TY - JOUR
T1 - Latent trait modeling of tau neuropathology in progressive supranuclear palsy
AU - Kouri, Naomi
AU - Murray, Melissa E.
AU - Reddy, Joseph S.
AU - Serie, Daniel J.
AU - Soto-Beasley, Alexandra
AU - Allen, Mariet
AU - Carrasquillo, Minerva M.
AU - Wang, Xue
AU - Castanedes, Monica Casey
AU - Baker, Matthew C.
AU - Rademakers, Rosa
AU - Uitti, Ryan J.
AU - Graff-Radford, Neill R.
AU - Wszolek, Zbigniew K.
AU - Schellenberg, Gerard D.
AU - Crook, Julia E.
AU - Ertekin-Taner, Nilüfer
AU - Ross, Owen A.
AU - Dickson, Dennis W.
N1 - Funding Information:
We thank the patients and their families for participating in and contributing to these research studies. DWD was supported by NIH awards: UG3 NS104095, R01 AG054449, U54 NS100693, P30 AG062677, as well as the Rainwater Charitable Foundation and the Robert E. Jacoby Professorship. OAR was supported in part by NIH awards: R01 NS78086, U54-NS100693, R01 AG56366, the US Department of Defense (W81XWH-17-1-0249), and American Parkinson Disease Association (APDA) Center for Advanced Research. 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. He serves as PI or Co-PI on Biogen, Inc. (228PD201), Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301), and Neuraly, Inc. (NLY01-PD-1) grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research. GDS was supported by awards: P01 AG017586, U54 NS100693, and UG3 NS104095.
Funding Information:
We thank the patients and their families for participating in and contributing to these research studies. DWD was supported by NIH awards: UG3 NS104095, R01 AG054449, U54 NS100693, P30 AG062677, as well as the Rainwater Charitable Foundation and the Robert E. Jacoby Professorship. OAR was supported in part by NIH awards: R01 NS78086, U54-NS100693, R01 AG56366, the US Department of Defense (W81XWH-17-1-0249), and American Parkinson Disease Association (APDA) Center for Advanced Research. 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. He serves as PI or Co-PI on Biogen, Inc. (228PD201), Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301), and Neuraly, Inc. (NLY01-PD-1) grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research. GDS was supported by awards: P01 AG017586, U54 NS100693, and UG3 NS104095.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/5
Y1 - 2021/5
N2 - Progressive supranuclear palsy (PSP) is the second most common neurodegenerative Parkinsonian disorder after Parkinson’s disease, and is characterized as a primary tauopathy. Leveraging the considerable clinical and neuropathologic heterogeneity associated with PSP, we measured tau neuropathology as quantitative traits to perform a genome-wide association study (GWAS) within PSP to identify genes and biological pathways that underlie the PSP disease process. In 882 PSP cases, semi-quantitative scores for phosphorylated tau-immunoreactive coiled bodies (CBs), neurofibrillary tangles (NFTs), tufted astrocytes (TAs), and tau threads were documented from 18 brain regions, and converted to latent trait (LT) variables using the R ltm package. LT analysis utilizes a multivariate regression model that links categorical responses to unobserved covariates allowing for a reduction of dimensionality, generating a single, continuous variable to account for the multiple lesions and brain regions assessed. We first tested for association with PSP LTs and the top PSP GWAS susceptibility loci. Significant SNP/LT associations were identified at rs242557 (MAPT H1c sub-haplotype) with hindbrain CBs and rs1768208 (MOBP) with forebrain tau threads. Digital microscopy was employed to quantify phosphorylated tau burden in midbrain tectum and red nucleus in 795 PSP cases and tau burdens were used as quantitative phenotypes in GWAS. Top associations were identified at rs1768208 with midbrain tectum and red nucleus tau burden. Additionally, we performed a PSP LT GWAS on an initial cohort, a follow-up SNP panel (37 SNPs, P < 10–5) in an extended cohort, and a combined analysis. Top SNP/LT associations were identified at SNPs in or near SPTBN5/EHD4, SEC13/ATP2B2, EPHB1/PPP2R3A, TBC1D8, IFNGR1/OLIG3, ST6GAL1, HK1, CALB1, and SGCZ. Finally, testing for SNP/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159/SPTBN5/EHD4 and rs154239/GHRL. Modeling tau neuropathology heterogeneity using LTs as quantitative phenotypes in a GWAS may provide substantial insight into biological pathways involved in PSP by affecting regional tau burden.
AB - Progressive supranuclear palsy (PSP) is the second most common neurodegenerative Parkinsonian disorder after Parkinson’s disease, and is characterized as a primary tauopathy. Leveraging the considerable clinical and neuropathologic heterogeneity associated with PSP, we measured tau neuropathology as quantitative traits to perform a genome-wide association study (GWAS) within PSP to identify genes and biological pathways that underlie the PSP disease process. In 882 PSP cases, semi-quantitative scores for phosphorylated tau-immunoreactive coiled bodies (CBs), neurofibrillary tangles (NFTs), tufted astrocytes (TAs), and tau threads were documented from 18 brain regions, and converted to latent trait (LT) variables using the R ltm package. LT analysis utilizes a multivariate regression model that links categorical responses to unobserved covariates allowing for a reduction of dimensionality, generating a single, continuous variable to account for the multiple lesions and brain regions assessed. We first tested for association with PSP LTs and the top PSP GWAS susceptibility loci. Significant SNP/LT associations were identified at rs242557 (MAPT H1c sub-haplotype) with hindbrain CBs and rs1768208 (MOBP) with forebrain tau threads. Digital microscopy was employed to quantify phosphorylated tau burden in midbrain tectum and red nucleus in 795 PSP cases and tau burdens were used as quantitative phenotypes in GWAS. Top associations were identified at rs1768208 with midbrain tectum and red nucleus tau burden. Additionally, we performed a PSP LT GWAS on an initial cohort, a follow-up SNP panel (37 SNPs, P < 10–5) in an extended cohort, and a combined analysis. Top SNP/LT associations were identified at SNPs in or near SPTBN5/EHD4, SEC13/ATP2B2, EPHB1/PPP2R3A, TBC1D8, IFNGR1/OLIG3, ST6GAL1, HK1, CALB1, and SGCZ. Finally, testing for SNP/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159/SPTBN5/EHD4 and rs154239/GHRL. Modeling tau neuropathology heterogeneity using LTs as quantitative phenotypes in a GWAS may provide substantial insight into biological pathways involved in PSP by affecting regional tau burden.
KW - Latent traits
KW - MAPT
KW - MOBP
KW - Progressive supranuclear palsy
KW - Tau
UR - http://www.scopus.com/inward/record.url?scp=85101740034&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85101740034&partnerID=8YFLogxK
U2 - 10.1007/s00401-021-02289-0
DO - 10.1007/s00401-021-02289-0
M3 - Article
C2 - 33635380
AN - SCOPUS:85101740034
SN - 0001-6322
VL - 141
SP - 667
EP - 680
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 5
ER -