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. Wszolek; Lawrence I. Golbe; Richard J. Caselli; Neill Graff-Radford; Irene Litvan; Matthew J. Farrer; Dennis W. Dickson; Mike Hutton; Dietrich A. Stephan

doi:10.1086/513320

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

Neurology

Research output: Contribution to journal › Article › peer-review

63 Scopus citations

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 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 language	English (US)
Pages (from-to)	769-778
Number of pages	10
Journal	American Journal of Human Genetics
Volume	80
Issue number	4
DOIs	https://doi.org/10.1086/513320
State	Published - 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.).

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Melquist, S., Craig, D. W., Huentelman, M. J., Crook, R., Pearson, J. V., Baker, M., Zismann, V. L., Gass, J., Adamson, J., Szelinger, S., Corneveaux, J., Cannon, A., Coon, K. D., Lincoln, S., Adler, C., Tuite, P., Calne, D. B., Bigio, E. H., Uitti, R. J., ... Stephan, D. A. (2007). Identification of a novel risk locus for progressive supranuclear palsy by a pooled genomewide scan of 500,288 single-nucleotide polymorphisms. American Journal of Human Genetics, 80(4), 769-778. https://doi.org/10.1086/513320

Melquist, S, Craig, DW, Huentelman, MJ, Crook, R, Pearson, JV, Baker, M, Zismann, VL, Gass, J, Adamson, J, Szelinger, S, Corneveaux, J, Cannon, A, Coon, KD, Lincoln, S, Adler, C, Tuite, P, Calne, DB, Bigio, EH, Uitti, RJ, Wszolek, ZK, Golbe, LI, Caselli, RJ, Graff-Radford, N, Litvan, I, Farrer, MJ, Dickson, DW, Hutton, M & Stephan, DA 2007, 'Identification of a novel risk locus for progressive supranuclear palsy by a pooled genomewide scan of 500,288 single-nucleotide polymorphisms', American Journal of Human Genetics, vol. 80, no. 4, pp. 769-778. https://doi.org/10.1086/513320

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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 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.",

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

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.). ",

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AU - Crook, Richard

AU - Pearson, John V.

AU - Baker, Matt

AU - Zismann, Victoria L.

AU - Gass, Jennifer

AU - Adamson, Jennifer

AU - Szelinger, Szabolcs

AU - Corneveaux, Jason

AU - Cannon, Ashley

AU - Coon, Keith D.

AU - Lincoln, Sarah

AU - Adler, Charles

AU - Tuite, Paul

AU - Calne, Donald B.

AU - Bigio, Eileen H.

AU - Uitti, Ryan J.

AU - Wszolek, Zbigniew K.

AU - Golbe, Lawrence I.

AU - Caselli, Richard J.

AU - Graff-Radford, Neill

AU - Litvan, Irene

AU - Farrer, Matthew J.

AU - Dickson, Dennis W.

AU - Hutton, Mike

AU - Stephan, Dietrich A.

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N2 - 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.

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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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