ArticlemedRxiv : the preprint server for health sciences2024
Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy.
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61 authors at 20 institutions in 11 countries.
Hui WangDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID 0000-0003-4043-5060
Timothy S ChangMovement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.ORCID 0000-0002-9225-9874
Beth A DombroskiDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Po-Liang ChengDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID 0009-0007-0046-0313
Vishakha PatilMovement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Leopoldo Valiente-BanuetMovement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Kurt FarrellDepartment of Pathology, Department of Artificial Intelligence & Human Health, Nash Family, Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Friedman Brain, Institute, Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Catriona McleanVictorian Brain Bank, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
Laura Molina-PorcelAlzheimer's disease and other cognitive disorders unit. Neurology Service, Hospital Clínic, Fundació Recerca Clínic Barcelona (FRCB). Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
Alex RajputMovement Disorders Program, Division of Neurology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Peter Paul De DeynLaboratory of Neurochemistry and Behavior, Experimental Neurobiology Unit, University of Antwerp, Wilrijk (Antwerp), Belgium.ORCID 0000-0002-2228-2964
Nathalie Le BastardFujirebio Europe NV, Technologiepark 6, 9052 Gent, Belgium.ORCID 0000-0002-7981-2866
Marla GearingDepartment of Pathology and Laboratory Medicine and Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
Laura Donker KaatNetherlands Brain Bank and Erasmus University, Netherlands.
John C Van SwietenNetherlands Brain Bank and Erasmus University, Netherlands.
Elise DopperNetherlands Brain Bank and Erasmus University, Netherlands.
Bernardino F GhettiDepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.ORCID 0000-0002-1842-8019
Kathy L NewellDepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.ORCID 0000-0002-1648-7357
Claire TroakesLondon Neurodegenerative Diseases Brain Bank, King's College London, London, UK.ORCID 0000-0002-1790-7376
Justo G de YébenesAutonomous University of Madrid, Madrid, Spain.
Alberto Rábano-GutierrezFundación CIEN (Centro de Investigación de Enfermedades Neurológicas) - Centro Alzheimer Fundación Reina Sofía, Madrid, Spain.
Tina MellerDepartment of Neurology, Philipps-Universität, Marburg, Germany.
Wolfgang H OertelDepartment of Neurology, Philipps-Universität, Marburg, Germany.ORCID 0000-0002-7582-8166
Gesine RespondekGerman Center for Neurodegenerative Diseases (DZNE), Munich, Germany.ORCID 0000-0002-6851-6164
Maria StamelouParkinson's disease and Movement Disorders Department, HYGEIA Hospital, Athens, Greece.
Thomas ArzbergerDepartment of Psychiatry and Psychotherapy, University Hospital Munich, Ludwig-Maximilians-University Munich, Germany.
Sigrun RoeberGerman Brain Bank, Neurobiobank Munich, Germany.
Ulrich MüllerGerman Brain Bank, Neurobiobank Munich, Germany.
Franziska HopfnerDepartment of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Pau PastorUnit of Neurodegenerative diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.ORCID 0000-0002-7493-8777
Alexis BriceSorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France.ORCID 0000-0002-0941-3990
Alexandra DurrSorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France.ORCID 0000-0002-8921-7104
Isabelle Le BerSorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France.
Thomas G BeachBanner Sun Health Research Institute, Sun City, AZ, USA.
Geidy E SerranoBanner Sun Health Research Institute, Sun City, AZ, USA.ORCID 0000-0002-9527-2011
Lili-Naz HazratiUniversity McGill, Montreal, Quebec, Canada.
Irene LitvanDepartment of Neuroscience, University of California, San Diego, CA, USA.ORCID 0000-0002-3485-3445
Rosa RademakersVIB Center for Molecular Neurology, University of Antwerp, Belgium.ORCID 0000-0002-4049-0863
Owen A RossDepartment of Neuroscience, Mayo Clinic Jacksonville, FL, USA.
Douglas GalaskoDepartment of Neuroscience, University of California, San Diego, CA, USA.
Adam L BoxerMemory and Aging Center, University of California, San Francisco, CA, USA.
Bruce L MillerMemory and Aging Center, University of California, San Francisco, CA, USA.ORCID 0000-0002-2152-4220
Willian W SeeleyMemory and Aging Center, University of California, San Francisco, CA, USA.
Vivanna M Van DeerlinDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID 0000-0002-7400-9097
Edward B LeeDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Charles L WhiteUniversity of Texas Southwestern Medical Center, Dallas, TX, USA.ORCID 0000-0002-3870-2804
Huw MorrisDepartmento of Clinical and Movement Neuroscience, University College of London, London, UK.ORCID 0000-0002-5473-3774
Rohan de SilvaReta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.ORCID 0000-0002-5052-5775
John F CraryDepartment of Pathology, Department of Artificial Intelligence & Human Health, Nash Family, Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Friedman Brain, Institute, Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Alison M GoateDepartment of Genetics and Genomic Sciences, New York, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID 0000-0002-0576-2472
Jeffrey S FriedmanFriedman Bioventure, Inc., Del Mar, CA, USA; Department of Genetics and Genomic Sciences, New York, NY, USA.
