Year: 2021
Type: article
Study design: Observational Study
Abstract: 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.
Source: Acta Neuropathologica
Authors: Naomi Kouri, Melissa E. Murray, Joseph S. Reddy, Daniel J. Serie, Alexandra Soto-Beasley, Mariet Allen, Minerva M. Carrasquillo, Xue Wang, Monica Casey Castanedes, Matthew C. Baker, Rosa Rademakers, Ryan J. Uitti, Neill R. Graff-Radford, Zbigniew K. Wszolek, Gerard D. Schellenberg, Julia E. Crook, Nilüfer Ertekin-Taner, Owen A. Ross, Dennis W. Dickson
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,480
Funders: Biohaven Pharmaceuticals, U.S. Department of Defense, Mayo Clinic, Biogen, American Parkinson Disease Association, Sol Goldman Charitable Trust, Rainwater Charitable Foundation, National Institutes of Health, National Institute on Aging, National Institute of Neurological Disorders and Stroke
Awards: G1269895679, G1496554343, G165997553, Integrative translational discovery of vascular risk factors in aging and dementia, G2040153736, Impact of coding and non-coding variation in progressive supranuclear palsy, G2456067965, G2844744810, G2908616768, G3271217858, G328015081, G344831414, G4033473731, G4047422026, G4119534169, Frontotemporal Dementias: Genotypes and Phenotypes, G5056103449, G5224552194, G580231493, G5850682332, G6284364378, G6364229960, Identifying genes and Pathways that impact Tau Toxicity in FTD, EARLY-ONSET PARKINSON'S DISEASE IS A MITOCHONDRIAL DISEASE: A NIGRAL MITOCHONDRIAL CYTOPATHY, Synergistic Interaction of amyloid-beta and alpha-synuclein in Lewy body Dementia, G7924335627, G9000002184, G9000081219, G9000088477, G9000100373, G9000105847, G9000161801, G9000182597, G9000183948, G9000218707
OpenAlex ID: W3130814816