Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes

作者：Kurt Farrell, Jack Humphrey, Timothy S. Chang, Yi Zhao, Yuk Yee Leung, Pavel P. Kuksa, Vishakha Patil, Wan‐Ping Lee, Amanda B Kuzma, Otto Valladares, Laura B. Cantwell, Hui Wang, Ashvin Ravi, Claudia De Sanctis, Natalia Han, Thomas D. Christie, Robina Afzal, Shrishtee Kandoi, Kristen Whitney, Margaret M. Krassner, Hadley W. Ressler, SoongHo Kim, Diana K. Dangoor, Megan A. Iida, Alicia Casella, Ruth H. Walker, Melissa J. Nirenberg, Alan E. Renton, Bergan Babrowicz, Giovanni Coppola, Towfique Raj, Günter U. Höglinger, Ulrich Müller, Lawrence I. Golbe, Huw R. Morris, John Hardy, Tamás Révész, Thomas T. Warner, Zane Jaunmuktane, Kin Y. Mok, Rosa Rademakers, Dennis W. Dickson, Owen A. Ross, Li‐San Wang, Alison Goate, Gerard Schellenberg, Daniel H. Geschwind, PSP Genetics Study Group, Franziska Hopfner, Sigrun Roeber, Jochen Herms, Claire Troakes, Ellen Gelpi, Yaroslau Compta, John C. van Swieten, Alex Rajput, Fairlie Hinton, Justo García de Yebenes, John F. Crary, Adam Naj · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-52025-x · 被引用次数：43 · 研究领域：Neurological diseases and metabolism、Parkinson's Disease Mechanisms and Treatments、RNA regulation and disease

Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer’s disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P < 5 × 10−8) associations, including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations reveal an oligodendrocytic signature that might distinguish PSP from AD and Parkinson’s disease in subsequent studies. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identifies oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, and an association with C4A expression in brain tissue, which may be driven by increased C4A copy number. Finally, histological studies demonstrate tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies, epigenomic and eQTL analyses, we identify potential causal roles for variation in MOBP, STX6, RUNX2, SLC...