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Author Notes:

Correspondence and requests for materials should be addressed to D.W.D. (email: dickson.dennis@mayo.edu) or to N.K. (email: kouri.naomi@mayo.edu).

Co-first authors N.K. and O.A.R. and senior authors G.D.S. and D.W.D. contributed equally to this project.

N.K., G.D.S. and D.W.D. initiated this study and were involved in all the aspects of data analysis and manuscript preparation.

N.K. conducted the analysis, wrote the manuscript, and prepared RNA samples for both eQTL and lincRNA expression studies.

O.A.R. and A.S.-O. generated the replication stage data.

B.D. organized the CBD DNA bank, and sample distribution for genotyping and phenotype distribution for analysis.

C.S.Y., N.E.-T. and S.G.Y. provided the eQTL data and analysis.

D.J.S. performed the genotype imputation analysis.

N.K., O.A.R., M.B., N.A.F. and A.S.-O. participated in Mayo Clinic sample preparation.

H.Y. and J.K. performed lincRNA expression studies.

L.B.C. coordinated sample acquisition and selection.

C.A.M., B.G., S.S., M.R.H., S.B., E.T.G., H.A.K., S.R., M.G., J.L.J., J.P.G.V., V.M.V.D., M.G., H.I.H., R.G.G., S.E.A., J.Q.T., V.M.L., G.K.W., C.L.W., G.U.H., U.M., B.F.B., K.A.J., J.E.P., Z.K.W., R.J.U., N.R.G.R., I.L., R.R., G.D.S. and D.W.D. participated in characterization, preparation, and contribution of CBD cases used in this study.

B.D. performed the initial association analysis and contributed to discussions of the manuscript.

O.A.R., L.I.G., J.C., R.R. and N.E.T. participated in data analysis discussions and reviewed the manuscript.

L.-S.W. participated in the initial association analysis.

H.H. supervised genotyping as well as platform and sample selection.

We gratefully acknowledge support of patients and their families for participating in this study, as well as the Foundation for PSP|CBD and Related Brain Diseases, and the PSP Genetics Study Group.

Competing financial interests: Dr. Trojanowski may accrue revenue in the future on patents submitted by the University of Pennsylvania wherein he is the co-inventor and he received revenue from the sale of Avid to Eli Lily as co-inventor on imaging-related patents submitted by the University of Pennsylvania.

He receives research support from the NIH, GSK, Janssen and several non-profits.

Subjects:

Research Funding:

N.K. is supported by a post-doctoral fellowship from the Karin & Sten Mortstedt CBD Solutions AB.

O.A.R. is supported by NIH P50 NS072187 and R01 NS078086.

D.W.D. is supported by NIH P50 NS072187, P50 AG016574, R01 AG037491, as well as State of Florida Alzheimer's Disease Initiative and the Foundation for PSP|CBD and Related Brain Diseases.

GDS is supported by NIH P01 AG017586 and grants from Foundation for PSP|CBD and Related Brain Diseases and Peebler PSP Research Foundation.

N.E.-T. is supported by R01 AG032990, R01 NS080820, and P50 AG0016574.

J.K. is supported by GHR Foundation.

J.Q.T. is supported by NIH P30 AG10124, P01 AG17586, and P50 NS53488.

B.G. is supported by NIH P30 AG10133.

C.L.W. is supported by NIH P30 AG012300.

G.U.H. is funded by the Deutsche Forschungsgemeinschaft (DFG: HO2402/6–2) and Bundesministerium für Bildung und Forschung (BMBF: EpiPD).

L.I.G. is supported by CBD Solutions, The Rainwater Charitable Foundation, and the American Parkinson's Disease Association.

U.M. was supported by Foundation for PSP|CBD and Related Brain Diseases.

I.L. is supported by MJFF, NIH, Foundation for PSP|CBD and Related Brain Diseases, and CBD Solutions.

Z.K.W. is partially supported by the NIH P50 NS072187, the Mayo Clinic Center for Regenerative Medicine, Neuroscience Focused Research Team programme, and a gift from Carl Edward Bolch, Jr and Susan Bass Bolch.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • TAU-GENE
  • GENOTYPE IMPUTATION
  • HAPLOTYPE
  • PROTEIN
  • EXPRESSION
  • PHOSPHATASE
  • TAUOPATHY
  • CRITERIA
  • DISEASE
  • GAKIN
  • Disease genetics
  • Genome-wide association studies
  • Movement disorders
  • Neurodegenerative diseases

Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy

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Journal Title:

Nature Communications

Volume:

Volume 6

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Type of Work:

Article | Final Publisher PDF

Abstract:

Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10-12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10-8), and 2p22 at SOS1 (rs963731; P=1.76 × 10-7). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10-7) and MAPT H1c (17q21; rs242557; P=7.91 × 10-6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).

Copyright information:

© 2015 Macmillan Publishers Limited. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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