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

• DOI: 10.1101/2023.11.09.565552
• Publication Date: 2023-11-13T23:25:12Z
• Authors: Kurt Farrell; Jack Humphrey; Timothy 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; Kristen Whitney; Margaret M. Krassner; Hadley Walsh; SoongHo Kim; Diana Dangoor; Megan A. Iida; Alicia Casella; Ruth H. Walker; Melissa J. Nirenberg; Alan E. Renton; Bergan Babrowicz; Giovanni Coppola; Towfique Raj; Günter U. Höglinger; Lawrence I. Golbe; Huw R. Morris; John Hardy; Tamas Revesz; Tom 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; ; John F. Crary; Adam Naj

AbstractProgressive supranuclear palsy (PSP) is a rare Parkinsonian disorder characterized by problems with movement, balance, cognition, and other symptoms. PSP differs from Alzheimer’s disease (AD) and other neurodegenerative diseases displaying abnormal forms of the microtubule-associated protein tau (“tauopathies”) by the presence of pathology not only in neurons, but also in astrocytes and oligodendrocytes. Genetic contributors may mediate these differences, however much of PSP genetics remains unexplained. Here we conducted the largest genome-wide association study (GWAS) of PSP to date including 2,779 cases (2,595 neuropathologically-confirmed) and 5,584 controls and identified 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 revealed a unique oligodendrocytic signature that distinguishes PSP from AD and Parkinson’s disease. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identified oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, as well as an association with elevatedC4Aexpression in bulk brain tissue which may be driven by increasedC4Acopy number in PSP cases. Finally, histological studies demonstrated abnormal tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies including epigenomic and eQTL analyses, we identified potential causal roles for variation inMOBP,STX6,RUNX2,SLCO1A2, andC4Ain the pathogenesis of PSP.