Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells

Hui Wang^{1

2}, Timothy S Chang³, Beth A Dombroski^{1

2}, Po-Liang Cheng^{1

2}, Ya-Qin Si⁴, Albert Tucci⁴, Vishakha Patil³, Leopoldo Valiente-Banuet³, Chong Li⁵, Kurt Farrell⁶, Catriona Mclean⁷, Laura Molina-Porcel^{8

9}, Alex Rajput¹⁰, Peter Paul De Deyn^{11

12}, Nathalie Le Bastard¹³, Marla Gearing¹⁴, Laura Donker Kaat¹⁵, John C Van Swieten¹⁵, Elise Dopper¹⁵, Bernardino F Ghetti¹⁶, Kathy L Newell¹⁶, Claire Troakes¹⁷, Justo G de Yébenes¹⁸, Alberto Rábano-Gutierrez¹⁹, Tina Meller²⁰, Wolfgang H Oertel²⁰, Gesine Respondek²¹, Maria Stamelou^{22

23}, Thomas Arzberger^{24

25}, Sigrun Roeber²⁵, Ulrich Müller²⁶, Franziska Hopfner²⁷, Pau Pastor^{28

29}, Alexis Brice³⁰, Alexandra Durr³⁰, Isabelle Le Ber³⁰, Thomas G Beach³¹, Geidy E Serrano³¹, Lili-Naz Hazrati³², Irene Litvan³³, Rosa Rademakers^{34

35}, Owen A Ross³⁵, Douglas Galasko³³, Adam L Boxer³⁶, Bruce L Miller³⁶, Willian W Seeley³⁶, Vivianna M Van Deerlin¹, Edward B Lee^{1

37}, Charles L White 3rd³⁸, Huw R Morris³⁹, Rohan de Silva⁴⁰, John F Crary⁶, Alison M Goate⁴¹, Jeffrey S Friedman⁴², Yaroslau Compta^{43

44}, Yuk Yee Leung^{1

2}, Giovanni Coppola^{3

45}, Adam C Naj^{1

2

46}, Li-San Wang^{1

2}; PSP Genetics Study Group; Clifton Dalgard⁴⁷, Dennis W Dickson³⁵, Günter U Höglinger^{21

27

48}, Jung-Ying Tzeng^{4

49}, Daniel H Geschwind^{3

50

51}, Gerard D Schellenberg^{1

2}, Wan-Ping Lee^{1

2}

Collaborators, Affiliations

Affiliations

¹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
² Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³ Movement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
⁴ Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA.
⁵ Department of Computer and Information Sciences, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA.
⁶ Department 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.
⁷ Victorian Brain Bank, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
⁸ Alzheimer'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.
⁹ Neurological Tissue Bank of the Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain.
¹⁰ Movement Disorders Program, Division of Neurology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
¹¹ Laboratory of Neurochemistry and Behavior, Experimental Neurobiology Unit, University of Antwerp, Antwerp, Belgium.
¹² Department of Neurology, University Medical Center Groningen, Groningen, The Netherlands.
¹³ Fujirebio Europe NV, Ghent, Belgium.
¹⁴ Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
¹⁵ Netherlands Brain Bank and Erasmus University, Rotterdam, The Netherlands.
¹⁶ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁷ London Neurodegenerative Diseases Brain Bank, King's College London, London, United Kingdom.
¹⁸ Autonomous University of Madrid, Madrid, Spain.
¹⁹ Fundación CIEN (Centro de Investigación de Enfermedades Neurológicas) - Centro Alzheimer Fundación Reina Sofía, Madrid, Spain.
²⁰ Department of Neurology, Philipps-Universität, Marburg, Germany.
²¹ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
²² Parkinson's Disease and Movement Disorders Department, HYGEIA Hospital, Athens, Greece.
²³ European University of Cyprus, Nicosia, Cyprus.
²⁴ Department of Psychiatry and Psychotherapy, University Hospital Munich, Ludwig-Maximilians-University Munich, Munich, Germany.
²⁵ Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
²⁶ Institute of Human Genetics, Justus-Liebig University Giessen, Giessen, Germany.
²⁷ Department of Neurology, LMU University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
²⁸ Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Barcelona, Spain.
²⁹ Neurosciences, The Germans Trias i Pujol Research Institute, Barcelona, Spain.
³⁰ Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France.
³¹ Banner Sun Health Research Institute, Sun City, Arizona, USA.
³² Department of Pathology, University McGill, Montreal, Quebec, Canada.
³³ Department of Neuroscience, University of California San Diego, La Jolla, California, USA.
³⁴ VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
³⁵ Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida, USA.
³⁶ Memory and Aging Center, University of California San Francisco, San Francisco, California, USA.
³⁷ Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
³⁸ University of Texas Southwestern Medical Center, Dallas, Texas, USA.
³⁹ Departmento of Clinical and Movement Neuroscience, University College of London, London, United Kingdom.
⁴⁰ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, United Kingdom.
⁴¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
⁴² Friedman Bioventure, Inc., Del Mar, California, USA.
⁴³ Parkinson'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.
⁴⁴ Fellow of the Royal Academy of Medicine of Catalonia, Barcelona, Spain.
⁴⁵ Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, USA.
⁴⁶ Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁴⁷ Department of Anatomy Physiology and Genetics, the American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
⁴⁸ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁴⁹ Department of Statistics, North Carolina State University, Raleigh, North Carolina, USA.
⁵⁰ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
⁵¹ Institute of Precision Health, University of California Los Angeles, Los Angeles, California, USA.