Yuk Yee LeungDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID 0000-0002-3047-5440
Giovanni CoppolaMovement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.ORCID 0000-0003-2105-1061
Adam C NajDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID 0000-0002-9621-2942
Li-San WangDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
PSP genetics study group
Dennis W DicksonDepartment of Neuroscience, Mayo Clinic Jacksonville, FL, USA.ORCID 0000-0001-7189-7917
Günter U HöglingerDepartment of Neurology, LMU University Hospital, Ludwig-Maximilians-Universität (LMU) München; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Gerard D SchellenbergDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Daniel H GeschwindMovement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Wan-Ping LeeDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID 0000-0002-5305-1181
University of Pennsylvania · USUniversity of California, Los Angeles · USCentre National de la Recherche Scientifique · FRHersenstichting · NLUniversity of California, San Francisco · USAllen Institute for Brain Science · USBanner Sun Health Research Institute · USDeutsche Bank (Germany) · DEGerman Center for Neurodegenerative Diseases · DEIndiana University School of MedicineMayo Clinic in Florida · USPhilipps University of Marburg · DEUniversity of California San Diego · USBanc de Sang i Teixits · ESEmory University · USEuropean University Cyprus · CYFlorey Institute of Neuroscience and Mental Health · AUFujirebio (Belgium) · BEFundacion Centro De Investigacion De Enfermedades Neurologicas · ESInstitut d'Investigació en Ciències de la Salut Germans Trias i Pujol · ES
Funding
Technology and Remote Assessment CoreU19AG063911 · NIA · MAYO CLINIC ROCHESTER · PI KEJAL KANTARCI · 2019 to 2026
$120.9MVascular Structure and Function in Cognitive AgingP01AG003949 · NIA · YESHIVA UNIVERSITY · PI STEVEN SUEY-MING CHIN · 1985 to 2026
$73.9MTDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2MAlzheimer's Disease Genetics ConsortiumU01AG032984 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID · 2009 to 2024
$60.4MSUPPLEMENT TO ALZHEIMERS DISEASE PATIENT REGISTRYU01AG006786 · NIA · MAYO CLINIC ROCHESTER · PI GRAFF-RADFORD, JONATHAN, JACK, CLIFFORD R. · 1986 to 2023
$49.6MTHE NIA GENETICS OF ALZHEIMER'S DISEASE DATA STORAGE SITEU24AG041689 · NIA · UNIVERSITY OF PENNSYLVANIA · PI LI-SAN WANG · 2012 to 2026
$42.3MTransgenic Mouse Models of Tau PathologiesP01AG017586 · NIA · UNIVERSITY OF PENNSYLVANIA · PI LEE, VIRGINIA M · 2000 to 2021
$37.3MTHE PGRN/TDP-43 AXIS IN ALZHEIMER?S DISEASE AND NEURODEGENERATIONP50AG016574 · NIA · MAYO CLINIC ROCHESTER · PI PETERSEN, RONALD C · 1999 to 2018
$36.9MUCSD Shiley-Marcos Alzheimer's Disease Research Center P30P30AG062429 · NIA · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI DOUGLAS R GALASKO · 2019 to 2026
$34.9MGenome Center for Alzheimer's Disease (GCAD)U54AG052427 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID, WANG, LI-SAN · 2016 to 2025
$32.8MResearch Education ComponentP30AG019610 · NIA · SUN HEALTH RESEARCH INSTITUTE · PI REIMAN, ERIC MICHAEL · 2001 to 2020
$32.5MResearch Education ComponentP30AG066514 · NIA · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Margaret Sewell · 2020 to 2026
$31.0MNIA NIH HHS K01 AG070326NIA NIH HHS K08 AG065519NIA NIH HHS K24 AG045333NIA NIH HHS P01 AG003949NIA NIH HHS P01 AG017216NIA NIH HHS P01 AG017586NIA NIH HHS P01 AG019724NIA NIH HHS P01 AG066597NIA NIH HHS P30 AG019610NIA NIH HHS P30 AG062429NIA NIH HHS P30 AG066511NIA NIH HHS P30 AG066514NIA NIH HHS P30 AG072976NIA NIH HHS P30 AG072979NIA NIH HHS P30 AG072980NIA NIH HHS P50 AG016574NIA NIH HHS P50 AG025711NIA NIH HHS R01 AG018023NIA NIH HHS R01 AG032990NIA NIH HHS R01 AG038791NIA NIH HHS R01 AG054008NIA NIH HHS R01 AG057234NIA NIH HHS R01 AG062348NIA NIH HHS R01 AG071756NIA NIH HHS R01 AG073482NIA NIH HHS R01 AG080001NIA NIH HHS RF1 AG060961NIA NIH HHS RF1 AG062348NIA NIH HHS RF1 AG074328NIA NIH HHS U01 AG006786NIA NIH HHS U01 AG032984NIA NIH HHS U01 AG046139NIA NIH HHS U19 AG063911NIA NIH HHS U24 AG041689NIA NIH HHS U54 AG052427NINDS NIH HHS P50 NS072187NINDS NIH HHS R01 NS080820NINDS NIH HHS R01 NS086736NINDS NIH HHS R01 NS095252NINDS NIH HHS R21 NS114764NINDS NIH HHS R25 NS098999NINDS NIH HHS U01 NS100610NINDS NIH HHS U24 NS072026NINDS NIH HHS U54 NS100693NINDS NIH HHS U54 NS123746NINDS NIH HHS UG3 NS104095NINDS NIH HHS UH3 NS104095
Abstract
Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results: Our analysis of common SNVs and indels confirmed known genetic loci at Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.
Indexed as
Apolipoprotein E (APOE)Genome-Wide Association Study (GWAS)Progressive Supranuclear Palsy (PSP)Structural Variants (SVs)Whole-Genome Sequencing (WGS)
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