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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 <jats:italic>ltm<\/jats:italic> 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 (<jats:italic>MAPT<\/jats:italic> H1c sub-haplotype) with hindbrain CBs and rs1768208 (<jats:italic>MOBP<\/jats:italic>) 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, <jats:italic>P<\/jats:italic>\u2009&lt;\u200910<jats:sup>\u20135<\/jats:sup>) in an extended cohort, and a combined analysis. Top SNP\/LT associations were identified at SNPs in or near <jats:italic>SPTBN5<\/jats:italic>\/<jats:italic>EHD4<\/jats:italic>, <jats:italic>SEC13<\/jats:italic>\/<jats:italic>ATP2B2<\/jats:italic>, <jats:italic>EPHB1<\/jats:italic>\/<jats:italic>PPP2R3A<\/jats:italic>, <jats:italic>TBC1D8<\/jats:italic>, <jats:italic>IFNGR1<\/jats:italic>\/<jats:italic>OLIG3<\/jats:italic>, <jats:italic>ST6GAL1<\/jats:italic>, <jats:italic>HK1<\/jats:italic>, <jats:italic>CALB1<\/jats:italic>, and <jats:italic>SGCZ<\/jats:italic>. Finally, testing for SNP\/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159\/<jats:italic>SPTBN5<\/jats:italic>\/<jats:italic>EHD4<\/jats:italic> and rs154239\/<jats:italic>GHRL<\/jats:italic>. 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.<\/jats:p>","DOI":"10.1007\/s00401-021-02289-0","type":"journal-article","created":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T10:08:35Z","timestamp":1614334115000},"page":"667-680","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Latent trait modeling of tau neuropathology in progressive supranuclear palsy"],"prefix":"10.1007","volume":"141","author":[{"given":"Naomi","family":"Kouri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa E.","family":"Murray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph S.","family":"Reddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Serie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Soto-Beasley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariet","family":"Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minerva M.","family":"Carrasquillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica Casey","family":"Castanedes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew C.","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Rademakers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan J.","family":"Uitti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neill R.","family":"Graff-Radford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zbigniew K.","family":"Wszolek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard D.","family":"Schellenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia E.","family":"Crook","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nil\u00fcfer","family":"Ertekin-Taner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen A.","family":"Ross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7189-7917","authenticated-orcid":false,"given":"Dennis W.","family":"Dickson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,26]]},"reference":[{"key":"2289_CR1","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1093\/brain\/awm301","volume":"131","author":"Z Ahmed","year":"2008","unstructured":"Ahmed Z, Josephs KA, Gonzalez J, DelleDonne A, Dickson DW (2008) Clinical and neuropathologic features of progressive supranuclear palsy with severe pallido-nigro-luysial degeneration and axonal dystrophy. 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