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[Preprint]. 2024 Feb 28:2024.02.26.24303379.

doi: 10.1101/2024.02.26.24303379.

Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub-haplotypes

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, Kurt Farrell⁵, Catriona Mclean⁶, Laura Molina-Porcel^{7

8}, Rajput Alex⁹, Peter Paul De Deyn^{10

11}, Nathalie Le Bastard¹², Marla Gearing¹³, Laura Donker Kaat¹⁴, John C Van Swieten¹⁴, Elise Dopper¹⁴, Bernardino F Ghetti¹⁵, Kathy L Newell¹⁵, Claire Troakes¹⁶, Justo G de Yébenes¹⁷, Alberto Rábano-Gutierrez¹⁸, Tina Meller¹⁹, Wolfgang H Oertel¹⁹, Gesine Respondek²⁰, Maria Stamelou^{21

22}, Thomas Arzberger^{23

24}, Sigrun Roeber²⁵, Ulrich Müller²⁵, Franziska Hopfner²⁶, Pau Pastor^{27

28}, Alexis Brice²⁹, Alexandra Durr²⁹, Isabelle Le Ber²⁹, Thomas G Beach³⁰, Geidy E Serrano³⁰, Lili-Naz Hazrati³¹, Irene Litvan³², Rosa Rademakers^{33

34}, Owen A Ross³⁴, Douglas Galasko³², Adam L Boxer³⁵, Bruce L Miller³⁵, Willian W Seeley³⁵, Vivianna M Van Deerlin¹, Edward B Lee^{1

36}, Charles L White 3rd³⁷, Huw R Morris³⁸, Rohan de Silva³⁹, John F Crary⁵, Alison M Goate⁴⁰, Jeffrey S Friedman⁴¹, Yuk Yee Leung^{1

2}, Giovanni Coppola^{3

42}, Adam C Naj^{1

2

43}, Li-San Wang^{1

2}; PSP genetics study group; Dennis W Dickson³⁴, Günter U Höglinger²⁶, Jung-Ying Tzeng^{4

44}, Daniel H Geschwind^{3

45

46}, Gerard D Schellenberg^{1

2}, 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 Bioinformatics Research Center, North Carolina State University, NC, USA.
⁵ 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.
⁶ Victorian Brain Bank, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
⁷ 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.
⁸ Neurological Tissue Bank of the Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain.
⁹ Movement Disorders Program, Division of Neurology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
¹⁰ Laboratory of Neurochemistry and Behavior, Experimental Neurobiology Unit, University of Antwerp, Wilrijk (Antwerp), Belgium.
¹¹ Department of Neurology, University Medical Center Groningen, NL-9713 AV Groningen, Netherlands.
¹² Fujirebio Europe NV, Technologiepark 6, 9052 Gent, Belgium.
¹³ Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
¹⁴ Netherlands Brain Bank and Erasmus University, Netherlands.
¹⁵ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁶ London Neurodegenerative Diseases Brain Bank, King's College London, London, UK.
¹⁷ Autonomous University of Madrid, Madrid, Spain.
¹⁸ Fundación CIEN (Centro de Investigación de Enfermedades Neurológicas) - Centro Alzheimer Fundación Reina Sofía, Madrid, Spain.
¹⁹ Department of Neurology, Philipps-Universität, Marburg, Germany.
²⁰ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
²¹ Parkinson's disease and Movement Disorders Department, HYGEIA Hospital, Athens, Greece.
²² European University of Cyprus, Nicosia, Cyprus.
²³ Department of Psychiatry and Psychotherapy, University Hospital Munich, Ludwig-Maximilians-University Munich, Germany.
²⁴ Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Germany.
²⁵ German Brain Bank, Neurobiobank Munich, Germany.
²⁶ 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.
²⁷ Unit of Neurodegenerative diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
²⁸ Neurosciences, The Germans Trias i Pujol Research Institute (IGTP) Badalona, Badalona, Spain.
²⁹ Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France.
³⁰ Banner Sun Health Research Institute, Sun City, AZ, USA.
³¹ University McGill, Montreal, Quebec, Canada.
³² Department of Neuroscience, University of California, San Diego, CA, USA.
³³ VIB Center for Molecular Neurology, University of Antwerp, Belgium.
³⁴ Department of Neuroscience, Mayo Clinic Jacksonville, FL, USA.
³⁵ Memory and Aging Center, University of California, San Francisco, CA, USA.
³⁶ Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
³⁷ University of Texas Southwestern Medical Center, Dallas, TX, USA.
³⁸ Departmento of Clinical and Movement Neuroscience, University College of London, London, UK.
³⁹ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.
⁴⁰ Department of Genetics and Genomic Sciences, New York, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴¹ Friedman Bioventure, Inc., Del Mar, CA, USA: Department of Genetics and Genomic Sciences, New York, NY, USA.
⁴² Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
⁴³ Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴⁴ Department of Statistics, North Carolina State University, NC, USA.
⁴⁵ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁴⁶ Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA, USA.

