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

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. Murray, Júlia Faura, Stephen J. Haggarty, Jeroen GJ. Rooij, Merel O. Mol, Ging-Yuek R. Hsiung, Caroline Graff, Linn Öijerstedt, Manuela Neumann, Yan Asmann, Shannon K. McDonnell, Saurabh Baheti, Keith A. Josephs, Jennifer L. Whitwell, Kevin F. Bieniek, Leah Forsberg, Hilary Heuer, Argentina Lario Lago, Ethan G. Geier, Jennifer S. Yokoyama, Alexis P. Oddi, Margaret Flanagan, Qinwen Mao, John R. Hodges, John B. Kwok, Kimiko Domoto-Reilly, Matthis Synofzik, Carlo Wilke, Chiadi Onyike, Bradford C. Dickerson, Bret M. Evers, Brittany N. Dugger, David G. Munoz, Julia Keith, Lorne Zinman, Ekaterina Rogaeva, EunRan Suh, Tamar Gefen, Changiz Geula, Sandra Weintraub, Janine Diehl-Schmid, Martin R. Farlow, Dieter Edbauer, Bryan K. Woodruff, Richard J. Caselli, Laura L. Donker Kaat, Edward D. Huey, Eric M. Reiman, Simon Mead, Andrew King, Sigrun Roeber, Alissa L. Nana, Nilufer Ertekin-Taner, David S. Knopman, Ronald C. Petersen, Leonard Petrucelli, Ryan J. Uitti, Zbigniew K. Wszolek, Eliana Marisa Ramos, Lea T. Grinberg, Maria Luisa Gorno Tempini, Howard J. Rosen, Salvatore Spina, Olivier Piguet, Murray Grossman, John Q. Trojanowski, C. Dirk Keene, Lee-Way Jin, Johannes Prudlo, Daniel H. Geschwind, Robert A. Rissman, Carlos Cruchaga, Bernardino Ghetti, Glenda M. Halliday, Thomas G. Beach, Geidy E. Serrano, Thomas Arzberger, Jochen Herms, Adam L. Boxer, Lawrence S. Honig, Jean P. Vonsattel, Oscar L. Lopez, Julia Kofler, Charles L. White, Marla Gearing, Jonathan Glass, Jonathan D. Rohrer, David J. Irwin, Edward B. Lee, Vivianna Deerlin, Rudolph Castellani, Marsel M. Mesulam, Maria C. Tartaglia, Elizabeth C. Finger, Claire Troakes, Safa Al-Sarraj, Clifton L. Dalgard, Bruce L. Miller, Harro Seelaar, Neill R. Graff-Radford, Bradley F. Boeve, Ian RA. Mackenzie, John C. Swieten, William W. Seeley, Kristel Sleegers, Dennis W. Dickson, Joanna M. Biernacka and Rosa Rademakers ()
Additional contact information
Cyril Pottier: Mayo Clinic
Fahri Küçükali: University of Antwerp
Matt Baker: Mayo Clinic
Anthony Batzler: Mayo Clinic
Gregory D. Jenkins: Mayo Clinic
Marka Blitterswijk: Mayo Clinic
Cristina T. Vicente: University of Antwerp
Wouter Coster: University of Antwerp
Sarah Wynants: University of Antwerp
Pieter Walle: University of Antwerp
Owen A. Ross: Mayo Clinic
Melissa E. Murray: Mayo Clinic
Júlia Faura: University of Antwerp
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
Linn Öijerstedt: Karolinska Institutet
Manuela Neumann: German Center for Neurodegenerative Diseases (DZNE)
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
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
Kimiko Domoto-Reilly: University of Washington
Matthis Synofzik: German Center for Neurodegenerative Diseases (DZNE)
Carlo Wilke: German Center for Neurodegenerative Diseases (DZNE)
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
Julia Keith: University of Toronto
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
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
Sigrun Roeber: Ludwig-Maximilians-University of Munich
Alissa L. Nana: University of California
Nilufer Ertekin-Taner: 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)
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
Jochen Herms: German Center for Neurodegenerative Diseases (DZNE)
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
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
Dennis W. Dickson: Mayo Clinic
Joanna M. Biernacka: Mayo Clinic
Rosa Rademakers: Mayo Clinic

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59216-0

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