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

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<sup>-8</sup>) 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, SLCO1A2, and C4A in PSP pathogenesis.

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Journal
Nature Communications
Published
2024-09-09
DOI
https://doi.org/10.1038/s41467-024-52025-x
Citations
36
Primary Topic
Neurological diseases and metabolism
Type
article
Field-Weighted Citation Impact
8.66

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article

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

Jack Humphrey, Wan‐Ping Lee, Alan E. Renton, Ruth H. Walker et al.
36 citations
Nature Communications
Neurological diseases and metabolism
8.66
article

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

Jack Humphrey, Wan‐Ping Lee, Alan E. Renton, Ruth H. Walker, Dennis W. Dickson, Alicia Casella, Tamás Révész, Timothy S. Chang, Thomas T. Warner, Hadley W. Ressler, Daniel H. Geschwind, Otto Valladares, John Hardy, Megan A. Iida, Diana K. Dangoor, Ashvin Ravi, Kurt Farrell, Vishakha Patil, Pavel P. Kuksa, Yuk Yee Leung, Li‐San Wang, Amanda B Kuzma, Thomas D. Christie, Rosa Rademakers, Melissa J. Nirenberg, Towfique Raj, Margaret M. Krassner, Zane Jaunmuktane, Yi Zhao, Lawrence I. Golbe, Günter U. Höglinger, Bergan Babrowicz, SoongHo Kim, Owen A. Ross, Natalia Han, Laura B. Cantwell, Huw R. Morris, Kristen Whitney, Kin Ying Mok, Alison Goate, Hui Wang, Ulrich Müller, Claudia De Sanctis, Shrishtee Kandoi, Robina Afzal, Giovanni Coppola
article en
36 citations

Abstract

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<sup>-8</sup>) 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, SLCO1A2, and C4A in PSP pathogenesis.

Nature CommunicationsVol. 15(1)
Rutgers, The State University of New Jersey (US), Allen Institute for Brain Science (US), University of Antwerp (BE), University of California, Los Angeles (US), King's College London (GB), Justus-Liebig-Universität Gießen (DE), Royal University Hospital (CA), German Center for Neurodegenerative Diseases (DE), Johnson University (US), Vision Australia (AU), University of California System (US), LMU Klinikum (DE), CurePSP (US), Munich Cluster for Systems Neurology (DE), Hospital Clínic de Barcelona (ES), James J. Peters VA Medical Center (US), UK Dementia Research Institute (GB), Penn Center for AIDS Research (US), VIB-UAntwerp Center for Molecular Neurology (BE), Mayo Clinic in Florida (US), National Hospital for Neurology and Neurosurgery (GB), Hospital Universitario Ramón y Cajal (ES), University College London (GB), Universitat de Barcelona (ES), University of Pennsylvania (US), Ludwig-Maximilians-Universität München (DE), Erasmus University Rotterdam (NL), Center for Autism and Related Disorders (US), Icahn School of Medicine at Mount Sinai (US)
U.S. Department of Veterans Affairs, Larry L. Hillblom Foundation, University of Southern California, University of Pennsylvania, Emory University, Mayo Foundation for Medical Education and Research, University of Washington, Johns Hopkins University, University of Pittsburgh, University of Louisville, CurePSP, Georgia Clinical and Translational Science Alliance, University College London, Deutsche Forschungsgemeinschaft, Volkswagen Foundation, Flinders University, Bundesministerium für Bildung und Forschung, University of Toronto, Universidad de Navarra, Universidad Autónoma de Madrid, Deutsches Zentrum für Neurodegenerative Erkrankungen, Ludwig-Maximilians-Universität München, Universitat de Barcelona, Universiteit Antwerpen, Julius-Maximilians-Universität Würzburg, National Institutes of Health, University of California, San Diego, School of Medicine, Indiana University, School of Medicine, Johns Hopkins University, National Institute on Aging, National Center for Advancing Translational Sciences
Openalex Percentile: Top 2%
Neurological diseases and metabolism
8.66
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