title: Identification of a novel risk locus for progressive supranuclear palsy by a pooled genomewide scan of 500,288 single-nucleotide polymorphisms.
abstract: To date, only the H1 MAPT haplotype has been consistently associated with risk of developing the neurodegenerative disease progressive supranuclear palsy (PSP). We hypothesized that additional genetic loci may be involved in conferring risk of PSP that could be identified through a pooling-based genomewide association study of >500,000 SNPs. Candidate SNPs with large differences in allelic frequency were identified by ranking all SNPs by their probe-intensity difference between cohorts. The MAPT H1 haplotype was strongly detected by this methodology, as was a second major locus on chromosome 11p12-p11 that showed evidence of association at allelic (P<.001), genotypic (P<.001), and haplotypic (P<.001) levels and was narrowed to a single haplotype block containing the DNA damage-binding protein 2 (DDB2) and lysosomal acid phosphatase 2 (ACP2) genes. Since DNA damage and lysosomal dysfunction have been implicated in aging and neurodegenerative processes, both genes are viable candidates for conferring risk of disease.
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Melquist
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.forename: Richard
authors.initials: R
authors.lastname: Crook
authors.forename: John V
authors.initials: JV
authors.lastname: Pearson
authors.forename: Matt
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authors.lastname: Baker
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Zismann
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gass
authors.forename: Jennifer
authors.initials: J
authors.lastname: Adamson
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Szelinger
authors.forename: Jason
authors.initials: J
authors.lastname: Corneveaux
authors.forename: Ashley
authors.initials: A
authors.lastname: Cannon
authors.forename: Keith D
authors.initials: KD
authors.lastname: Coon
authors.forename: Sarah
authors.initials: S
authors.lastname: Lincoln
authors.forename: Charles
authors.initials: C
authors.lastname: Adler
authors.forename: Paul
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authors.lastname: Tuite
authors.forename: Donald B
authors.initials: DB
authors.lastname: Calne
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Uitti
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Golbe
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Caselli
authors.forename: Neill
authors.initials: N
authors.lastname: Graff-Radford
authors.forename: Irene
authors.initials: I
authors.lastname: Litvan
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Mike
authors.initials: M
authors.lastname: Hutton
authors.forename: Dietrich A
authors.initials: DA
authors.lastname: Stephan
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013494:Supranuclear Palsy, Progressive / Q000235:genetics*
chemical_list: C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; C520783:ACP2 protein, human; D000135:Acid Phosphatase