at the MAPT locus. Such homoplasy can confound single SNP tests for association. We do not detect evidence that the set of SNPs forming the H1c haplotype in general or rs242557 in particular are pathogenic for LOAD.

Conclusion: In conclusion, we employed two contemporary haplotype analysis tools to perform haplotype association analysis at the MAPT locus. Our data suggest that the tagged SNPs forming the H1c haplotype do not have a causal role in the pathogenesis of LOAD.

Figure 1

Plot of single marker association and pair-wise LD analysis of all SNPs forming the H1C haplotype. (a) The position of the markers and the ref sequence is with respect to the genome assembly hg17/May2004.(b) Association analysis of H1C haplotype SNPs with LOAD; plot of -log(P) for case-control test at the allelic level with LOAD. (c) Linkage disequilibrium plot depicting the D' value; the blocks are shaded corresponding to the values which were obtained from the LD analysis program haploview.

Figure 2

Haplotype Network of the MAPT locus: Each oval represents a specific haplotype. Branches represent mutational steps between haplotypes. The figure shows the haplotype identification number, the nucleic acid base at each locus of the haplotype and the number of times it was inferred in this sample set.