Molecular Neurodegeneration (Aug 2024)
Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy
- Hui Wang,
- Timothy S. Chang,
- Beth A. Dombroski,
- Po-Liang Cheng,
- Vishakha Patil,
- Leopoldo Valiente-Banuet,
- Kurt Farrell,
- Catriona Mclean,
- Laura Molina-Porcel,
- Alex Rajput,
- Peter Paul De Deyn,
- Nathalie Le Bastard,
- Marla Gearing,
- Laura Donker Kaat,
- John C. Van Swieten,
- Elise Dopper,
- Bernardino F. Ghetti,
- Kathy L. Newell,
- Claire Troakes,
- Justo G. de Yébenes,
- Alberto Rábano-Gutierrez,
- Tina Meller,
- Wolfgang H. Oertel,
- Gesine Respondek,
- Maria Stamelou,
- Thomas Arzberger,
- Sigrun Roeber,
- Ulrich Müller,
- Franziska Hopfner,
- Pau Pastor,
- Alexis Brice,
- Alexandra Durr,
- Isabelle Le Ber,
- Thomas G. Beach,
- Geidy E. Serrano,
- Lili-Naz Hazrati,
- Irene Litvan,
- Rosa Rademakers,
- Owen A. Ross,
- Douglas Galasko,
- Adam L. Boxer,
- Bruce L. Miller,
- Willian W. Seeley,
- Vivanna M. Van Deerlin,
- Edward B. Lee,
- Charles L. White,
- Huw Morris,
- Rohan de Silva,
- John F. Crary,
- Alison M. Goate,
- Jeffrey S. Friedman,
- Yuk Yee Leung,
- Giovanni Coppola,
- Adam C. Naj,
- Li-San Wang,
- P. S. P. genetics study group,
- Clifton Dalgard,
- Dennis W. Dickson,
- Günter U. Höglinger,
- Gerard D. Schellenberg,
- Daniel H. Geschwind,
- Wan-Ping Lee
Affiliations
- Hui Wang
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania
- Timothy S. Chang
- Movement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles
- Beth A. Dombroski
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania
- Po-Liang Cheng
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania
- Vishakha Patil
- Movement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles
- Leopoldo Valiente-Banuet
- Movement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles
- Kurt Farrell
- 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
- Catriona Mclean
- Victorian Brain Bank, The Florey Institute of Neuroscience and Mental Health
- Laura Molina-Porcel
- 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
- Alex Rajput
- Movement Disorders Program, Division of Neurology, University of Saskatchewan
- Peter Paul De Deyn
- Laboratory of Neurochemistry and Behavior, Experimental Neurobiology Unit, University of Antwerp
- Nathalie Le Bastard
- Fujirebio Europe NV
- Marla Gearing
- Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University School of Medicine
- Laura Donker Kaat
- Netherlands Brain Bank and Erasmus University
- John C. Van Swieten
- Netherlands Brain Bank and Erasmus University
- Elise Dopper
- Netherlands Brain Bank and Erasmus University
- Bernardino F. Ghetti
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine
- Kathy L. Newell
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine
- Claire Troakes
- London Neurodegenerative Diseases Brain Bank, King’s College London
- Justo G. de Yébenes
- Autonomous University of Madrid
- Alberto Rábano-Gutierrez
- Fundación CIEN (Centro de Investigación de Enfermedades Neurológicas) - Centro Alzheimer Fundación Reina Sofía
- Tina Meller
- Department of Neurology, Philipps-Universität
- Wolfgang H. Oertel
- Department of Neurology, Philipps-Universität
- Gesine Respondek
- German Center for Neurodegenerative Diseases (DZNE)
- Maria Stamelou
- Parkinson’s Disease and Movement Disorders Department, HYGEIA Hospital
- Thomas Arzberger
- Department of Psychiatry and Psychotherapy, University Hospital Munich, Ludwig-Maximilians-University Munich
- Sigrun Roeber
- German Brain Bank, Neurobiobank Munich
- Ulrich Müller
- German Brain Bank, Neurobiobank Munich
- Franziska Hopfner
- 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)
- Pau Pastor
- Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias I Pujol, Badalona
- Alexis Brice
- Sorbonne Université, Paris Brain Institute – Institut du Cerveau – ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière
- Alexandra Durr
- Sorbonne Université, Paris Brain Institute – Institut du Cerveau – ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière
- Isabelle Le Ber
- Sorbonne Université, Paris Brain Institute – Institut du Cerveau – ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière
- Thomas G. Beach
- Banner Sun Health Research Institute
- Geidy E. Serrano
- Banner Sun Health Research Institute
- Lili-Naz Hazrati
- University McGill
- Irene Litvan
- Department of Neuroscience, University of California
- Rosa Rademakers
- VIB Center for Molecular Neurology, University of Antwerp
- Owen A. Ross
- Department of Neuroscience, Mayo Clinic Jacksonville
- Douglas Galasko
- Department of Neuroscience, University of California
- Adam L. Boxer
- Memory and Aging Center, University of California
- Bruce L. Miller
- Memory and Aging Center, University of California
- Willian W. Seeley
- Memory and Aging Center, University of California
- Vivanna M. Van Deerlin
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania
- Edward B. Lee
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania
- Charles L. White
- University of Texas Southwestern Medical Center
- Huw Morris
- Departmento of Clinical and Movement Neuroscience, University College of London
- Rohan de Silva
- Reta Lila Weston Institute, UCL Queen Square Institute of Neurology
- John F. Crary
- 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
- Alison M. Goate
- Department of Genetics and Genomic Sciences, New York, NY, USA; Icahn School of Medicine at Mount Sinai
- Jeffrey S. Friedman
- Friedman Bioventure, Inc.
- Yuk Yee Leung
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania
- Giovanni Coppola
- Movement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles
- Adam C. Naj
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania
- Li-San Wang
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania
- P. S. P. genetics study group
- Clifton Dalgard
- Department of Anatomy Physiology and Genetics, the American Genome Center, Uniformed Services University of the Health Sciences
- Dennis W. Dickson
- Department of Neuroscience, Mayo Clinic Jacksonville
- Günter U. Höglinger
- 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)
- Gerard D. Schellenberg
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania
- Daniel H. Geschwind
- Movement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles
- Wan-Ping Lee
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania
- DOI
- https://doi.org/10.1186/s13024-024-00747-3
- Journal volume & issue
-
Vol. 19,
no. 1
pp. 1 – 16
Abstract
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
- Progressive Supranuclear Palsy (PSP)
- Whole-Genome Sequencing (WGS)
- Genome-Wide Association Study (GWAS)
- Structural Variants (SVs)
- Apolipoprotein E (APOE)
