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[Preprint]. 2024 Jan 30:2023.12.28.23300612.

doi: 10.1101/2023.12.28.23300612.

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy

Hui Wang^{1

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

2}, Po-Liang Cheng^{1

2}, Vishakha Patil³, Leopoldo Valiente-Banuet³, Kurt Farrell⁴, Catriona Mclean⁵, Laura Molina-Porcel^{6

7}, Alex Rajput⁸, Peter Paul De Deyn^{9

10}, Nathalie Le Bastard¹¹, Marla Gearing¹², Laura Donker Kaat¹³, John C Van Swieten¹³, Elise Dopper¹³, Bernardino F Ghetti¹⁴, Kathy L Newell¹⁴, Claire Troakes¹⁵, Justo G de Yébenes¹⁶, Alberto Rábano-Gutierrez¹⁷, Tina Meller¹⁸, Wolfgang H Oertel¹⁸, Gesine Respondek¹⁹, Maria Stamelou^{20

21}, Thomas Arzberger^{22

23}, Sigrun Roeber²⁴, Ulrich Müller²⁴, Franziska Hopfner²⁵, Pau Pastor^{26

27}, Alexis Brice²⁸, Alexandra Durr²⁸, Isabelle Le Ber²⁸, Thomas G Beach²⁹, Geidy E Serrano²⁹, Lili-Naz Hazrati³⁰, Irene Litvan³¹, Rosa Rademakers^{32

33}, Owen A Ross³³, Douglas Galasko³¹, Adam L Boxer³⁴, Bruce L Miller³⁴, Willian W Seeley³⁴, Vivanna M Van Deerlin¹, Edward B Lee^{1

35}, Charles L White 3rd³⁶, Huw Morris³⁷, Rohan de Silva³⁸, John F Crary⁴, Alison M Goate³⁹, Jeffrey S Friedman⁴⁰, Yuk Yee Leung^{1

2}, Giovanni Coppola^{3

41}, Adam C Naj^{1

2

25}, Li-San Wang^{1

2}; PSP genetics study group; Dennis W Dickson³³, Günter U Höglinger⁴², Gerard D Schellenberg^{1

2}, Daniel H Geschwind^{3

43

44}, Wan-Ping Lee^{1

2}

Affiliations

¹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Movement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ 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 & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Victorian Brain Bank, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
⁶ 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.
⁷ Neurological Tissue Bank of the Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain.
⁸ Movement Disorders Program, Division of Neurology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
⁹ Laboratory of Neurochemistry and Behavior, Experimental Neurobiology Unit, University of Antwerp, Wilrijk (Antwerp), Belgium.
¹⁰ Department of Neurology, University Medical Center Groningen, NL-9713 AV Groningen, Netherlands.
¹¹ Fujirebio Europe NV, Technologiepark 6, 9052 Gent, Belgium.
¹² Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
¹³ Netherlands Brain Bank and Erasmus University, Netherlands.
¹⁴ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁵ London Neurodegenerative Diseases Brain Bank, King's College London, London, UK.
¹⁶ Autonomous University of Madrid, Madrid, Spain.
¹⁷ Fundación CIEN (Centro de Investigación de Enfermedades Neurológicas) - Centro Alzheimer Fundación Reina Sofía, Madrid, Spain.
¹⁸ Department of Neurology, Philipps-Universität, Marburg, Germany.
¹⁹ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
²⁰ Parkinson's disease and Movement Disorders Department, HYGEIA Hospital, Athens, Greece.
²¹ European University of Cyprus, Nicosia, Cyprus.
²² Department of Psychiatry and Psychotherapy, University Hospital Munich, Ludwig-Maximilians-University Munich, Germany.
²³ Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Germany.
²⁴ German Brain Bank, Neurobiobank Munich, Germany.
²⁵ Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁶ Unit of Neurodegenerative diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
²⁷ Neurosciences, The Germans Trias i Pujol Research Institute (IGTP) Badalona, Badalona, Spain.
²⁸ Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France.
²⁹ Banner Sun Health Research Institute, Sun City, AZ, USA.
³⁰ University McGill, Montreal, Quebec, Canada.
³¹ Department of Neuroscience, University of California, San Diego, CA, USA.
³² VIB Center for Molecular Neurology, University of Antwerp, Belgium.
³³ Department of Neuroscience, Mayo Clinic Jacksonville, FL, USA.
³⁴ Memory and Aging Center, University of California, San Francisco, CA, USA.
³⁵ Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
³⁶ University of Texas Southwestern Medical Center, Dallas, TX, USA.
³⁷ Departmento of Clinical and Movement Neuroscience, University College of London, London, UK.
³⁸ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.
³⁹ Department of Genetics and Genomic Sciences, New York, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴⁰ Friedman Bioventure, Inc., Del Mar, CA, USA; Department of Genetics and Genomic Sciences, New York, NY, USA.
⁴¹ Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
⁴² Department 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.
⁴³ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁴⁴ Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA, USA.

