ArticleMovement disorders : official journal of the Movement Disorder Society2025
Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells.
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4 citing papers in PubMed.
- Founder mutations in movement disorders: global distribution, molecular mechanisms, and clinical consequences-a scoping review.Neurogenetics · 2026Article
- Opposite molecular sex correlations in tauopathy paralleled by motor and cognitive efficacy of davunetide in women.Molecular psychiatry · 2026Article
- Emerging directions in tauopathy research.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- Multifactorial etiology of progressive supranuclear palsy (PSP): the genetic component.Acta neuropathologica · 2025Review
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Authors and funding
67 authors.
Hui WangDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.ORCID https://orcid.org/0000-0003-4043-5060
Timothy S ChangMovement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.ORCID https://orcid.org/0000-0002-9225-9874
Beth A DombroskiDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.ORCID https://orcid.org/0000-0002-5334-1306
Po-Liang ChengDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.ORCID https://orcid.org/0009-0007-0046-0313
Ya-Qin SiBioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA.ORCID https://orcid.org/0000-0002-9968-9754
Albert TucciBioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA.ORCID https://orcid.org/0000-0001-5703-7208
Vishakha PatilMovement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Leopoldo Valiente-BanuetMovement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Chong LiDepartment of Computer and Information Sciences, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA.ORCID https://orcid.org/0000-0003-1949-4074
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 and Research CoRE, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.ORCID https://orcid.org/0000-0001-6955-7278
Catriona McleanVictorian Brain Bank, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.ORCID https://orcid.org/0000-0002-0302-5727
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.ORCID https://orcid.org/0000-0003-4068-8578
Alex RajputMovement Disorders Program, Division of Neurology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.ORCID https://orcid.org/0000-0001-9656-318X
Peter Paul De DeynLaboratory of Neurochemistry and Behavior, Experimental Neurobiology Unit, University of Antwerp, Antwerp, Belgium.ORCID https://orcid.org/0000-0002-2228-2964
Nathalie Le BastardFujirebio Europe NV, Ghent, Belgium.ORCID https://orcid.org/0000-0002-7981-2866
Marla GearingDepartment of Pathology and Laboratory Medicine and Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.ORCID https://orcid.org/0000-0002-1959-7412
Laura Donker KaatNetherlands Brain Bank and Erasmus University, Rotterdam, The Netherlands.ORCID https://orcid.org/0009-0007-2436-0931
John C Van SwietenNetherlands Brain Bank and Erasmus University, Rotterdam, The Netherlands.ORCID https://orcid.org/0000-0001-6278-6844
Elise DopperNetherlands Brain Bank and Erasmus University, Rotterdam, The Netherlands.
Bernardino F GhettiDepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.ORCID https://orcid.org/0000-0002-1842-8019
Kathy L NewellDepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Claire TroakesLondon Neurodegenerative Diseases Brain Bank, King's College London, London, United Kingdom.ORCID https://orcid.org/0000-0002-1790-7376
Justo G de YébenesAutonomous University of Madrid, Madrid, Spain.ORCID https://orcid.org/0000-0003-0452-3223
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.ORCID https://orcid.org/0000-0002-0239-6585
Wolfgang H OertelDepartment of Neurology, Philipps-Universität, Marburg, Germany.ORCID https://orcid.org/0000-0002-7582-8166
Gesine RespondekGerman Center for Neurodegenerative Diseases (DZNE), Munich, Germany.ORCID https://orcid.org/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, Munich, Germany.
Sigrun RoeberCenter for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
Ulrich MüllerInstitute of Human Genetics, Justus-Liebig University Giessen, Giessen, Germany.
Franziska HopfnerDepartment of Neurology, LMU University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.ORCID https://orcid.org/0000-0001-6524-0281
Pau PastorUnit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Barcelona, Spain.ORCID https://orcid.org/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 https://orcid.org/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 https://orcid.org/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, Arizona, USA.ORCID https://orcid.org/0000-0003-3296-6128
Geidy E SerranoBanner Sun Health Research Institute, Sun City, Arizona, USA.ORCID https://orcid.org/0000-0002-9527-2011
Lili-Naz HazratiDepartment of Pathology, University McGill, Montreal, Quebec, Canada.ORCID https://orcid.org/0000-0003-2715-1485
Irene LitvanDepartment of Neuroscience, University of California San Diego, La Jolla, California, USA.ORCID https://orcid.org/0000-0002-3485-3445
Rosa RademakersVIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
Owen A RossDepartment of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida, USA.ORCID https://orcid.org/0000-0003-4813-756X
Douglas GalaskoDepartment of Neuroscience, University of California San Diego, La Jolla, California, USA.ORCID https://orcid.org/0000-0001-6195-3241
Adam L BoxerMemory and Aging Center, University of California San Francisco, San Francisco, California, USA.ORCID https://orcid.org/0000-0002-1215-5064
Bruce L MillerMemory and Aging Center, University of California San Francisco, San Francisco, California, USA.ORCID https://orcid.org/0000-0002-2152-4220
Willian W SeeleyMemory and Aging Center, University of California San Francisco, San Francisco, California, USA.
