TY - JOUR
T1 - MAPT subhaplotypes in corticobasal degeneration
T2 - assessing associations with disease risk, severity of tau pathology, and clinical features
AU - Valentino, Rebecca R.
AU - Koga, Shunsuke
AU - Walton, Ronald L.
AU - Soto-Beasley, Alexandra I.
AU - Kouri, Naomi
AU - DeTure, Michael A.
AU - Murray, Melissa E.
AU - Johnson, Patrick W.
AU - Petersen, Ronald C.
AU - Boeve, Bradley F.
AU - Uitti, Ryan J.
AU - Wszolek, Zbigniew K.
AU - Dickson, Dennis W.
AU - Ross, Owen A.
AU - Heckman, Michael G.
N1 - Funding Information:
OAR and DWD are both supported by NINDS Tau Center without Walls Program (U54-NS100693) and NIH (UG3-NS104095). OAR is supported by NIH (P50-NS072187; R01- NS078086; U54-NS100693; U54- NS110435), DOD (W81XWH-17-1-0249) The Michael J. Fox Foundation, The Little Family Foundation, the Mayo Clinic Foundation, and the Center for Individualized Medicine. DWD receives research support from the NIH (P50-AG016574; U54-NS100693; P01-AG003949), CurePSP, the Tau Consortium, and the Robert E. Jacoby Professorship. ZKW is partially supported by the Mayo Clinic Center for Regenerative Medicine, the gifts from The Sol Goldman Charitable Trust, and the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson’s Research Foundation. SK is supported by a post-doctoral fellowship from the Karin & Sten Mortstedt CBD Solutions AB. The funding organizations and sponsors had no role in any of the following: design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Funding Information:
We would like to thank all those who have contributed to our research, including Dr. Peter Davies, Feinstein Institute, Long Island, NY for his invaluable tau antibodies, and particularly the patients and families who donated brain, blood and DNA samples for this work. We would like to acknowledge the continuous commitment, technical support and teamwork offered by Linda G. Rousseau, Virginia R. Phillips, and Monica Castanedes-Casey. This work was supported in part by; the Mayo Clinic Florida Tau Center WithOut Walls (NINDS U54-NS100693); an American Parkinson Disease Association (APDA), Mayo Clinic Information and Referral Center, and an APDA Center for Advanced Research. Samples included in this study were clinical controls or brain donors to the brain bank at Mayo Clinic in Jacksonville which is supported by CurePSP and the Tau Consortium.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - The microtubule-associated protein tau (MAPT) H1 haplotype is the strongest genetic risk factor for corticobasal degeneration (CBD). However, the specific H1 subhaplotype association is not well defined, and it is not clear whether any MAPT haplotypes influence severity of tau pathology or clinical presentation in CBD. Therefore, in the current study we examined 230 neuropathologically confirmed CBD cases and 1312 controls in order to assess associations of MAPT haplotypes with risk of CBD, severity of tau pathology (measured as semi-quantitative scores for coiled bodies, neurofibrillary tangles, astrocytic plaques, and neuropil threads), age of CBD onset, and disease duration. After correcting for multiple testing (P < 0.0026 considered as significant), we confirmed the strong association between the MAPT H2 haplotype and decreased risk of CBD (Odds ratio = 0.26, P = 2 × 10−12), and also observed a novel association between the H1d subhaplotype and an increased CBD risk (Odds ratio = 1.76, P = 0.002). Additionally, although not statistically significant after correcting for multiple testing, the H1c haplotype was associated with a higher risk of CBD (Odds ratio = 1.49, P = 0.009). No MAPT haplotypes were significantly associated with any tau pathology measures, age of CBD onset, or disease duration. Though replication will be important and there is potential that population stratification could have influenced our findings, these results suggest that several MAPT H1 subhaplotypes are primarily responsible for the strong association between MAPT H1 and risk of CBD, but that H1 subhaplotypes are unlikely to play a major role in driving tau pathology or clinical features. Our findings also indicate that similarities in MAPT haplotype risk-factor profile exist between CBD and the related tauopathy progressive supranuclear palsy, with H2, H1d, and H1c displaying associations with both diseases.
AB - The microtubule-associated protein tau (MAPT) H1 haplotype is the strongest genetic risk factor for corticobasal degeneration (CBD). However, the specific H1 subhaplotype association is not well defined, and it is not clear whether any MAPT haplotypes influence severity of tau pathology or clinical presentation in CBD. Therefore, in the current study we examined 230 neuropathologically confirmed CBD cases and 1312 controls in order to assess associations of MAPT haplotypes with risk of CBD, severity of tau pathology (measured as semi-quantitative scores for coiled bodies, neurofibrillary tangles, astrocytic plaques, and neuropil threads), age of CBD onset, and disease duration. After correcting for multiple testing (P < 0.0026 considered as significant), we confirmed the strong association between the MAPT H2 haplotype and decreased risk of CBD (Odds ratio = 0.26, P = 2 × 10−12), and also observed a novel association between the H1d subhaplotype and an increased CBD risk (Odds ratio = 1.76, P = 0.002). Additionally, although not statistically significant after correcting for multiple testing, the H1c haplotype was associated with a higher risk of CBD (Odds ratio = 1.49, P = 0.009). No MAPT haplotypes were significantly associated with any tau pathology measures, age of CBD onset, or disease duration. Though replication will be important and there is potential that population stratification could have influenced our findings, these results suggest that several MAPT H1 subhaplotypes are primarily responsible for the strong association between MAPT H1 and risk of CBD, but that H1 subhaplotypes are unlikely to play a major role in driving tau pathology or clinical features. Our findings also indicate that similarities in MAPT haplotype risk-factor profile exist between CBD and the related tauopathy progressive supranuclear palsy, with H2, H1d, and H1c displaying associations with both diseases.
KW - Corticobasal degeneration
KW - Genetics
KW - MAPT
KW - Neuropathology
UR - http://www.scopus.com/inward/record.url?scp=85097244272&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097244272&partnerID=8YFLogxK
U2 - 10.1186/s40478-020-01097-z
DO - 10.1186/s40478-020-01097-z
M3 - Article
C2 - 33287913
AN - SCOPUS:85097244272
SN - 2051-5960
VL - 8
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
IS - 1
M1 - 218
ER -