ArticleMolecular neurodegeneration2024
Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy.
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Article in Molecular neurodegeneration, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 26 papers, 1 of them a synthesis that pooled it.
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26citing papers in PubMed, 1 pooled it
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Who cites it
26 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Apolipoprotein E Alleles Across the Spectrum of Frontotemporal Lobar Degeneration: A Systematic Review and Meta-Analysis.International journal of molecular sciences · 2026Pooled it
- AZP2006 in Progressive Supranuclear Palsy: Outcomes from a Phase 2a Multicenter, Randomized Trial, and Open-Label Extension on Safety, Biomarkers, and Disease Progression.Movement disorders : official journal of the Movement Disorder Society · 2025Trial
- Data-driven modelling of tau pathology reveals distinct progressive supranuclear palsy subtypes.Brain : a journal of neurology · 2026Article
- Single-nucleus epigenomic dysregulation unmasks genetic risk-associated neurodegenerative glia states.Nature communications · 2026Article
- Article
- A critical appraisal of the link between apolipoprotein E and Tau.Current opinion in neurology · 2026Review
- Short tandem repeat expansions in patients with neurodegenerative dementia.EBioMedicine · 2026Article
- APOE genotype differentially modulates prion pathology in a mouse model.Acta neuropathologica communications · 2026Article
- Flipping APOE to reverse Alzheimer's disease traits.Nature neuroscience · 2025Article
- APOE4 to APOE2 allelic switching in mice improves Alzheimer's disease-related metabolic signatures, neuropathology and cognition.Nature neuroscience · 2025Article
- APOE Genotype Differentially Modulates Prion Pathology in a Mouse Model.Research square · 2025Article
- Long-read genome sequencing and multi-omics in aging and neurodegeneration.medRxiv : the preprint server for health sciences · 2025Article
- Review
- Identifying Common Disease Trajectories of Progressive Supranuclear Palsy with Electronic Health Records.Movement disorders clinical practice · 2025Article
- Neuroinflammation distinguishes HLA haplotypes in progressive supranuclear palsy.medRxiv : the preprint server for health sciences · 2025Article
- A Spanish-Portuguese GWAS of progressive supranuclear palsy reveals a novel risk locus in NFASC.European journal of human genetics : EJHG · 2025Article
- Multifactorial etiology of progressive supranuclear palsy (PSP): the genetic component.Acta neuropathologica · 2025Review
- Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- The Genetic Background of the Immunological and Inflammatory Aspects of Progressive Supranuclear Palsy.International journal of molecular sciences · 2025Review
- Magnetic Resonance Imaging in the Neuroimaging of Progressive Supranuclear Palsy-Parkinsonism Predominant: Limitations and Strengths in Clinical Evaluation.Diagnostics (Basel, Switzerland) · 2025Article
Corrections and comments
- Erratum issued
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Authors and funding
62 authors.
Hui Wang *Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Timothy S Chang *Movement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
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.
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, VIC, 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, SK, Canada.
Peter Paul De DeynLaboratory of Neurochemistry and Behavior, Experimental Neurobiology Unit, University of Antwerp, Wilrijk (Antwerp), Belgium.
Nathalie Le BastardFujirebio Europe NV, Technologiepark 6, 9052, Ghent, Belgium.
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, Rotterdam, Netherlands.
John C Van SwietenNetherlands Brain Bank and Erasmus University, Rotterdam, Netherlands.
Elise DopperNetherlands Brain Bank and Erasmus University, Rotterdam, Netherlands.
Bernardino F GhettiDepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Kathy L NewellDepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Claire TroakesLondon Neurodegenerative Diseases Brain Bank, King's College London, London, UK.
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.
Gesine RespondekGerman Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
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, Munich, Germany.
Sigrun RoeberGerman Brain Bank, Neurobiobank Munich, Munich, Germany.
Ulrich MüllerGerman Brain Bank, Neurobiobank Munich, Munich, Germany.
Franziska HopfnerDepartment 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.
Pau PastorUnit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias I Pujol, Badalona, Barcelona, Spain.