PMID: 40055946
PMCID: PMC12089919
DOI: 10.1002/mds.30150

Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells

Hui Wang et al. Mov Disord. 2025 May.

. 2025 May;40(5):950-961.

doi: 10.1002/mds.30150. Epub 2025 Mar 8.

Authors

Affiliations

¹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
² Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³ Movement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
⁴ Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA.
⁵ Department of Computer and Information Sciences, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, USA.
⁶ Department 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.
⁷ Victorian Brain Bank, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
⁸ Alzheimer'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.
⁹ Neurological Tissue Bank of the Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain.
¹⁰ Movement Disorders Program, Division of Neurology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
¹¹ Laboratory of Neurochemistry and Behavior, Experimental Neurobiology Unit, University of Antwerp, Antwerp, Belgium.
¹² Department of Neurology, University Medical Center Groningen, Groningen, The Netherlands.
¹³ Fujirebio Europe NV, Ghent, Belgium.
¹⁴ Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
¹⁵ Netherlands Brain Bank and Erasmus University, Rotterdam, The Netherlands.
¹⁶ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁷ London Neurodegenerative Diseases Brain Bank, King's College London, London, United Kingdom.
¹⁸ Autonomous University of Madrid, Madrid, Spain.
¹⁹ Fundación CIEN (Centro de Investigación de Enfermedades Neurológicas) - Centro Alzheimer Fundación Reina Sofía, Madrid, Spain.
²⁰ Department of Neurology, Philipps-Universität, Marburg, Germany.
²¹ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
²² Parkinson's Disease and Movement Disorders Department, HYGEIA Hospital, Athens, Greece.
²³ European University of Cyprus, Nicosia, Cyprus.
²⁴ Department of Psychiatry and Psychotherapy, University Hospital Munich, Ludwig-Maximilians-University Munich, Munich, Germany.
²⁵ Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
²⁶ Institute of Human Genetics, Justus-Liebig University Giessen, Giessen, Germany.
²⁷ Department of Neurology, LMU University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
²⁸ Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Barcelona, Spain.
²⁹ Neurosciences, The Germans Trias i Pujol Research Institute, Barcelona, Spain.
³⁰ Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France.
³¹ Banner Sun Health Research Institute, Sun City, Arizona, USA.
³² Department of Pathology, University McGill, Montreal, Quebec, Canada.
³³ Department of Neuroscience, University of California San Diego, La Jolla, California, USA.
³⁴ VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
³⁵ Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida, USA.
³⁶ Memory and Aging Center, University of California San Francisco, San Francisco, California, USA.
³⁷ Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
³⁸ University of Texas Southwestern Medical Center, Dallas, Texas, USA.
³⁹ Departmento of Clinical and Movement Neuroscience, University College of London, London, United Kingdom.
⁴⁰ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, United Kingdom.
⁴¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.
⁴² Friedman Bioventure, Inc., Del Mar, California, USA.
⁴³ Parkinson'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.
⁴⁴ Fellow of the Royal Academy of Medicine of Catalonia, Barcelona, Spain.
⁴⁵ Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, USA.
⁴⁶ Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁴⁷ Department of Anatomy Physiology and Genetics, the American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
⁴⁸ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁴⁹ Department of Statistics, North Carolina State University, Raleigh, North Carolina, USA.
⁵⁰ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
⁵¹ Institute of Precision Health, University of California Los Angeles, Los Angeles, California, USA.

PMID: 40055946
PMCID: PMC12089919
DOI: 10.1002/mds.30150

Abstract

Background: The 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).

Objective: To investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP.

Methods: Utilizing 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.

Results: We 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.

Conclusions: The 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.

Keywords: 17q21.31; H1 and H2 haplotypes; copy number variations; progressive supranuclear palsy; single‐cell gene expression.

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Figures

**FIG. 1**
The association between the copy number of γ and MAPT sub‐haplotypes. The number of haplotypes (2 × the number of individuals) are showed on each bar. The percentage of H1c is showed in brackets. The MAPT sub‐haplotypes on H1 that were associated with the risk of progressive supranuclear palsy or have an allele frequency >0.05 were color coded. All the other MAPT sub‐haplotypes were included in the ‘Other’ category. The color information: H1c (#45526C), H1b (#2B8CBE), H1d (#4EB3D3), H1e (#5AB4AC), H1g (#C7EAE5), H1h (#DFC27D), H1o (#8C510A), and Other (#D6DCE5). [Color figure can be viewed at wileyonlinelibrary.com]

**FIG. 2**
The association between the copy number of γ and gene expression. (A) Schematic plot of gene locations at 17q.21.31. (B) Gene expression values for three genes on the γ duplication. Total RNA was isolated from the cerebellum of 191 samples. (C) Gene expression values for three genes on the γ duplication. Total RNA was isolated from the temporal cortex of 189 samples. (**D–E**) *LRRC37A*/*LRRC37A2* pseudobulk expression for different cell types in dorsolateral prefrontal cortex stratified by the number of γ duplication. Pseudobulk counts were log‐normalized using AggregateExpression function from Seurat. CPM, counts per million. [Color figure can be viewed at wileyonlinelibrary.com]

See this image and copyright information in PMC

References

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Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells

Collaborators

Affiliations

Copy Number Variation and Haplotype Analysis of 17q21.31 Reveals Increased Risk Associated with Progressive Supranuclear Palsy and Gene Expression Changes in Neuronal Cells

Authors

Collaborators

Affiliations

Abstract

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References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

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