IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-59216-0.html
   My bibliography  Save this article

Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing

Author

Listed:
  • Cyril Pottier

    (Mayo Clinic
    University of Antwerp
    VIB Center for Molecular Neurology, VIB
    Washington University School of Medicine)

  • Fahri Küçükali

    (University of Antwerp
    VIB Center for Molecular Neurology, VIB)

  • Matt Baker

    (Mayo Clinic)

  • Anthony Batzler

    (Mayo Clinic)

  • Gregory D. Jenkins

    (Mayo Clinic)

  • Marka Blitterswijk

    (Mayo Clinic)

  • Cristina T. Vicente

    (University of Antwerp
    VIB Center for Molecular Neurology, VIB)

  • Wouter Coster

    (University of Antwerp
    VIB Center for Molecular Neurology, VIB)

  • Sarah Wynants

    (University of Antwerp
    VIB Center for Molecular Neurology, VIB)

  • Pieter Walle

    (University of Antwerp
    VIB Center for Molecular Neurology, VIB)

  • Owen A. Ross

    (Mayo Clinic)

  • Melissa E. Murray

    (Mayo Clinic)

  • Júlia Faura

    (University of Antwerp
    VIB Center for Molecular Neurology, VIB)

  • Stephen J. Haggarty

    (Massachusetts General Hospital and Harvard Medical School)

  • Jeroen GJ. Rooij

    (Erasmus Medical Center)

  • Merel O. Mol

    (Erasmus Medical Center)

  • Ging-Yuek R. Hsiung

    (University of British Columbia)

  • Caroline Graff

    (Karolinska Institutet
    Karolinska University Hospital)

  • Linn Öijerstedt

    (Karolinska Institutet
    Karolinska University Hospital)

  • Manuela Neumann

    (German Center for Neurodegenerative Diseases (DZNE)
    University of Tübingen)

  • Yan Asmann

    (Mayo Clinic)

  • Shannon K. McDonnell

    (Mayo Clinic)

  • Saurabh Baheti

    (Mayo Clinic)

  • Keith A. Josephs

    (Mayo Clinic)

  • Jennifer L. Whitwell

    (Mayo Clinic)

  • Kevin F. Bieniek

    (Mayo Clinic
    University of Texas Health Science Center San Antonio)

  • Leah Forsberg

    (Mayo Clinic)

  • Hilary Heuer

    (University of California)

  • Argentina Lario Lago

    (University of California)

  • Ethan G. Geier

    (University of California)

  • Jennifer S. Yokoyama

    (University of California)

  • Alexis P. Oddi

    (University of California)

  • Margaret Flanagan

    (University of Texas Health Science Center San Antonio)

  • Qinwen Mao

    (University of Utah)

  • John R. Hodges

    (University of Sydney)

  • John B. Kwok

    (University of Sydney
    University of New South Wales)

  • Kimiko Domoto-Reilly

    (University of Washington)

  • Matthis Synofzik

    (German Center for Neurodegenerative Diseases (DZNE)
    University of Tübingen)

  • Carlo Wilke

    (German Center for Neurodegenerative Diseases (DZNE)
    University of Tübingen)

  • Chiadi Onyike

    (Johns Hopkins University)

  • Bradford C. Dickerson

    (Case Western Reserve University)

  • Bret M. Evers

    (University of Texas Southwestern Medical Center)

  • Brittany N. Dugger

    (University of California, Davis Medical Center)

  • David G. Munoz

    (St. Michael’s Hospital
    University of Toronto)

  • Julia Keith

    (University of Toronto
    Sunnybrook Health Sciences Centre)

  • Lorne Zinman

    (Sunnybrook Health Sciences Centre)

  • Ekaterina Rogaeva

    (University of Toronto)

  • EunRan Suh

    (Perelman School of Medicine at the University of Pennsylvania)

  • Tamar Gefen

    (Northwestern University)

  • Changiz Geula

    (Northwestern University)

  • Sandra Weintraub

    (Northwestern University)

  • Janine Diehl-Schmid

    (Technical University of Munich
    Geriatrics and Neurology)

  • Martin R. Farlow

    (Indiana University School of Medicine)

  • Dieter Edbauer

    (German Center for Neurodegenerative Diseases (DZNE))

  • Bryan K. Woodruff

    (Mayo Clinic)

  • Richard J. Caselli

    (Mayo Clinic)

  • Laura L. Donker Kaat

    (Erasmus Medical Center)

  • Edward D. Huey

    (Brown University)

  • Eric M. Reiman

    (Banner Alzheimer’s Institute)

  • Simon Mead

    (Institute of Prion Diseases)

  • Andrew King

    (King’s College London
    King’s College Hospital NHS Foundation Trust)

  • Sigrun Roeber

    (Ludwig-Maximilians-University of Munich)

  • Alissa L. Nana

    (University of California)

