TY - JOUR
T1 - Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci
AU - Sanchez-Contreras, Monica Y.
AU - Kouri, Naomi
AU - Cook, Casey N.
AU - Serie, Daniel J.
AU - Heckman, Michael G.
AU - Finch, Nicole A.
AU - Caselli, Richard J.
AU - Uitti, Ryan J.
AU - Wszolek, Zbigniew K.
AU - Graff-Radford, Neill
AU - Petrucelli, Leonard
AU - Wang, Li San
AU - Schellenberg, Gerard D.
AU - Dickson, Dennis W.
AU - Rademakers, Rosa
AU - Ross, Owen A.
N1 - Funding Information:
The study was supported by NINDS P50-NS072187, U54-NS100693, P01-AG003949, U01-AG006786, R35-NS097261, R35-NS097273 and R01-NS078086. The Mayo Clinic brain bank for neurodegenerative disorders is supported by the Tau Consortium and CurePSP Foundation. This work was support in part by The Mayo Clinic Foundation and the Center for Individualized Medicine. The CurePSP foundation Grant#619R1-2016-03. All sources of funding had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Funding Information:
We would like to thank all those who have contributed to our research, particularly the patients and families who donated brain, blood and DNA samples for this work. We would like to acknowledge the original PSP Genetics Study Group for the primary GWAS study. The Mayo Clinic Florida is Morris K. Udall Parkinson’s Disease Research Center of Excellence (NINDS P50 #NS072187). CC, LP, GDS, DWD, RR and OAR are supported by a NINDS Tau Center without Walls (U54-NS10069). OAR is supported by the R01-NS078086 and the Mayo Clinic Foundation and the Center for Individualized Medicine. RR is supported by the R35-NS097261.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/7/9
Y1 - 2018/7/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85049947086&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049947086&partnerID=8YFLogxK
U2 - 10.1186/s13024-018-0267-3
DO - 10.1186/s13024-018-0267-3
M3 - Article
C2 - 29986742
AN - SCOPUS:85049947086
SN - 1750-1326
VL - 13
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
IS - 1
M1 - 37
ER -