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

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).

Acknowledgment statement for any data distributed by NIAGADS:

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), funded by the National Institute on Aging.

For investigators using Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes – Farrell et al., 2024 data:

The authors would like to acknowledge the following tissue repositories for providing the materials necessary to conduct the study: University of Louisville, Australian Brain Bank Network and Flinders University, Barcelona Biobanc and The University of Barcelona, Brain-Net Germany and Neurobiobank Munich, Emory University, Harvard Brain Tissue Resource Center, McLean Brain Bank, Indiana University School of Medicine, Johns Hopkins University, London brain bank, Los Angeles Veterans Association hospital brain bank, Ludwig-Maximilians- Universität München, German Center for Neurodegenerative Diseases (DZNE), Madrid (Universidad Autónoma de Madrid Spain), Massachusetts General Institute for Neurodegenerative Disease, Mayo Clinic Jacksonville, Netherlands Brain Bank and Erasmus University, New York Brain Bank, Columbia University, University of Paris, Southern Texas University, Sun Health Research Institute, University College London Queen Square Institute of NeurologyQueen Square Brain Bank for Neurological Disorders, University of California San Diego, University of California San Francisco Memory and Aging Center, University of Antwerp, University of Michigan, University of Navarra, University of Saskatchewan, University of Southern California, University of Toronto, University of Washington, University of Würzburg, Victorian Brain Bank, Boston University, Emory University, Netherlands Brain Bank and Erasmus University, Oregon Health Sciences University, University of Pittsburgh, University of Miami, University of Washington, University of California Irvine and the NIH Neurobiobank

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 AG021886) 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)

Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes – Farrell et al., 2024

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Acknowledgment statement for any data distributed by NIAGADS:

For investigators using Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes – Farrell et al., 2024 data:

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