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Human Molecular Genetics Advance Access originally published online on September 29, 2005
Human Molecular Genetics 2005 14(21):3281-3292; doi:10.1093/hmg/ddi361
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Rosa Rademakers1,{dagger}, Stacey Melquist4,{dagger}, Marc Cruts1, Jessie Theuns1, Jurgen Del-Favero1, Parvoneh Poorkaj7,8,9,10, Matt Baker4, Kristel Sleegers1, Richard Crook4, Tim De Pooter1, Samira Bel Kacem1, Jennifer Adamson4, Dirk Van den Bossche1, Marleen Van den Broeck1, Jennifer Gass4, Ellen Corsmit1, Peter De Rijk1, Natalie Thomas5, Sebastiaan Engelborghs2,3, Michael Heckman6, Irene Litvan11, Julia Crook6, Peter P. De Deyn2,3, Dennis Dickson5, Gerard D. Schellenberg7,8,9,10, Christine Van Broeckhoven1,*,{ddagger} and Michael L. Hutton4,{ddagger}

1Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, 2Division of Neurology, Middelheim Hospital, 3Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Belgium, 4Department of Neuroscience, 5Department of Pathology and 6Biostatistics Unit, Mayo Clinic, Jacksonville, FL, USA and 7Department of Medicine, 8Department of Neurology, 9Department of Pharmacology and 10Geriatric Research Education and Clinical Center, Seattle Veterans Affairs Medical Center, University of Washington, Seattle, WA, USA and 11University of Louisville School of Medicine, Louisville, KY, USA

* To whom correspondence should be addressed at: Department of Molecular Genetics (VIB8), Neurodegenerative Brain Diseases Research Group, University of Antwerp, Building V – Room 0.10, Universiteitsplein 1, B-2610 Antwerpen, Belgium. Tel: +32 32651001; Fax: +32 32651012; Email: christine.vanbroeckhoven{at}ua.ac.be

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 the expression of genes in other neurodegenerative disorders. Luciferase reporter data indicated that the 182 bp conserved regulatory region, in which htSNP167 is located, is transcriptionally 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 could not 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.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

{ddagger} The authors wish it to be known that, in their opinion, the last two authors should be regarded as joint Last Authors.


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