Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci

Monica Y. Sanchez-Contreras, Naomi Kouri, Casey Cook, Daniel J. Serie, Michael G. Heckman, Nicole A. Finch, Richard John Caselli, Ryan J. Uitti, Zbigniew K Wszolek, Neill R Graff Radford, Leonard Petrucelli, Li San Wang, Gerard D. Schellenberg, Dennis W Dickson, Rosa V Rademakers, Owen A Ross

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background: Progressive supranuclear palsy (PSP) is a parkinsonian neurodegenerative tauopathy affecting brain regions involved in motor function, including the basal ganglia, diencephalon and brainstem. While PSP is largely considered to be a sporadic disorder, cases with suspected familial inheritance have been identified and the common MAPT H1haplotype is a major genetic risk factor. Due to the relatively low prevalence of PSP, large sample sizes can be difficult to achieve, and this has limited the ability to detect true genetic risk factors at the genome-wide statistical threshold for significance in GWAS data. With this in mind, in this study we genotyped the genetic variants that displayed the strongest degree of association with PSP (P<1E-4) in the previous GWAS in a new cohort of 533 pathologically-confirmed PSP cases and 1172 controls, and performed a combined analysis with the previous GWAS data. Results: Our findings validate the known association of loci at MAPT, MOBP, EIF2AK3 and STX6 with risk of PSP, and uncover novel associations with SLCO1A2 (rs11568563) and DUSP10 (rs6687758) variants, both of which were classified as non-significant in the original GWAS. Conclusions: Resolving the genetic architecture of PSP will provide mechanistic insights and nominate candidate genes and pathways for future therapeutic intervention strategies.

Original languageEnglish (US)
Article number37
JournalMolecular Neurodegeneration
Volume13
Issue number1
DOIs
StatePublished - Jul 9 2018

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Progressive Supranuclear Palsy
Genome-Wide Association Study
Tauopathies
Diencephalon
Basal Ganglia
Sample Size
Brain Stem
Genome
Brain

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci. / Sanchez-Contreras, Monica Y.; Kouri, Naomi; Cook, Casey; Serie, Daniel J.; Heckman, Michael G.; Finch, Nicole A.; Caselli, Richard John; Uitti, Ryan J.; Wszolek, Zbigniew K; Graff Radford, Neill R; Petrucelli, Leonard; Wang, Li San; Schellenberg, Gerard D.; Dickson, Dennis W; Rademakers, Rosa V; Ross, Owen A.

In: Molecular Neurodegeneration, Vol. 13, No. 1, 37, 09.07.2018.

Research output: Contribution to journalArticle

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abstract = "Background: Progressive supranuclear palsy (PSP) is a parkinsonian neurodegenerative tauopathy affecting brain regions involved in motor function, including the basal ganglia, diencephalon and brainstem. While PSP is largely considered to be a sporadic disorder, cases with suspected familial inheritance have been identified and the common MAPT H1haplotype is a major genetic risk factor. Due to the relatively low prevalence of PSP, large sample sizes can be difficult to achieve, and this has limited the ability to detect true genetic risk factors at the genome-wide statistical threshold for significance in GWAS data. With this in mind, in this study we genotyped the genetic variants that displayed the strongest degree of association with PSP (P<1E-4) in the previous GWAS in a new cohort of 533 pathologically-confirmed PSP cases and 1172 controls, and performed a combined analysis with the previous GWAS data. Results: Our findings validate the known association of loci at MAPT, MOBP, EIF2AK3 and STX6 with risk of PSP, and uncover novel associations with SLCO1A2 (rs11568563) and DUSP10 (rs6687758) variants, both of which were classified as non-significant in the original GWAS. Conclusions: Resolving the genetic architecture of PSP will provide mechanistic insights and nominate candidate genes and pathways for future therapeutic intervention strategies.",
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AU - Serie, Daniel J.

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AU - Finch, Nicole A.

AU - Caselli, Richard John

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AU - Petrucelli, Leonard

AU - Wang, Li San

AU - Schellenberg, Gerard D.

AU - Dickson, Dennis W

AU - Rademakers, Rosa V

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