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07.03.2017 | Original Paper

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

verfasst von: Jennifer S. Yokoyama, 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, 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. Desikan, International FTD-Genomics Consortium (IFGC)

Erschienen in: Acta Neuropathologica | Ausgabe 5/2017

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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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Titel: Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia
verfasst von: Jennifer S. Yokoyama
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
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. Desikan
International FTD-Genomics Consortium (IFGC)
Publikationsdatum: 07.03.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Acta Neuropathologica / Ausgabe 5/2017
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-017-1693-y

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