PMID: 38464214
PMCID: PMC10925353
DOI: 10.1101/2024.02.26.24303379

Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub-haplotypes

Hui Wang et al. medRxiv. 2024.

[Preprint]. 2024 Feb 28:2024.02.26.24303379.

doi: 10.1101/2024.02.26.24303379.

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 Bioinformatics Research Center, North Carolina State University, NC, USA.
⁵ 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.
⁶ Victorian Brain Bank, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
⁷ 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.
⁸ Neurological Tissue Bank of the Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain.
⁹ Movement Disorders Program, Division of Neurology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
¹⁰ Laboratory of Neurochemistry and Behavior, Experimental Neurobiology Unit, University of Antwerp, Wilrijk (Antwerp), Belgium.
¹¹ Department of Neurology, University Medical Center Groningen, NL-9713 AV Groningen, Netherlands.
¹² Fujirebio Europe NV, Technologiepark 6, 9052 Gent, Belgium.
¹³ Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
¹⁴ Netherlands Brain Bank and Erasmus University, Netherlands.
¹⁵ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁶ London Neurodegenerative Diseases Brain Bank, King's College London, London, UK.
¹⁷ Autonomous University of Madrid, Madrid, Spain.
¹⁸ Fundación CIEN (Centro de Investigación de Enfermedades Neurológicas) - Centro Alzheimer Fundación Reina Sofía, Madrid, Spain.
¹⁹ Department of Neurology, Philipps-Universität, Marburg, Germany.
²⁰ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
²¹ Parkinson's disease and Movement Disorders Department, HYGEIA Hospital, Athens, Greece.
²² European University of Cyprus, Nicosia, Cyprus.
²³ Department of Psychiatry and Psychotherapy, University Hospital Munich, Ludwig-Maximilians-University Munich, Germany.
²⁴ Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Germany.
²⁵ German Brain Bank, Neurobiobank Munich, Germany.
²⁶ 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.
²⁷ Unit of Neurodegenerative diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
²⁸ Neurosciences, The Germans Trias i Pujol Research Institute (IGTP) Badalona, Badalona, Spain.
²⁹ Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France.
³⁰ Banner Sun Health Research Institute, Sun City, AZ, USA.
³¹ University McGill, Montreal, Quebec, Canada.
³² Department of Neuroscience, University of California, San Diego, CA, USA.
³³ VIB Center for Molecular Neurology, University of Antwerp, Belgium.
³⁴ Department of Neuroscience, Mayo Clinic Jacksonville, FL, USA.
³⁵ Memory and Aging Center, University of California, San Francisco, CA, USA.
³⁶ Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
³⁷ University of Texas Southwestern Medical Center, Dallas, TX, USA.
³⁸ Departmento of Clinical and Movement Neuroscience, University College of London, London, UK.
³⁹ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.
⁴⁰ Department of Genetics and Genomic Sciences, New York, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴¹ Friedman Bioventure, Inc., Del Mar, CA, USA: Department of Genetics and Genomic Sciences, New York, NY, USA.
⁴² Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
⁴³ Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴⁴ Department of Statistics, North Carolina State University, NC, USA.
⁴⁵ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁴⁶ Institute of Precision Health, University of California, Los Angeles, Los Angeles, CA, USA.

PMID: 38464214
PMCID: PMC10925353
DOI: 10.1101/2024.02.26.24303379

Abstract

Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, β, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study.

Objective: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, β, and γ duplications, with the risk of PSP and MAPT sub-haplotypes.

Design setting and participants: Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, β, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023.

Main outcomes and measures: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models.

Results: The copy numbers of α and β were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10^-5) for H1β1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10^-6) for H1β1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10^-8) for H1β1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10^-2) for H1β1γ4. Moreover, H1β1γ3 is in linkage disequilibrium with H1c (R² = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1β1γ1 to 77% in H1β1γ4.

Conclusions and relevance: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.

Keywords: 17q21.31; Copy number variation (CNV); H1 and H2 haplotypes; MAPT; Progressive Supranuclear Palsy (PSP).

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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:. Structural forms of 17q21.31 and *MAPT* sub-haplotypes**
Structural forms of 17q.21.31 in less than 1% of individuals were excluded. Structural forms with H2 background are also excluded since there is only one *MAPT* sub-haplotypes for H2. The number above each bar is the total number of *haplotypes* for the specific structural form of 17q21.31 and the percentage that are also *MAPT* sub-haplotypes (H1o, H1c, H1d, H1g, H1h) associated with increased risk of PSP. Besides, the percentage of H1β1γ3 that is H1c and the percentage of of H1β2γ1 that is H1b are displayed. A. In phased haplotypes from all samples, the proportion of *MAPT* sub-haplotypes in each structural form of 17q21.31. B. In H1H2 individuals, the proportion of *MAPT* sub-haplotypes in each structural form of 17q21.31.

See this image and copyright information in PMC

References

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This is a preprint.

Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub-haplotypes

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Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub-haplotypes

Authors

Affiliations

Abstract

Conflict of interest statement

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