Identification of a novel risk locus for progressive supranuclear palsy by a pooled genomewide scan of 500,288 single-nucleotide polymorphisms |
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Authors: | Melquist Stacey Craig David W Huentelman Matthew J Crook Richard Pearson John V Baker Matt Zismann Victoria L Gass Jennifer Adamson Jennifer Szelinger Szabolcs Corneveaux Jason Cannon Ashley Coon Keith D Lincoln Sarah Adler Charles Tuite Paul Calne Donald B Bigio Eileen H Uitti Ryan J Wszolek Zbigniew K Golbe Lawrence I Caselli Richard J Graff-Radford Neill Litvan Irene Farrer Matthew J Dickson Dennis W Hutton Mike Stephan Dietrich A |
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Institution: | Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA. |
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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. |
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