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

      research-article
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      Nature Communications
      Nature Publishing Group UK
      Genome-wide association studies, Genetics of the nervous system, Neurodegenerative diseases, Dementia

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          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 −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, SLCO1A2, and C4A in PSP pathogenesis.

          Abstract

          The authors present the largest genome-wide association study to date for a rare Parkinsonian disorder, progressive supranuclear palsy (PSP). They include follow-up investigations of the identified susceptibility loci, functional consequences, and cell-specific pathologies, providing insights into genetic and molecular mechanisms underlying PSP.

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          Most cited references85

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          Trimmomatic: a flexible trimmer for Illumina sequence data

          Motivation: Although many next-generation sequencing (NGS) read preprocessing tools already existed, we could not find any tool or combination of tools that met our requirements in terms of flexibility, correct handling of paired-end data and high performance. We have developed Trimmomatic as a more flexible and efficient preprocessing tool, which could correctly handle paired-end data. Results: The value of NGS read preprocessing is demonstrated for both reference-based and reference-free tasks. Trimmomatic is shown to produce output that is at least competitive with, and in many cases superior to, that produced by other tools, in all scenarios tested. Availability and implementation: Trimmomatic is licensed under GPL V3. It is cross-platform (Java 1.5+ required) and available at http://www.usadellab.org/cms/index.php?page=trimmomatic Contact: usadel@bio1.rwth-aachen.de Supplementary information: Supplementary data are available at Bioinformatics online.
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            Fiji: an open-source platform for biological-image analysis.

            Fiji is a distribution of the popular open-source software ImageJ focused on biological-image analysis. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biology research communities.
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              STAR: ultrafast universal RNA-seq aligner.

              Accurate alignment of high-throughput RNA-seq data is a challenging and yet unsolved problem because of the non-contiguous transcript structure, relatively short read lengths and constantly increasing throughput of the sequencing technologies. Currently available RNA-seq aligners suffer from high mapping error rates, low mapping speed, read length limitation and mapping biases. To align our large (>80 billon reads) ENCODE Transcriptome RNA-seq dataset, we developed the Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure. STAR outperforms other aligners by a factor of >50 in mapping speed, aligning to the human genome 550 million 2 × 76 bp paired-end reads per hour on a modest 12-core server, while at the same time improving alignment sensitivity and precision. In addition to unbiased de novo detection of canonical junctions, STAR can discover non-canonical splices and chimeric (fusion) transcripts, and is also capable of mapping full-length RNA sequences. Using Roche 454 sequencing of reverse transcription polymerase chain reaction amplicons, we experimentally validated 1960 novel intergenic splice junctions with an 80-90% success rate, corroborating the high precision of the STAR mapping strategy. STAR is implemented as a standalone C++ code. STAR is free open source software distributed under GPLv3 license and can be downloaded from http://code.google.com/p/rna-star/.
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                Author and article information

