. 2015 Jun 16:6:7247.

doi: 10.1038/ncomms8247.

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

Naomi Kouri¹, Owen A Ross¹, Beth Dombroski², Curtis S Younkin^{1

3}, Daniel J Serie³, Alexandra Soto-Ortolaza¹, Matthew Baker¹, Ni Cole A Finch¹, Hyejin Yoon¹, Jungsu Kim¹, Shinsuke Fujioka¹, Catriona A McLean⁴, Bernardino Ghetti⁵, Salvatore Spina⁵, Laura B Cantwell², Martin R Farlow⁶, Jordan Grafman^{7

8}, Edward D Huey⁹, Mi Ryung Han², Sherry Beecher², Evan T Geller², Hans A Kretzschmar¹, Sigrun Roeber¹⁰, Marla Gearing¹¹, Jorge L Juncos¹², Jean Paul G Vonsattel¹³, Vivianna M Van Deerlin², Murray Grossman¹⁴, Howard I Hurtig¹⁴, Rachel G Gross¹⁴, Steven E Arnold¹⁵, John Q Trojanowski², Virginia M Lee², Gregor K Wenning¹⁶, Charles L White¹⁷, Günter U Höglinger^{18

19

20}, Ulrich Müller²¹, Bernie Devlin²², Lawrence I Golbe²³, Julia Crook^{1

3}, Joseph E Parisi²⁴, Bradley F Boeve²⁵, Keith A Josephs²⁵, Zbigniew K Wszolek²⁶, Ryan J Uitti²⁶, Neill R Graff-Radford²⁶, Irene Litvan²⁷, Steven G Younkin¹, Li-San Wang², Nilüfer Ertekin-Taner^{1

26}, Rosa Rademakers¹, Hakon Hakonarsen²⁸, Gerard D Schellenberg², Dennis W Dickson¹

Affiliations

¹ Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA.
² Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
³ Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA.
⁴ Victorian Brain Bank Network, Mental Health Research Institute, Parksville, Victoria 3052, Australia.
⁵ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
⁶ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
⁷ Cognitive Neuroscience Laboratory, Brain Injury Research, Rehabilitation Institute of Chicago, Chicago, Illinois 60611, USA.
⁸ Department of Physical Medicine and Rehabilitation, Northwestern University, Illinois 60208, USA.
⁹ Departments of Psychiatry and Neurology, Columbia University, New York, New York10027, USA.
¹⁰ Institut for Neuropathology and Prion Research and Brain Net Germany, Ludwig-Maximilians-Universität, Munich 80539, Germany.
¹¹ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30307, USA.
¹² Department of Neurology, Emory University, Atlanta, Georgia 30307, USA.
¹³ Department of Pathology and the Taub Institute for Research on Alzheimer's disease and the Aging Brain, Columbia University, New York, New York 10027, USA.
¹⁴ Department of Neurology, University of Pennsylvania Health System, Philadelphia, Pennsylvania 19104, USA.
¹⁵ Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
¹⁶ Department of Neurology, Innsbruck Medical University, Innsbruck 6020, Austria.
¹⁷ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
¹⁸ Department of Neurology, Technical University Munich, 81377 Munich, Germany.
¹⁹ Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), 81677 Munich, Germany.
²⁰ Department of Neurology, Philipps University, 35033 Marburg, Germany.
²¹ Institut for Humangenetik, Justus-Liebig-Universität, Giessen 35390, Germany.
²² Department of Human Genetics, University of Pittsburgh, Pittsburg, Pennsylvania 15260, USA.
²³ Department of Neurology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.
²⁴ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
²⁵ Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA.
²⁶ Department of Neurology, Mayo Clinic, Jacksonville, Florida 32224, USA.
²⁷ Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.
²⁸ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

PMID: 26077951
PMCID: PMC4469997
DOI: 10.1038/ncomms8247

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

Naomi Kouri et al. Nat Commun. 2015.

. 2015 Jun 16:6:7247.

doi: 10.1038/ncomms8247.

Authors

Affiliations

¹ Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA.
² Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
³ Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA.
⁴ Victorian Brain Bank Network, Mental Health Research Institute, Parksville, Victoria 3052, Australia.
⁵ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
⁶ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
⁷ Cognitive Neuroscience Laboratory, Brain Injury Research, Rehabilitation Institute of Chicago, Chicago, Illinois 60611, USA.
⁸ Department of Physical Medicine and Rehabilitation, Northwestern University, Illinois 60208, USA.
⁹ Departments of Psychiatry and Neurology, Columbia University, New York, New York10027, USA.
¹⁰ Institut for Neuropathology and Prion Research and Brain Net Germany, Ludwig-Maximilians-Universität, Munich 80539, Germany.
¹¹ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30307, USA.
¹² Department of Neurology, Emory University, Atlanta, Georgia 30307, USA.
¹³ Department of Pathology and the Taub Institute for Research on Alzheimer's disease and the Aging Brain, Columbia University, New York, New York 10027, USA.
¹⁴ Department of Neurology, University of Pennsylvania Health System, Philadelphia, Pennsylvania 19104, USA.
¹⁵ Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
¹⁶ Department of Neurology, Innsbruck Medical University, Innsbruck 6020, Austria.
¹⁷ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
¹⁸ Department of Neurology, Technical University Munich, 81377 Munich, Germany.
¹⁹ Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), 81677 Munich, Germany.
²⁰ Department of Neurology, Philipps University, 35033 Marburg, Germany.
²¹ Institut for Humangenetik, Justus-Liebig-Universität, Giessen 35390, Germany.
²² Department of Human Genetics, University of Pittsburgh, Pittsburg, Pennsylvania 15260, USA.
²³ Department of Neurology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.
²⁴ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
²⁵ Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA.
²⁶ Department of Neurology, Mayo Clinic, Jacksonville, Florida 32224, USA.
²⁷ Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.
²⁸ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

PMID: 26077951
PMCID: PMC4469997
DOI: 10.1038/ncomms8247

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).

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Conflict of interest statement

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.

Figures

**Figure 1. Regional association plots.**
(a–d) Top loci associated with CBD compared with controls in the Discovery Stage (152 CBD, 3,311 controls) and the Replication Stage (67 CBD, 457 controls). The most significant association is at 17q21, tagging the 1.2 Mb inversion containing *MAPT* (a). New susceptibility loci for CBD are located at 8p12 (b), 3p22 (c) and 2p22 (d). Genetic association testing was performed using conditional logistic regression analysis under an additive model and corrected for population substructure using the first principal component from multidimensional scaling analysis (MDS) as a covariate (λ=1.01). The y axis is −log₁₀ P values and x axis is the genomic location of each SNP (circles) genotyped and imputed. Linkage disequilibrium coefficients were derived from hg19 (1,000 Genomes March 2012, European population) and local estimates of recombination rates are from HapMap samples (2008–03_rel22_B36; http://hapmap.ncbi.nlm.nih.gov). The random effects meta-analysis top SNP at each locus (purple diamonds).

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

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Grants and funding

LinkOut - more resources

Full Text Sources

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Medical

Miscellaneous