Identification of a novel risk locus for progressive supranuclear palsy by a pooled genomewide scan of 500,288 single-nucleotide polymorphisms

Stacey Melquist, David W. Craig, Matthew J. Huentelman, Richard Crook, John V. Pearson, Matt Baker, Victoria L. Zismann, Jennifer Gass, Jennifer Adamson, Szabolcs Szelinger, Jason Corneveaux, Ashley Cannon, Keith D. Coon, Sarah Lincoln, Charles Adler, Paul Tuite, Donald B. Calne, Eileen H. Bigio, Ryan J. Uitti, Zbigniew K. WszolekLawrence I. Golbe, Richard J. Caselli, Neill Graff-Radford, Irene Litvan, Matthew J. Farrer, Dennis W. Dickson, Mike Hutton, Dietrich A. Stephan

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


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 maybe 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.

Original languageEnglish (US)
Pages (from-to)769-778
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - Apr 2007

Bibliographical note

Funding Information:
We are grateful to the patients and their families for their cooperation in this project. We also thank the Society for Progressive Supranuclear Palsy brain bank for providing samples. We thank John Gonzalez and Monica Castanedes-Casey in the Neuropathology Laboratory at Mayo Clinic Jacksonville for technical assistance. This research was funded by National Institutes of Aging grant PO1 AG 17216 (to M.H., D.W.D., and M.J.F.); the Mayo Foundation, USA; The Society for Progressive Supranuclear Palsy; and a Robert and Clarice Smith Fellowship. S.M. was funded by the National Research Service Award postdoctoral fellowship AG24030. Funding was also provided by a foundation grant from the Stardust Foundation (to D.W.C.) and the National Institutes of Health Neuroscience Blueprint grant 1U24NS043571 (to D.A.S.).


Dive into the research topics of 'Identification of a novel risk locus for progressive supranuclear palsy by a pooled genomewide scan of 500,288 single-nucleotide polymorphisms'. Together they form a unique fingerprint.

Cite this