  • Nilufer Ertekin-Taner

    (Mayo Clinic
    Mayo Clinic)

  • David S. Knopman

    (Mayo Clinic)

  • Ronald C. Petersen

    (Mayo Clinic)

  • Leonard Petrucelli

    (Mayo Clinic)

  • Ryan J. Uitti

    (Mayo Clinic)

  • Zbigniew K. Wszolek

    (Mayo Clinic)

  • Eliana Marisa Ramos

    (University of California)

  • Lea T. Grinberg

    (University of California)

  • Maria Luisa Gorno Tempini

    (University of California)

  • Howard J. Rosen

    (University of California)

  • Salvatore Spina

    (University of California)

  • Olivier Piguet

    (University of Sydney)

  • Murray Grossman

    (Perelman School of Medicine at the University of Pennsylvania)

  • John Q. Trojanowski

    (Perelman School of Medicine at the University of Pennsylvania)

  • C. Dirk Keene

    (Harborview Medical Center)

  • Lee-Way Jin

    (University of California, Davis Medical Center)

  • Johannes Prudlo

    (German Center for Neurodegenerative Diseases (DZNE)
    Rostock University Medical Center)

  • Daniel H. Geschwind

    (University of California)

  • Robert A. Rissman

    (Keck School of Medicine of the University of Southern California)

  • Carlos Cruchaga

    (Washington University School of Medicine)

  • Bernardino Ghetti

    (Indiana University School of Medicine)

  • Glenda M. Halliday

    (University of Sydney)

  • Thomas G. Beach

    (Banner Sun Health Research Institute)

  • Geidy E. Serrano

    (Banner Sun Health Research Institute)

  • Thomas Arzberger

    (Ludwig-Maximilians-University of Munich
    University Hospital, Ludwig-Maximilians-University of Munich)

  • Jochen Herms

    (German Center for Neurodegenerative Diseases (DZNE)
    Ludwig-Maximilians-University of Munich)

  • Adam L. Boxer

    (University of California)

  • Lawrence S. Honig

    (Columbia University Irving Medical Center)

  • Jean P. Vonsattel

    (Columbia University Irving Medical Center)

  • Oscar L. Lopez

    (University of Pittsburgh)

  • Julia Kofler

    (University of Pittsburgh)

  • Charles L. White

    (University of Texas Southwestern Medical Center)

  • Marla Gearing

    (Emory University)

  • Jonathan Glass

    (Emory University)

  • Jonathan D. Rohrer

    (University College London, Queen Square Institute of Neurology)

  • David J. Irwin

    (Perelman School of Medicine at the University of Pennsylvania)

  • Edward B. Lee

    (Perelman School of Medicine at the University of Pennsylvania)

  • Vivianna Deerlin

    (Perelman School of Medicine at the University of Pennsylvania)

  • Rudolph Castellani

    (Northwestern University)

  • Marsel M. Mesulam

    (Northwestern University)

  • Maria C. Tartaglia

    (University of Toronto)

  • Elizabeth C. Finger

    (University of Western Ontario)

  • Claire Troakes

    (King’s College London)

  • Safa Al-Sarraj

    (King’s College London
    King’s College Hospital NHS Foundation Trust)

  • Clifton L. Dalgard

    (Uniformed Services University of the Health Sciences)

  • Bruce L. Miller

    (University of California)

  • Harro Seelaar

    (Erasmus Medical Center)

  • Neill R. Graff-Radford

    (Mayo Clinic)

  • Bradley F. Boeve

    (Mayo Clinic)

  • Ian RA. Mackenzie

    (University of British Columbia)

  • John C. Swieten

    (Erasmus Medical Center)

  • William W. Seeley

    (University of California)

  • Kristel Sleegers

    (University of Antwerp
    VIB Center for Molecular Neurology, VIB)

  • Dennis W. Dickson

    (Mayo Clinic)

  • Joanna M. Biernacka

    (Mayo Clinic
    Mayo Clinic)

  • Rosa Rademakers

    (Mayo Clinic
    University of Antwerp
    VIB Center for Molecular Neurology, VIB)

Abstract

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 patients and 3,153 controls compiled from 26 institutions/brain banks in North America, Europe and Australia, and meta-analysis with the Dementia-seq cohort. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyzes, we further identify genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified C3AR1, SMG8, VIPR1, RBPJL, L3MBTL1 and ANO9, as novel subtype-specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signaling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.

Suggested Citation

  • Cyril Pottier & Fahri Küçükali & Matt Baker & Anthony Batzler & Gregory D. Jenkins & Marka Blitterswijk & Cristina T. Vicente & Wouter Coster & Sarah Wynants & Pieter Walle & Owen A. Ross & Melissa E., 2025. "Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59216-0
    DOI: 10.1038/s41467-025-59216-0
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-59216-0
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-59216-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59216-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.