title: Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia.
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.
authors.affiliation: 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.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Yokoyama
authors.affiliation: Department of Psychiatry, Washington University, St. Louis, MO, USA.
authors.forename: Celeste M
authors.initials: CM
authors.lastname: Karch
authors.affiliation: Department of Cognitive Sciences, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Chun C
authors.initials: CC
authors.lastname: Fan
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
authors.forename: Luke W
authors.initials: LW
authors.lastname: Bonham
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, 32224, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kouri
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, 32224, USA.
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, 32224, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, 32224, USA.
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
authors.affiliation: NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurology, Technical University of Munich, Munich, Germany and German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Günter U
authors.initials: GU
authors.lastname: Höglinger
authors.affiliation: Institut for Humangenetik, Justus-Liebig-Universität, Giessen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, UCL, London, WC1N 3BG, UK.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ferrari
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology, UCL, London, WC1N 3BG, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Science Center, Lubbock, TX, USA.
authors.forename: Parastoo
authors.initials: P
authors.lastname: Momeni
authors.affiliation: Neuroradiology Section, L-352, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 92037-0841, USA.
authors.forename: Leo P
authors.initials: LP
authors.lastname: Sugrue
authors.affiliation: Neuroradiology Section, L-352, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 92037-0841, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Hess
authors.affiliation: Neuroradiology Section, L-352, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 92037-0841, USA.
authors.forename: A
authors.initials: A
authors.lastname: James Barkovich
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Boxer
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
authors.forename: Gil D
authors.initials: GD
authors.lastname: Rabinovici
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Rosen
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schmansky
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.|Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Fischl
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, 32224, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: Department of Neurology, Technical University of Munich, Munich, Germany and German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andreassen
authors.affiliation: Department of Cognitive Sciences, University of California, San Diego, La Jolla, CA, USA.|Departments of Radiology and Neurosciences, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Dale
authors.affiliation: 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.
authors.forename: Rahul S
authors.initials: RS
authors.lastname: Desikan
mesh_terms: D001480:Basal Ganglia Diseases / Q000235:genetics / Q000473:pathology; D057180:Frontotemporal Dementia / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D012307:Risk Factors; D013494:Supranuclear Palsy, Progressive / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D024801:Tauopathies / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins