Shared Genetic Risk Between Corticobasal Degeneration, Progressive Supranuclear Palsy, and Frontotemporal Dementia
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UC San Diego UC San Diego Previously Published Works Title Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia. Permalink https://escholarship.org/uc/item/78j6x9mk Journal Acta neuropathologica, 133(5) ISSN 0001-6322 Authors Yokoyama, Jennifer S Karch, Celeste M Fan, Chun C et al. Publication Date 2017-05-01 DOI 10.1007/s00401-017-1693-y Peer reviewed eScholarship.org Powered by the California Digital Library University of California Acta Neuropathol (2017) 133:825–837 DOI 10.1007/s00401-017-1693-y ORIGINAL PAPER Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia Jennifer S. Yokoyama1 · Celeste M. Karch2 · Chun C. Fan3 · Luke W. Bonham1 · Naomi Kouri4 · Owen A. Ross4 · Rosa Rademakers4 · Jungsu Kim4 · Yunpeng Wang5 · Günter U. Höglinger6 · Ulrich Müller7 · Raffaele Ferrari8 · John Hardy8 · International FTD-Genomics Consortium (IFGC) · Parastoo Momeni9 · Leo P. Sugrue10 · Christopher P. Hess10 · A. James Barkovich10 · Adam L. Boxer1 · William W. Seeley1 · Gil D. Rabinovici1 · Howard J. Rosen1 · Bruce L. Miller1 · Nicholas J. Schmansky11 · Bruce Fischl11,12 · Bradley T. Hyman13 · Dennis W. Dickson4 · Gerard D. Schellenberg14 · Ole A. Andreassen6 · Anders M. Dale3,15 · Rahul S. Desikan10 Received: 14 December 2016 / Revised: 1 March 2017 / Accepted: 2 March 2017 / Published online: 7 March 2017 © Springer-Verlag Berlin Heidelberg 2017 Abstract Corticobasal degeneration (CBD), progressive and p values) from large genome-wide association studies supranuclear palsy (PSP) and a subset of frontotemporal (total n 14,286 cases and controls) and recently estab- = dementia (FTD) are neurodegenerative disorders charac- lished genetic methods, we investigated the genetic over- terized by tau inclusions in neurons and glia (tauopathies). lap between CBD and PSP and CBD and FTD. We found Although clinical, pathological and genetic evidence sug- up to 800-fold enrichment of genetic risk in CBD across gests overlapping pathobiology between CBD, PSP, and different levels of signifcance for PSP or FTD. In addition FTD, the relationship between these disorders is still not to NSF (tagging the MAPT H1 haplotype), we observed well understood. Using summary statistics (odds ratios that SNPs in or near MOBP, CXCR4, EGFR, and GLDC showed signifcant genetic overlap between CBD and PSP, whereas only SNPs tagging the MAPT haplotype over- J. S. Yokoyama and C. M. Karch equally contributed. lapped between CBD and FTD. The risk alleles of the Electronic supplementary material The online version of this shared SNPs were associated with expression changes in article (doi:10.1007/s00401-017-1693-y) contains supplementary cis-genes. Evaluating transcriptome levels across adult material, which is available to authorized users. * Jennifer S. Yokoyama 8 Department of Molecular Neuroscience, Institute [email protected] of Neurology, UCL, London WC1N 3BG, UK * Rahul S. Desikan 9 Laboratory of Neurogenetics, Department of Internal [email protected] Medicine, Texas Tech University Health Science Center, Lubbock, TX, USA 1 Department of Neurology, Memory and Aging Center, 10 Neuroradiology Section, L‑352, Department of Radiology University of California, San Francisco, 675 Nelson Rising and Biomedical Imaging, University of California, San Lane, Suite 190, San Francisco, CA 94158, USA Francisco, 505 Parnassus Avenue, San Francisco, CA 2 Department of Psychiatry, Washington University, St. Louis, 92037‑0841, USA MO, USA 11 Athinoula A. Martinos Center for Biomedical Imaging, 3 Department of Cognitive Sciences, University of California, Department of Radiology, Massachusetts General Hospital, San Diego, La Jolla, CA, USA Charlestown, MA, USA 4 Department of Neuroscience, Mayo Clinic College 12 Computer Science and Artifcial Intelligence Laboratory of Medicine, Jacksonville, FL 32224, USA (CSAIL), Massachusetts Institute of Technology, Cambridge, MA, USA 5 NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo 13 Department of Neurology, Massachusetts General Hospital, University Hospital, Oslo, Norway Charlestown, MA, USA 6 Department of Neurology, Technical University of Munich, 14 Department of Pathology and Laboratory Medicine, Munich, Germany and German Center for Neurodegenerative University of Pennsylvania Perelman School of Medicine, Diseases (DZNE), Munich, Germany Philadelphia, PA, USA 7 Institut for Humangenetik, Justus-Liebig-Universität, 15 Departments of Radiology and Neurosciences, University Giessen, Germany of California, San Diego, La Jolla, CA, USA 1 3 826 Acta Neuropathol (2017) 133:825–837 human brains, we found a unique neuroanatomic gene