PMID: 38234807
PMCID: PMC10793533
DOI: 10.1101/2023.12.28.23300612

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy

Hui Wang et al. medRxiv. 2024.

[Preprint]. 2024 Jan 30:2023.12.28.23300612.

doi: 10.1101/2023.12.28.23300612.

Authors

Affiliations

¹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
² Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Movement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ 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 & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Victorian Brain Bank, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
⁶ 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.
⁷ Neurological Tissue Bank of the Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain.
⁸ Movement Disorders Program, Division of Neurology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
⁹ Laboratory of Neurochemistry and Behavior, Experimental Neurobiology Unit, University of Antwerp, Wilrijk (Antwerp), Belgium.
¹⁰ Department of Neurology, University Medical Center Groningen, NL-9713 AV Groningen, Netherlands.
¹¹ Fujirebio Europe NV, Technologiepark 6, 9052 Gent, Belgium.
¹² Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
¹³ Netherlands Brain Bank and Erasmus University, Netherlands.
¹⁴ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁵ London Neurodegenerative Diseases Brain Bank, King's College London, London, UK.
¹⁶ Autonomous University of Madrid, Madrid, Spain.
¹⁷ Fundación CIEN (Centro de Investigación de Enfermedades Neurológicas) - Centro Alzheimer Fundación Reina Sofía, Madrid, Spain.
¹⁸ Department of Neurology, Philipps-Universität, Marburg, Germany.
¹⁹ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
²⁰ Parkinson's disease and Movement Disorders Department, HYGEIA Hospital, Athens, Greece.
²¹ European University of Cyprus, Nicosia, Cyprus.
²² Department of Psychiatry and Psychotherapy, University Hospital Munich, Ludwig-Maximilians-University Munich, Germany.
²³ Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Germany.
²⁴ German Brain Bank, Neurobiobank Munich, Germany.
²⁵ Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁶ Unit of Neurodegenerative diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
²⁷ Neurosciences, The Germans Trias i Pujol Research Institute (IGTP) Badalona, Badalona, Spain.
²⁸ Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France.
²⁹ Banner Sun Health Research Institute, Sun City, AZ, USA.
³⁰ University McGill, Montreal, Quebec, Canada.
³¹ Department of Neuroscience, University of California, San Diego, CA, USA.
³² VIB Center for Molecular Neurology, University of Antwerp, Belgium.
³³ Department of Neuroscience, Mayo Clinic Jacksonville, FL, USA.
³⁴ Memory and Aging Center, University of California, San Francisco, CA, USA.
³⁵ Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
³⁶ University of Texas Southwestern Medical Center, Dallas, TX, USA.
³⁷ Departmento of Clinical and Movement Neuroscience, University College of London, London, UK.
³⁸ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.
³⁹ Department of Genetics and Genomic Sciences, New York, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴⁰ Friedman Bioventure, Inc., Del Mar, CA, USA; Department of Genetics and Genomic Sciences, New York, NY, USA.
⁴¹ Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
⁴² Department 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.
⁴³ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁴⁴ Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA, USA.

