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


CONCLUSIONS
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.
Mukherjee
Odity
O
Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA. odity@icarus.wustl.edu <odity@icarus.wustl.edu>
Kauwe
John S K
JS
Mayo
Kevin
K
Morris
John C
JC
Goate
Alison M
AM
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D016022:Case-Control Studies; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016875:tau Proteins / Q000235:genetics*
C054369:MAPT protein, human; D016875:tau Proteins