Vivianna M Van DeerlinDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.ORCID https://orcid.org/0000-0002-7400-9097
Edward B LeeDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.ORCID https://orcid.org/0000-0002-4589-1180
Charles L WhiteUniversity of Texas Southwestern Medical Center, Dallas, Texas, USA.ORCID https://orcid.org/0000-0002-3870-2804
Huw R MorrisDepartmento of Clinical and Movement Neuroscience, University College of London, London, United Kingdom.ORCID https://orcid.org/0000-0002-5473-3774
Rohan de SilvaReta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, United Kingdom.
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 and Research CoRE, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.ORCID https://orcid.org/0000-0002-0556-293X
Alison M GoateDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.ORCID https://orcid.org/0000-0002-0576-2472
Jeffrey S FriedmanFriedman Bioventure, Inc., Del Mar, California, USA.
Yaroslau ComptaParkinson's Disease & Movement Disorders Unit, Hospital Clínic de Barcelona; IDIBAPS, CIBERNED (CB06/05/0018-ISCIII), ERN- RND, UBNeuro - Maria de Maeztu Excellence Centre, Universitat de Barcelona, Barcelona, Spain.
Yuk Yee LeungDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.ORCID https://orcid.org/0000-0002-3047-5440
Giovanni CoppolaMovement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Adam C NajDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Li-San WangDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.ORCID https://orcid.org/0000-0002-3684-0031
PSP Genetics Study Group
Clifton DalgardDepartment of Anatomy Physiology and Genetics, the American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
Dennis W DicksonDepartment of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida, USA.ORCID https://orcid.org/0000-0001-7189-7917
Günter U HöglingerGerman Center for Neurodegenerative Diseases (DZNE), Munich, Germany.ORCID https://orcid.org/0000-0001-7587-6187
Jung-Ying TzengBioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA.ORCID https://orcid.org/0000-0002-5505-1775
Daniel H GeschwindMovement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Gerard D SchellenbergDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.ORCID https://orcid.org/0000-0003-1115-2475
Wan-Ping LeeDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.ORCID https://orcid.org/0000-0002-5305-1181
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 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
$67.2MAlzheimer'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
$37.3MResearch 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 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
$32.5MCurePSPLarry L. Hillblom Foundation 2021-A-005-SUP YQSMichael J Fox FoundationNIA 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 P01 AG066597NIA NIH HHS P01 AG084497NIA NIH HHS P30 AG019610NIA NIH HHS P30 AG062422NIA 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 AG023501NIA 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 AG074328NIA 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 AG052427NIH HHS 1R21NS114764-01A1NIH HHS 2R01AG038791-06ANIH HHS 3UH3NS104095NIH HHS 5UG3NS104095NIH HHS K01-AG070326NIH HHS K08-AG065519NIH HHS P01-AG-017586NIH HHS P01 AG019724NIH HHS P01-AG-066597NIH HHS P0544014NIH HHS P30AG062429NIH HHS P30-AG066511NIH HHS P30 AG066514NIH HHS P30-AG072976NIH HHS P30-AG072979NIH HHS P30-AG072980NIH HHS P30AG072980NIH HHS P30 AG19610NIH HHS P50 AG016574NIH HHS R01AG038791NIH HHS R01 AG054008NIH HHS R01 AG057234NIH HHS R01 AG060961NIH HHS R01 AG062348NIH HHS R01AG071756NIH HHS R01AG073482NIH HHS R01-AG080001NIH HHS R01 NS086736NIH HHS R01 NS095252NIH HHS R25NS098999NIH HHS RF1-AG074328NIH HHS U01AG032984NIH HHS U01NS100610NIH HHS U19AG063911NIH HHS U19 AG063911-1NIH HHS U24-AG041689NIH HHS U24AG041689NIH HHS U24 NS072026NIH HHS U54-AG052427NIH HHS U54AG052427NIH HHS U54- AG052427NIH HHS U54 NS100693NIH HHS U54-NS123746NINDS 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 NS104095Rainwater Charitable FoundationReta Lila Weston Trust
Abstract
backgroundThe 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP).
objectiveTo investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP.
methodsUtilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP.
resultsWe found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub-haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up-regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down-regulating KANSL1. Single-nucleus RNA-seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up-regulates LRRC37A/LRRC37A2 in neuronal cells.
conclusionsThe copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Indexed as
Chromosomes, Human, Pair 17DNA Copy Number VariationsGenetic Predisposition to DiseaseNeuronsSupranuclear Palsy, ProgressiveAgedFemaleGene ExpressionHaplotypesHumansMaleMiddle Aged17q21.31copy number variationsH1 and H2 haplotypesprogressive supranuclear palsysingle‐cell gene expression
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