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Acta Neuropathologica

, Volume 133, Issue 5, pp 825–837 | Cite as

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

  • Jennifer S. YokoyamaEmail author
  • Celeste M. Karch
  • Chun C. Fan
  • Luke W. Bonham
  • Naomi Kouri
  • Owen A. Ross
  • Rosa Rademakers
  • Jungsu Kim
  • Yunpeng Wang
  • Günter U. Höglinger
  • Ulrich Müller
  • Raffaele Ferrari
  • John Hardy
  • International FTD-Genomics Consortium (IFGC)
  • Parastoo Momeni
  • Leo P. Sugrue
  • Christopher P. Hess
  • A. James Barkovich
  • Adam L. Boxer
  • William W. Seeley
  • Gil D. Rabinovici
  • Howard J. Rosen
  • Bruce L. Miller
  • Nicholas J. Schmansky
  • Bruce Fischl
  • Bradley T. Hyman
  • Dennis W. Dickson
  • Gerard D. Schellenberg
  • Ole A. Andreassen
  • Anders M. Dale
  • Rahul S. DesikanEmail author
Original Paper

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.

Keywords

Progressive Supranuclear Palsy Progressive Supranuclear Palsy Tauopathy MAPT Region Progressive Supranuclear Palsy Case 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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.

Supplementary material

401_2017_1693_MOESM1_ESM.docx (2.4 mb)
Supplementary material 1 (DOCX 2492 kb)
401_2017_1693_MOESM2_ESM.csv (9 kb)
Supplementary material 2 (CSV 9 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Jennifer S. Yokoyama
    • 1
    Email author
  • Celeste M. Karch
    • 2
  • Chun C. Fan
    • 3
  • Luke W. Bonham
    • 1
  • Naomi Kouri
    • 4
  • Owen A. Ross
    • 4
  • Rosa Rademakers
    • 4
  • Jungsu Kim
    • 4
  • Yunpeng Wang
    • 5
  • Günter U. Höglinger
    • 6
  • Ulrich Müller
    • 7
  • Raffaele Ferrari
    • 8
  • John Hardy
    • 8
  • International FTD-Genomics Consortium (IFGC)
  • Parastoo Momeni
    • 9
  • Leo P. Sugrue
    • 10
  • Christopher P. Hess
    • 10
  • A. James Barkovich
    • 10
  • Adam L. Boxer
    • 1
  • William W. Seeley
    • 1
  • Gil D. Rabinovici
    • 1
  • Howard J. Rosen
    • 1
  • Bruce L. Miller
    • 1
  • Nicholas J. Schmansky
    • 11
  • Bruce Fischl
    • 11
    • 12
  • Bradley T. Hyman
    • 13
  • Dennis W. Dickson
    • 4
  • Gerard D. Schellenberg
    • 14
  • Ole A. Andreassen
    • 6
  • Anders M. Dale
    • 3
    • 15
  • Rahul S. Desikan
    • 10
    Email author
  1. 1.Department of Neurology, Memory and Aging CenterUniversity of California, San FranciscoSan FranciscoUSA
  2. 2.Department of PsychiatryWashington UniversitySt. LouisUSA
  3. 3.Department of Cognitive SciencesUniversity of California, San DiegoLa JollaUSA
  4. 4.Department of NeuroscienceMayo Clinic College of MedicineJacksonvilleUSA
  5. 5.NORMENT; Institute of Clinical MedicineUniversity of Oslo and Division of Mental Health and Addiction, Oslo University HospitalOsloNorway
  6. 6.Department of NeurologyTechnical University of Munich, Munich, Germany and German Center for Neurodegenerative Diseases (DZNE)MunichGermany
  7. 7.Institut for HumangenetikJustus-Liebig-UniversitätGiessenGermany
  8. 8.Department of Molecular NeuroscienceInstitute of Neurology, UCLLondonUK
  9. 9.Laboratory of Neurogenetics, Department of Internal MedicineTexas Tech University Health Science CenterLubbockUSA
  10. 10.Neuroradiology Section, L-352, Department of Radiology and Biomedical ImagingUniversity of California, San FranciscoSan FranciscoUSA
  11. 11.Athinoula A. Martinos Center for Biomedical Imaging, Department of RadiologyMassachusetts General HospitalCharlestownUSA
  12. 12.Computer Science and Artificial Intelligence Laboratory (CSAIL)Massachusetts Institute of TechnologyCambridgeUSA
  13. 13.Department of NeurologyMassachusetts General HospitalCharlestownUSA
  14. 14.Department of Pathology and Laboratory MedicineUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaUSA
  15. 15.Departments of Radiology and NeurosciencesUniversity of California, San DiegoLa JollaUSA

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