Alexis BriceSorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France.
Alexandra DurrSorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France.
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.
Lili-Naz HazratiUniversity McGill, Montreal, QC, Canada.
Irene LitvanDepartment of Neuroscience, University of California, San Diego, CA, USA.
Rosa RademakersVIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
Owen A RossDepartment of Neuroscience, Mayo Clinic Jacksonville, 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.
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.
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.
Huw MorrisDepartmento of Clinical and Movement Neuroscience, University College of London, London, UK.
Rohan de SilvaReta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.
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.
Jeffrey S FriedmanFriedman Bioventure, Inc., Del Mar, CA, USA.
Yuk Yee LeungDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Giovanni CoppolaMovement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Adam C NajDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Li-San WangDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
P. S. P. genetics study group
Clifton DalgardDepartment of Anatomy Physiology and Genetics, the American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Dennis W DicksonDepartment of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USA. Dickson.Dennis@mayo.edu.
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. guenter.hoeglinger@med.uni-muenchen.de.
Gerard D SchellenbergDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. gerardsc@pennmedicine.upenn.edu.
Daniel H GeschwindMovement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. dhg@mednet.ucla.edu.
Wan-Ping LeeDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. wan-ping.lee@pennmedicine.upenn.edu.ORCID 0000-0002-5305-1181
Funding
Vascular Structure and Function in Cognitive AgingP01AG003949 · NIA · YESHIVA UNIVERSITY · PI Richard B. LIPTON · 1985 to 2026
$73.9MTDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2MSUPPLEMENT TO ALZHEIMERS DISEASE PATIENT REGISTRYU01AG006786 · NIA · MAYO CLINIC ROCHESTER · PI GRAFF-RADFORD, JONATHAN, JACK, CLIFFORD R. · 1986 to 2023
$49.6MTransgenic Mouse Models of Tau PathologiesP01AG017586 · NIA · UNIVERSITY OF PENNSYLVANIA · PI LEE, VIRGINIA M · 2000 to 2021
$37.3MResearch Education ComponentP30AG062422 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Katherine P Rankin · 2019 to 2026
$36.9MTHE 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 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 ComponentP30AG072980 · NIA · BANNER HEALTH · PI ALIREZA ATRI · 2021 to 2026
$24.9MResearch Education ComponentP30AG072979 · NIA · UNIVERSITY OF PENNSYLVANIA · PI DAVID A WOLK · 2021 to 2026
$24.8MIntegrating the exposome and methylome to inform brain molecular changes in ADRD across established diverse cohorts.U01AG046139 · NIA · UNIVERSITY OF FLORIDA · PI ERTEKIN-TANER, NILUFER, FUNK, CORY · 2013 to 2022
$24.6MNIA NIH HHS K01 AG070326NIA NIH HHS K08 AG065519NIA NIH HHS P01 AG003949NIA NIH HHS P01 AG017216NIA NIH HHS P01 AG017586NIA NIH HHS P01 AG019724NIA NIH HHS P30 AG019610NIA NIH HHS P30 AG062422NIA NIH HHS P30 AG062429NIA 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 RF1 AG074328NIA NIH HHS U01 AG006786NIA NIH HHS U01 AG046139NIA NIH HHS U54 AG052427NIH HHS 5UG3NS104095NIH HHS RF1-AG074328NINDS NIH HHS P50 NS072187NINDS NIH HHS R01 NS080820NINDS NIH HHS U24 NS072026NINDS NIH HHS U54 NS100693NINDS NIH HHS UG3 NS104095
Abstract
backgroundProgressive 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).
methodIn 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.
resultsOur analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10
conclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.
Indexed as
Genetic Predisposition to DiseaseGenome-Wide Association StudyPolymorphism, Single NucleotideSupranuclear Palsy, ProgressiveWhole Genome SequencingAgedAged, 80 and overFemaleHumansMaleMiddle AgedApolipoprotein E (APOE)Genome-Wide Association Study (GWAS)Progressive Supranuclear Palsy (PSP)Structural Variants (SVs)Whole-Genome Sequencing (WGS)
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