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Human Molecular Genetics Advance Access published online on September 29, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi361
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received July 5, 2005
Revised September 12, 2005
Accepted September 21, 2005

Article

High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy

Rosa Rademakers 1, Stacey Melquist 2, Marc Cruts 1, Jessie Theuns 1, Jurgen Del-Favero 1, Parvoneh Poorkaj 3, Matt Baker 2, Kristel Sleegers 1, Richard Crook 2, Tim De Pooter 1, Samira Bel Kacem 1, Jennifer Adamson 2, Dirk Van den Bossche 1, Marleen Van den Broeck 1, Jennifer Gass 2, Ellen Corsmit 1, Peter De Rijk 1, Natalie Thomas 4, Sebastiaan Engelborghs 5, Michael Heckman 6, Julia Crook 6, Peter P. De Deyn 5, Dennis Dickson 4, Gerard D. Schellenberg 3, Christine Van Broeckhoven PhD DSc7*, and Michael L. Hutton 2

1 Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Institute Born-Bunge, University of Antwerp, Belgium
2 Department of Neuroscience, Mayo Clinic, Jacksonville, USA
3 Departments of Medicine, Neurology, and Pharmacology, University of Washington, Geriatric Research Education and Clinical Center, Seattle Veterans Affairs Medical Center, Seattle, USA
4 Department of Pathology, Mayo Clinic College of Medicine, Jacksonville, USA
5 Division of Neurology, Middelheim Hospital, and Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Belgium
6 Biostatistics Unit, Mayo Clinic, Jacksonville, USA
7 Department of Molecular Genetics (VIB8), Neurodegenerative Brain Diseases Research Group, University of Antwerp, Building V - Room 0.10, Universiteitsplein 1, B-2610 Antwerpen, Belgium

* To whom correspondence should be addressed.
Christine Van Broeckhoven, E-mail: christine.vanbroeckhoven{at}ua.ac.be


  Abstract

Two extended haplotypes exist across the tau gene - H1 and H2 - with H1 consistently associated with increased risk of progressive supranuclear palsy (PSP). Using 15 haplotype tagging SNPs (htSNPs), capturing > 95 % of MAPT haplotype diversity, we performed association analysis in a US sample of 274 predominantly pathologically confirmed PSP patients and 424 matched control individuals. We found that PSP risk is associated with one of two major ancestral H1 haplotypes, H1B, increasing from 14 % in control individuals to 22 % in PSP patients (p < 0.001). In young PSP patients, the H1B risk could be localized to a 22 kb regulatory region in intron 0 (p < 0.001), and could be fully explained by one SNP, htSNP167, creating a LBP-1c/LSF/CP2 site, shown to regulate expression of genes in other neurodegenerative disorders. Luciferase reporter data indicated that the 182 bp conserved regulatory region, in which htSNP167 is located, is transcriptional active with both alleles differentially influencing expression. Further, we replicated the htSNP167 association in a second independently ascertained US PSP patient-control sample. However, the htSNP association showed that H1 risk alone couldn't explain the overall differences in H1 and H2 frequencies in PSP patients and control individuals. Thus, risk variants on different H1 htSNP haplotypes and protective variants on H2 contribute to population risk for PSP.


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