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

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 RabinoviciHoward 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) (BENUSSI L, BINETTI G, GHIDONI R sono autori IRCCS)

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)825-837
Number of pages13
JournalActa Neuropathologica
Volume133
Issue number5
DOIs
Publication statusPublished - May 2017
Externally publishedYes

    Fingerprint

Keywords

  • Basal Ganglia Diseases
  • Frontotemporal Dementia
  • Humans
  • Inclusion Bodies
  • Neurons
  • Risk Factors
  • Supranuclear Palsy, Progressive
  • Tauopathies
  • tau Proteins
  • Journal Article

Cite this

Yokoyama, J. S., Karch, C. M., Fan, C. C., Bonham, L. W., Kouri, N., Ross, O. A., Rademakers, R., Kim, J., Wang, Y., Höglinger, G. U., Müller, U., Ferrari, R., Hardy, J., Momeni, P., Sugrue, L. P., Hess, C. P., James Barkovich, A., Boxer, A. L., Seeley, W. W., ... International FTD-Genomics Consortium (IFGC) (BENUSSI L, BINETTI G, GHIDONI R sono autori IRCCS) (2017). Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia. Acta Neuropathologica, 133(5), 825-837. https://doi.org/10.1007/s00401-017-1693-y