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Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia

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Abstract

Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) are neurodegenerative disorders characterized by tau inclusions in neurons and glia (tauopathies). Although clinical, pathological and genetic evidence suggests overlapping pathobiology between CBD, PSP, and FTD, the relationship between these disorders is still not well understood. Using summary statistics (odds ratios and p values) from large genome-wide association studies (total n = 14,286 cases and controls) and recently established genetic methods, we investigated the genetic overlap between CBD and PSP and CBD and FTD. We found up to 800-fold enrichment of genetic risk in CBD across different levels of significance for PSP or FTD. In addition to NSF (tagging the MAPT H1 haplotype), we observed that SNPs in or near MOBP, CXCR4, EGFR, and GLDC showed significant genetic overlap between CBD and PSP, whereas only SNPs tagging the MAPT haplotype overlapped between CBD and FTD. The risk alleles of the shared SNPs were associated with expression changes in cis-genes. Evaluating transcriptome levels across adult human brains, we found a unique neuroanatomic gene expression signature for each of the five overlapping gene loci (omnibus ANOVA p < 2.0 × 10−16). Functionally, we found that these shared risk genes were associated with protein interaction and gene co-expression networks and showed enrichment for several neurodevelopmental pathways. Our findings suggest: (1) novel genetic overlap between CBD and PSP beyond the MAPT locus; (2) strong ties between CBD and FTD through the MAPT clade, and (3) unique combinations of overlapping genes that may, in part, influence selective regional or neuronal vulnerability observed in specific tauopathies.

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Acknowledgements

Primary support for data analyses was provided by the Larry L. Hillblom Foundation 2012-A-015-FEL and 2016-A-005-SUP (JSY), AFTD Susan Marcus Memorial Fund Clinical Research Grant (JSY), NIA K01 AG049152 (JSY), NIA K01 AG046374 (CMK), U24DA041123 (AMD, RSD), National Alzheimer’s Coordinating Center (NACC) Junior Investigator (JI) Award (RSD), RSNA Resident/Fellow Grant (RSD), Foundation of ASNR Alzheimer’s Imaging Grant (RSD), Alzheimer’s Society Grant 284 (RF), and the Tau Consortium. GUH was supported by the Deutsche Forschungsgemeinschaft (DFG, HO2402/6-2 and Munich Cluster for Systems Neurology SyNergy), and the NOMIS Foundation (FTLD project). The PSP-GWAS was funded by a Grant from the CurePSP Foundation, the Peebler PSP Research Foundation.

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Author notes

  1. J. S. Yokoyama and C. M. Karch equally contributed.

Authors and Affiliations

  1. Department of Neurology, Memory and Aging Center, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA

    Jennifer S. Yokoyama, Luke W. Bonham, Adam L. Boxer, William W. Seeley, Gil D. Rabinovici, Howard J. Rosen & Bruce L. Miller

  2. Department of Psychiatry, Washington University, St. Louis, MO, USA

    Celeste M. Karch

  3. Department of Cognitive Sciences, University of California, San Diego, La Jolla, CA, USA

    Chun C. Fan & Anders M. Dale

  4. Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, 32224, USA

    Naomi Kouri, Owen A. Ross, Rosa Rademakers, Jungsu Kim & Dennis W. Dickson

  5. NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

    Yunpeng Wang

  6. Department of Neurology, Technical University of Munich, Munich, Germany and German Center for Neurodegenerative Diseases (DZNE), Munich, Germany

    Günter U. Höglinger & Ole A. Andreassen

  7. Institut for Humangenetik, Justus-Liebig-Universität, Giessen, Germany

    Ulrich Müller

  8. Department of Molecular Neuroscience, Institute of Neurology, UCL, London, WC1N 3BG, UK

    Raffaele Ferrari & John Hardy

  9. Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, TX, USA

    Parastoo Momeni

  10. Neuroradiology Section, L-352, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 92037-0841, USA

    Leo P. Sugrue, Christopher P. Hess, A. James Barkovich & Rahul S. Desikan

  11. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA

    Nicholas J. Schmansky & Bruce Fischl

  12. Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology, Cambridge, MA, USA

    Bruce Fischl

  13. Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA

    Bradley T. Hyman

  14. Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Gerard D. Schellenberg

  15. Departments of Radiology and Neurosciences, University of California, San Diego, La Jolla, CA, USA

    Anders M. Dale

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  1. Jennifer S. Yokoyama
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International FTD-Genomics Consortium (IFGC)

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Correspondence to Jennifer S. Yokoyama or Rahul S. Desikan.

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Yokoyama, J.S., Karch, C.M., Fan, C.C. et al. Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia. Acta Neuropathol 133, 825–837 (2017). https://doi.org/10.1007/s00401-017-1693-y

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