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Acta Neuropathol. 2017 May;133(5):825-837. doi: 10.1007/s00401-017-1693-y. Epub 2017 Mar 7.

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

Author information

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.yokoyama@ucsf.edu.
2
Department of Psychiatry, Washington University, St. Louis, MO, USA.
3
Department of Cognitive Sciences, University of California, San Diego, La Jolla, CA, USA.
4
Department of Neurology, Memory and Aging Center, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
5
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, 32224, USA.
6
NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
7
Department of Neurology, Technical University of Munich, Munich, Germany and German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
8
Institut for Humangenetik, Justus-Liebig-Universität, Giessen, Germany.
9
Department of Molecular Neuroscience, Institute of Neurology, UCL, London, WC1N 3BG, UK.
10
Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, TX, USA.
11
Neuroradiology Section, L-352, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 92037-0841, USA.
12
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.
13
Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology, Cambridge, MA, USA.
14
Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
15
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
16
Departments of Radiology and Neurosciences, University of California, San Diego, La Jolla, CA, USA.
17
Neuroradiology Section, L-352, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 92037-0841, USA. rahul.desikan@ucsf.edu.

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.

PMID:
28271184
PMCID:
PMC5429027
DOI:
10.1007/s00401-017-1693-y
[Indexed for MEDLINE]
Free PMC Article

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