independently identifed SNPs within MOBP as increas- expression signature for each of the fve overlapping ing disease risk [24] indicating that shared genetic risk 16 gene loci (omnibus ANOVA p < 2.0 10− ). Function- may explain susceptibility to tau aggregates. Still, few, if × ally, we found that these shared risk genes were associated any, studies have systematically evaluated genetic over- with protein interaction and gene co-expression networks lap between these three tauopathies. and showed enrichment for several neurodevelopmental Combining GWAS from multiple disorders and phe- pathways. Our fndings suggest: (1) novel genetic overlap notypes provides insights into genetic pleiotropy (defned between CBD and PSP beyond the MAPT locus; (2) strong as a single gene or variant being associated with more ties between CBD and FTD through the MAPT clade, and than one distinct phenotype) and could identify shared (3) unique combinations of overlapping genes that may, in genetic risk factors. In this study, using recently validated part, infuence selective regional or neuronal vulnerability methods for systematically assessing genetic overlap, we observed in specifc tauopathies. investigated shared gene loci between tauopathies. Tak- ing advantage of several large GWAS [15, 20, 24], we Introduction sought to identify SNPs jointly associated with CBD and PSP or FTD. Collectively referred to as tauopathies, corticobasal degen- eration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) spectrum disorders are neurodegenerative diseases defned by the intracellular, Methods abnormal flamentous accumulations of the microtubule- associated protein tau, encoded by MAPT [26]. Neuropatho- Participant samples logically, tau deposits in CBD and PSP consist primarily of 4-repeat (4R) tau inclusions, and a large fraction of insoluble We evaluated complete GWAS results in the form of sum- tau is present within neurons, astrocytes and oligodendrocytes mary statistics (p values and odds ratios) for CBD, FTD [25]. Whereas CBD pathology predominantly affects fore- and PSP (see Table 1). We assessed GWAS summary sta- brain structures (including the neocortex) and midbrain struc- tistic data from 152 autopsy-proven CBD cases and 3311 tures (including the substantia nigra), PSP pathology demon- controls at 533,898 SNPs (Table 1). The CBD GWAS strates a predilection for affecting hindbrain regions including sample has been previously described in detail (see the tectum, tegmentum, midbrain as well as the globus palli- [24]). Briefy, the CBD cases were collected from eight dus and diencephalon [14, 16]. In comparison, approximately institutions and controls were recruited from the Chil- half of FTD spectrum cases, encompassing behavioral variant dren’s Hospital of Philadelphia Health Care Network. FTD (bvFTD), semantic variant primary progressive aphasia The National Institute of Health Offce of Rare Diseases (svPPA), non-fuent variant PPA (nfvPPA), and FTD over- Research criteria were used for making a neuropathologic lapping with motor neuron disease (FTD-MND), are caused diagnosis of CBD [12]. We obtained phase I FTD-GWAS by underlying tau pathology. Approximately half of bvFTD summary statistic data from the International FTD- clinical syndromes result from underlying Pick’s disease, Genomics Consortium (IFGC), which consisted of 2154 which is characterized by predominantly 3R tau inclusions clinical FTD cases and 4308 controls with genotyped and (Pick bodies) in the frontal, temporal and insular cortical gray imputed data at 6,026,384 SNPs (Table 1, for additional matter [25]. The majority of nfvPPA clinical cases are due to details, see [15]). The FTD dataset included multiple sub- underlying tau pathology, including PSP, CBD, and Pick’s types within the FTD spectrum: bvFTD, svPPA, nfvPPA, disease [9, 17, 21, 28]. Although neuropathologically dis- and FTD-MND. We obtained publicly available PSP- tinct, there is considerable molecular and biomarker overlap GWAS summary statistic data from the NIA Genetics of between CBD, PSP and a subset of FTD [13]. Importantly, the biological basis of selective neuroanatomic or neuronal vulnerability within each tauopathy is poorly understood. Table 1 Summary data from all GWAS used in the current study Genetic factors can offer novel insight into molecular Disease/trait Total N # SNPs References mechanisms underlying disease risk. Recent genome- wide association studies (GWAS) have shown that single Corticobasal degeneration 3463 533,898 [24] nucleotide polymorphisms (SNPs) within the H1 hap- (CBD)—phase 1 lotype of the MAPT locus are associated with increased Progressive supranuclear palsy 4361 531,451 [20] risk for CBD, PSP, and FTD [20, 24, 32]. Additionally, (PSP)—phase