TY - JOUR
T1 - Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia
AU - International FTD-Genomics Consortium (IFGC)
AU - Yokoyama, Jennifer S.
AU - Karch, Celeste M.
AU - Fan, Chun C.
AU - Bonham, Luke W.
AU - Kouri, Naomi
AU - Ross, Owen A.
AU - Rademakers, Rosa
AU - Kim, Jungsu
AU - Wang, Yunpeng
AU - Höglinger, Günter U.
AU - Müller, Ulrich
AU - Ferrari, Raffaele
AU - Hardy, John
AU - Momeni, Parastoo
AU - Sugrue, Leo P.
AU - Hess, Christopher P.
AU - James Barkovich, A.
AU - Boxer, Adam L.
AU - Seeley, William W.
AU - Rabinovici, Gil D.
AU - Rosen, Howard J.
AU - Miller, Bruce L.
AU - Schmansky, Nicholas J.
AU - Fischl, Bruce
AU - Hyman, Bradley T.
AU - Dickson, Dennis W.
AU - Schellenberg, Gerard D.
AU - Andreassen, Ole A.
AU - Dale, Anders M.
AU - Desikan, Rahul S.
N1 - Publisher Copyright:
© 2017, Springer-Verlag Berlin Heidelberg.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85014531490&partnerID=8YFLogxK
U2 - 10.1007/s00401-017-1693-y
DO - 10.1007/s00401-017-1693-y
M3 - Article
C2 - 28271184
AN - SCOPUS:85014531490
SN - 0001-6322
VL - 133
SP - 825
EP - 837
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 5
ER -