The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts
Introduction
A common inversion divides the microtubule associated protein tau (MAPT) locus into two major haplotype clades, H1 and H2 (Baker et al., 1999, Stefansson et al., 2005, Rademakers et al., 2005, Hardy et al., 2004). Our group and others have shown that the H2 clade is a single unrecombining haplotype covering several genes and ∼ 1.6 Mb on chromosome 17q21 (Pittman et al., 2004, Stefansson et al., 2005, Cruts et al., 2005). In contrast, the more common H1 clade shows considerable diversity and has a normal pattern of linkage disequilibrium except with respect to H2 (Pittman et al., 2004, Rademakers et al., 2005). We have further shown, and others have confirmed, that a variant of this clade, MAPT H1c, is largely responsible for the association between the H1 clade and the sporadic tauopathies (Pittman et al., 2004, Rademakers et al., 2005). We reported that this same haplotype, H1c, was also associated with increased risk for AD (Myers et al., 2005).
Most positive genetic associations for AD have not been replicated (http://www.alzforum.org/res/com/gen/alzgene/default.asp) and the interpretation of the replicating and non-replicating studies is not clear cut in cases where different populations have been used in the follow up studies. While many journals have adopted the policy of requiring internal replications before publication, this has complicated, rather than simplified matters, because it is not transparent whether studies on different populations have occurred sequentially or in parallel.
With this in mind, we had two goals in this study: first, we wanted to test for our reported H1c association in a sample set which was identical in ascertainment to our first study (entirely neuropathological specimens of cases and controls derived from US Brain Banks, largely those funded through the NIA/NIH Alzheimer initiative: see Acknowledgments); and second, if it did replicate, we wanted to try and dissect the biological mechanism of the association of this haplotype with tangle diseases. Since all the MAPT haplotypes are comprised of non-coding changes, there are essentially two plausible mechanisms underpinning pathogenicity: an effect on transcription or an effect on splicing.
Section snippets
Late onset AD replication-single locus analysis
We genotyped the same 6 polymorphisms we used previously to tag the haplotype diversity of the MAPT locus (see Pittman et al., 2005, Myers et al., 2005) in our replicate set of 296 cases and 128 controls obtained from NIA funded brain banks at ADC centers throughout the United States (see Acknowledgments). Table 1 shows the summary statistics for this replicate set and our total series, which includes the US and UK populations, we had published on previously. By single locus analysis, rs2471738
Discussion
We report herein our confirmation of the MAPT H1c association with AD in a sample series of pathologically confirmed cases and controls with similar ascertainment and characteristics. Our confirmation is precise: the same haplotype H1c is associated with AD to the same extent as we had previously reported. This association has the same direction and magnitude and is of the same haplotype with which we had previously shown (also, largely in US pathological specimens) an association with the
Genetic analysis
All samples were of Caucasian origin and pathologically confirmed at autopsy. The replicate US series was obtained from 8 additional NACC funded brain banks with in the US. Forty percent of the replicate series had Braak and Braak staging. All controls were free of neuropathology at autopsy. DNA was prepared using the Qiagen DNeasy kit (Qiagen, Hilden, Germany, cat #: 69504). The same SNPs were used in this paper as in our previous report (Myers et al., 2005). All genotyping was performed by
Acknowledgments
Many data and biomaterials were collected from several NIA-NACC funded sites. Marcelle Morrison-Bogorad, PhD, Tony Phelps, PhD, and Walter Kukull, PhD, are thanked for helping to co-ordinate this collection. The directors, pathologist and technicians involved include the following: National Institute on Aging: Ruth Seemann, Dan Brady, MD; John Hopkins Alzheimer’s Disease Research Center (NIA grant # AG 05146): Juan C. Troncoso, MD, Dr. Olga Pletnikova; University of California, Los Angeles (NIA
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