TitleShared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia.
Publication TypeJournal Article
Year of Publication2017
AuthorsYokoyama JS, Karch CM, Fan CC, Bonham LW, Kouri N, Ross OA, Rademakers R, Kim J, Wang Y, Höglinger GU, Müller U, Ferrari R, Hardy J, Momeni P, Sugrue LP, Hess CP, A Barkovich J, Boxer AL, Seeley WW, Rabinovici GD, Rosen HJ, Miller BL, Schmansky NJ, Fischl B, Hyman BT, Dickson DW, Schellenberg GD, Andreassen OA, Dale AM, Desikan RS
Corporate AuthorsInternational FTD-Genomics Consortium(IFGC)
JournalActa Neuropathol
Date Published2017 May
KeywordsBasal Ganglia Diseases, Frontotemporal Dementia, Humans, Inclusion Bodies, Neurons, Risk Factors, Supranuclear Palsy, Progressive, tau Proteins, Tauopathies

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). 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.

Alternate JournalActa Neuropathol.
PubMed ID28271184
PubMed Central IDPMC5429027
Grant ListK01 AG049152 / AG / NIA NIH HHS / United States
K24 AG045333 / AG / NIA NIH HHS / United States
P01 AG017586 / AG / NIA NIH HHS / United States
R01 AG038791 / AG / NIA NIH HHS / United States
U24 DA041123 / DA / NIDA NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
K01 AG046374 / AG / NIA NIH HHS / United States
P50 AG005134 / AG / NIA NIH HHS / United States
R01 AG032306 / AG / NIA NIH HHS / United States
U54 NS092089 / NS / NINDS NIH HHS / United States