title: High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy.
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 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.
authors.affiliation: Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Belgium.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Stacey
authors.initials: S
authors.lastname: Melquist
authors.forename: Marc
authors.initials: M
authors.lastname: Cruts
authors.forename: Jessie
authors.initials: J
authors.lastname: Theuns
authors.forename: Jurgen
authors.initials: J
authors.lastname: Del-Favero
authors.forename: Parvoneh
authors.initials: P
authors.lastname: Poorkaj
authors.forename: Matt
authors.initials: M
authors.lastname: Baker
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.forename: Richard
authors.initials: R
authors.lastname: Crook
authors.forename: Tim
authors.initials: T
authors.lastname: De Pooter
authors.forename: Samira
authors.initials: S
authors.lastname: Bel Kacem
authors.forename: Jennifer
authors.initials: J
authors.lastname: Adamson
authors.forename: Dirk
authors.initials: D
authors.lastname: Van den Bossche
authors.forename: Marleen
authors.initials: M
authors.lastname: Van den Broeck
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gass
authors.forename: Ellen
authors.initials: E
authors.lastname: Corsmit
authors.forename: Peter
authors.initials: P
authors.lastname: De Rijk
authors.forename: Natalie
authors.initials: N
authors.lastname: Thomas
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Michael
authors.initials: M
authors.lastname: Heckman
authors.forename: Irene
authors.initials: I
authors.lastname: Litvan
authors.forename: Julia
authors.initials: J
authors.lastname: Crook
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Dennis
authors.initials: D
authors.lastname: Dickson
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hutton
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping; D040461:Gene Components; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008156:Luciferases; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013494:Supranuclear Palsy, Progressive / Q000235:genetics*; D014481:United States; D044465:White People / Q000235:genetics; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D016875:tau Proteins; D008156:Luciferases