Abstract
Progressive 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 elevated C4A expression in bulk brain tissue which may be driven by increased C4A copy 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 in MOBP, STX6, RUNX2, SLCO1A2, and C4A in the pathogenesis of PSP.
Competing Interest Statement
AMG is an SAB member for Genentech and Muna Therapeutics. HM consultants for Roche, Aprinoia, AI Therapeutics and Amylyx and is a co-applicant on a patent application PCT/GB2012/052140.
Footnotes
The PSP genetics study group is a multisite collaboration including: German Center for Neurodegenerative Diseases (DZNE), Munich; Department of Neurology, LMU Hospital, Ludwig-Maximilians-Universität (LMU), Munich, Germany (Franziska Hopfner, Günter Höglinger); German Center for Neurodegenerative Diseases (DZNE), Munich; Center for Neuropathology and Prion Research, LMU Hospital, Ludwig-Maximilians-Universität (LMU), Munich, Germany (Sigrun Roeber, Jochen Herms); MRC Centre for Neurodegeneration Research, King’s College London, London, UK (Claire Troakes); Movement Disorders Unit, Neurology Department and Neurological Tissue Bank and Neurology Department, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Catalonia, Spain (Ellen Gelpi; Yaroslau Compta); Department of Neurology and Netherlands Brain Bank, Erasmus Medical Centre, Rotterdam, The Netherlands (John C. van Swieten); Division of Neurology, Royal University Hospital, University of Saskatchewan, Canada (Alex Rajput); Australian Brain Bank Network in collaboration with the Victorian Brain Bank Network, Australia (Fairlie Hinton), Department of Neurology, Hospital Ramón y Cajal, Madrid, Spain (Justo García de Yebenes)
Funding:
Crary/Farrell Labs: [R01 AG054008, R01 NS095252, R01 AG060961, R01 NS086736, and R01 AG062348 P30 AG066514 to J.F.C. K01 AG070326 and CurePSP 685-2023-06-Pathway to K.F.], the Rainwater Charitable Foundation / Tau Consortium, Karen Strauss Cook Research Scholar Award, Stuart Katz & Dr. Jane Martin.
Penn/Lee/Naj/Wang/Schellenberg Labs: [P01 AG017586, U54 NS100693, and UG3 NS104095; RF1 AG074328-01, and P30 AG072979; CurePSP Consortium; Controls were drawn from the ADGC (U01 AG032984, RC2 AG036528), and included samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA). We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible; Control data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689); additional salary and analytical support were provided by NIA grants R01 AG054060 and RF1 AG061351]
Raj/Humphrey/Ravi: [R56-AG055824, U01-AG068880 U54-NS123743 to J.H., A.R., and T.R.]
Goate Lab: [Rainwater Charitable Foundation, NS123746]
UCLA/Geschwind lab: [K08AG065519, 3UH3NS104095, Larry L Hillblom Foundation, Tau Consortium]
Ross/Dickson: U54 NS100693, P50 AG016574, CurePSP Foundation, Mayo Foundation. Hardy lab: The Dolby Foundation
Höglinger Lab: Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198), DFG (HO2402/18-1 MSAomics), the German Federal Ministry of Education and Research (BMBF, 01KU1403A EpiPD; 01EK1605A HitTau); Niedersächsisches Ministerium für Wissenschaft und Kunst / VolkswagenStiftung (Niedersächsisches Vorab), Petermax-Müller Foundation (Etiology and Therapy of Synucleinopathies and Tauopathies).
Conflicts of Interest:
AMG is an SAB member for Genentech and Muna Therapeutics.
HM consultants for Roche, Aprinoia, AI Therapeutics and Amylyx and is a co-applicant on a patent application PCT/GB2012/052140.