                Contributors
                John.crary@mountsinai.org
                Adamnaj@pennmedicine.upenn.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                9 September 2024
                9 September 2024
                2024
                : 15
                : 7880
                Affiliations
                [1 ]Department of Pathology, Icahn School of Medicine at Mount Sinai, ( https://ror.org/04a9tmd77) New York, NY USA
                [2 ]Department of Artificial Intelligence & Human Health, Icahn School of Medicine at Mount Sinai, ( https://ror.org/04a9tmd77) New York, NY USA
                [3 ]Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, ( https://ror.org/04a9tmd77) New York, NY USA
                [4 ]Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, ( https://ror.org/04a9tmd77) New York, NY USA
                [5 ]Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, ( https://ror.org/04a9tmd77) New York, NY USA
                [6 ]Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, ( https://ror.org/04a9tmd77) New York, NY USA
                [7 ]Department of Genetics & Genomic Science, Icahn School of Medicine at Mount Sinai, ( https://ror.org/04a9tmd77) New York, NY USA
                [8 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Penn Neurodegeneration Genomics Center, Perelman School of Medicine, , University of Pennsylvania, ; Philadelphia, PA USA
                [9 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, , University of Pennsylvania, ; Philadelphia, PA USA
                [10 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, , University of Pennsylvania, ; Philadelphia, PA USA
                [11 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Institute for Biomedical Informatics, Perelman School of Medicine, , University of Pennsylvania, ; Philadelphia, PA USA
                [12 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Department of Neurology, David Geffen School of Medicine, , University of California, ; Los Angeles, CA USA
                [13 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Department of Human Genetics, David Geffen School of Medicine, , University of California, ; Los Angeles, CA USA
                [14 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Institute for Precision Health, , University of California, ; Los Angeles, CA USA
                [15 ]GRID grid.274295.f, ISNI 0000 0004 0420 1184, Department of Neurology, , James J. Peters Veterans Affairs Medical Center, ; Bronx, NY USA
                [16 ]Department of Neurology, Icahn School of Medicine at Mount Sinai, ( https://ror.org/04a9tmd77) New York, NY USA
                [17 ]GRID grid.411095.8, ISNI 0000 0004 0477 2585, Department of Neurology, , Ludwig-Maximilians-Universität Hospital, ; Munich, Germany
                [18 ]Munich Cluster for Systems Neurology (SyNergy), ( https://ror.org/025z3z560) Munich, Germany
                [19 ]German Center for Neurodegenerative Diseases (DZNE), ( https://ror.org/043j0f473) Munich, Germany
                [20 ]Institute of Human Genetics, Justus-Liebig University, ( https://ror.org/033eqas34) Giessen, Germany
                [21 ]GRID grid.430387.b, ISNI 0000 0004 1936 8796, Department of Neurology, , Rutgers Robert Wood Johnson Medical School, ; New Brunswick, NJ USA
                [22 ]CurePSP, Inc., ( https://ror.org/00qfsn733) New York, NY USA
                [23 ]Department of Clinical and Movement Neurosciences, University College London, ( https://ror.org/02jx3x895) London, UK
                [24 ]Queen Square Institute of Neurology, University College London, ( https://ror.org/02jx3x895) London, UK
                [25 ]GRID grid.83440.3b, ISNI 0000000121901201, Dementia Research Institute, , University College London, ; London, UK
                [26 ]Queen Square Brain Bank for Neurological Disorders, University College London, ( https://ror.org/02jx3x895) London, UK
                [27 ]VIB Center for Molecular Neurology, University of Antwerp, ( https://ror.org/008x57b05) Antwerp, Belgium
                [28 ]Department of Biomedical Sciences, University of Antwerp, ( https://ror.org/008x57b05) Antwerp, Belgium
                [29 ]Department of Neuroscience, Mayo Clinic, ( https://ror.org/02qp3tb03) Jacksonville, FL USA
                [30 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Program in Neurogenetics, David Geffen School of Medicine, , University of California, ; Los Angeles, CA USA
                [31 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Center for Autism Research and Treatment Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, , University of California, ; Los Angeles, CA USA
                [32 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Center for Neuropathology and Prion Research, LMU Hospital, , Ludwig-Maximilians-Universität (LMU), ; Munich, Germany
                [33 ]MRC Centre for Neurodegeneration Research, King’s College London, ( https://ror.org/0220mzb33) London, UK
                [34 ]GRID grid.5841.8, ISNI 0000 0004 1937 0247, Movement Disorders Unit, Neurology Department and Neurological Tissue Bank and Neurology Department, Hospital Clínic de Barcelona, , University of Barcelona, ; Barcelona, Catalonia Spain
                [35 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Neurology and Netherlands Brain Bank, , Erasmus Medical Centre, ; Rotterdam, The Netherlands
                [36 ]GRID grid.25152.31, ISNI 0000 0001 2154 235X, Division of Neurology, Royal University Hospital, , University of Saskatchewan, ; Saskatoon, Canada
                [37 ]Australian Brain Bank Network in collaboration with the Victorian Brain Bank Network, Carlton, Australia
                [38 ]GRID grid.411347.4, ISNI 0000 0000 9248 5770, Department of Neurology, , Hospital Ramón y Cajal, ; Madrid, Spain
                Author information
                http://orcid.org/0000-0002-6274-6620
                http://orcid.org/0000-0002-9225-9874
                http://orcid.org/0000-0002-3047-5440
                http://orcid.org/0000-0003-2248-6403
                http://orcid.org/0000-0002-5305-1181
                http://orcid.org/0000-0002-6064-5420
                http://orcid.org/0000-0001-8055-2187
                http://orcid.org/0000-0003-3892-6733
                http://orcid.org/0000-0001-6702-8268
                http://orcid.org/0000-0002-9355-5704
                http://orcid.org/0000-0001-7587-6187
                http://orcid.org/0000-0002-5473-3774
                http://orcid.org/0000-0001-6195-6995
                http://orcid.org/0000-0001-7738-8881
                http://orcid.org/0000-0002-4049-0863
                http://orcid.org/0000-0001-7189-7917
                http://orcid.org/0000-0003-4813-756X
                http://orcid.org/0000-0002-0576-2472
                http://orcid.org/0000-0003-2896-3450
                http://orcid.org/0000-0002-0556-293X
                http://orcid.org/0000-0002-9621-2942
                Article
                52025
                10.1038/s41467-024-52025-x
                11385559
                39251599
                97303a80-8bd1-47ca-a313-ddff08756464
                © The Author(s) 2024

                Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

                History
                : 15 November 2023
                : 23 August 2024
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                © Springer Nature Limited 2024

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                genome-wide association studies,genetics of the nervous system,neurodegenerative diseases,dementia

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