PMID: 38234807
PMCID: PMC10793533
DOI: 10.1101/2023.12.28.23300612

Update in

Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy.
Wang H, Chang TS, Dombroski BA, Cheng PL, Patil V, Valiente-Banuet L, Farrell K, Mclean C, Molina-Porcel L, Rajput A, De Deyn PP, Le Bastard N, Gearing M, Kaat LD, Van Swieten JC, Dopper E, Ghetti BF, Newell KL, Troakes C, de Yébenes JG, Rábano-Gutierrez A, Meller T, Oertel WH, Respondek G, Stamelou M, Arzberger T, Roeber S, Müller U, Hopfner F, Pastor P, Brice A, Durr A, Le Ber I, Beach TG, Serrano GE, Hazrati LN, Litvan I, Rademakers R, Ross OA, Galasko D, Boxer AL, Miller BL, Seeley WW, Van Deerlin VM, Lee EB, White CL 3rd, Morris H, de Silva R, Crary JF, Goate AM, Friedman JS, Leung YY, Coppola G, Naj AC, Wang LS; P. S. P. genetics study group; Dalgard C, Dickson DW, Höglinger GU, Schellenberg GD, Geschwind DH, Lee WP. Wang H, et al. Mol Neurodegener. 2024 Aug 16;19(1):61. doi: 10.1186/s13024-024-00747-3. Mol Neurodegener. 2024. PMID: 39152475 Free PMC article.

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 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^-3) in PSP.

Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Keywords: Apolipoprotein E (APOE); Genome-Wide Association Study (GWAS); Progressive Supranuclear Palsy (PSP); Structural Variants (SVs); Whole-Genome Sequencing (WGS).

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Conflict of interest statement

Competing interests Laura Molina-Porcel received income from Biogen as a consultant in 2022. Gesine Respondek is now employed by Roche (Hoffmann-La Roche, Basel, Switzerland) since 2021. Her affiliation whilst completing her contribution to this manuscript was German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. Thomas G Beach is a consultant for Aprinoia Therapeutics and a Scientific Advisor and stock option holder for Vivid Genomics. Huw Morris is employed by UCL. In the last 12 months he reports paid consultancy from Roche, Aprinoia, AI Therapeutics and Amylyx; lecture fees/honoraria - BMJ, Kyowa Kirin, Movement Disorders Society. Huw Morris is a co-applicant on a patent application related to C9ORF72 - Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). Giovanni Coppola is currently an employee of Regeneron Pharmaceuticals. Alison Goate serves on the SAB for Genentech and Muna Therapeutics.

Figures

**Fig. 1:. Manhattan plot of SNVs/indels for PSP.**
Loci with a suggestive or genome-wide significant signal are annotated (novel loci in red and known loci in black). Variants with a P- value below 1 × 10⁻¹⁴ are not shown. The red horizontal line represents genome-wide significance level (5 × 10⁻⁸). The blue horizontal line represents suggestive significance level (1 × 10⁻⁶).

**Fig. 2:. Association analysis of rare SNVs/indels.**
A. Manhattan plot for genes with protein truncating variants or damaging missense variants. B. Q-Q plot of gene P-values with protein truncating variants or damaging missense variants.

See this image and copyright information in PMC

References

1. Hauw JJ, Daniel SE, Dickson D, Horoupian DS, Jellinger K, Lantos PL, et al. Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology. 1994;44(11):2015–2015. - PubMed
1. Stamelou M, Respondek G, Giagkou N, Whitwell JL, Kovacs GG, Höglinger GU. Evolving concepts in progressive supranuclear palsy and other 4-repeat tauopathies. Nat Rev Neurol. 2021. Oct;17(10):601–20. - PubMed
1. Hoglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, et al. Clinical Diagnosis of Progressive Supranuclear Palsy: The Movement Disorder Society Criteria. Mov Disord Off J Mov Disord Soc. 2017. Jun;32(6):853–64. - PMC - PubMed
1. Lukic MJ, Respondek G, Kurz C, Compta Y, Gelpi E, Ferguson LW, et al. Long-Duration Progressive Supranuclear Palsy: Clinical Course and Pathological Underpinnings. Ann Neurol. 2022;92(4):637–49. - PubMed
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This is a preprint.

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy

Affiliations

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy

Authors

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Abstract

Conflict of interest statement

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