Nature Communications (Apr 2025)
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 van Blitterswijk,
- Cristina T. Vicente,
- Wouter De Coster,
- Sarah Wynants,
- Pieter Van de Walle,
- Owen A. Ross,
- Melissa E. Murray,
- Júlia Faura,
- Stephen J. Haggarty,
- Jeroen GJ. van 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 Van 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. van Swieten,
- William W. Seeley,
- Kristel Sleegers,
- Dennis W. Dickson,
- Joanna M. Biernacka,
- Rosa Rademakers
Affiliations
- Cyril Pottier
- Department of Neuroscience, Mayo Clinic
- Fahri Küçükali
- Department of Biomedical Sciences, University of Antwerp
- Matt Baker
- Department of Neuroscience, Mayo Clinic
- Anthony Batzler
- Department of Quantitative Health Sciences, Mayo Clinic
- Gregory D. Jenkins
- Department of Quantitative Health Sciences, Mayo Clinic
- Marka van Blitterswijk
- Department of Neuroscience, Mayo Clinic
- Cristina T. Vicente
- Department of Biomedical Sciences, University of Antwerp
- Wouter De Coster
- Department of Biomedical Sciences, University of Antwerp
- Sarah Wynants
- Department of Biomedical Sciences, University of Antwerp
- Pieter Van de Walle
- Department of Biomedical Sciences, University of Antwerp
- Owen A. Ross
- Department of Neuroscience, Mayo Clinic
- Melissa E. Murray
- Department of Neuroscience, Mayo Clinic
- Júlia Faura
- Department of Biomedical Sciences, University of Antwerp
- Stephen J. Haggarty
- Department of Neurology, Massachusetts General Hospital and Harvard Medical School
- Jeroen GJ. van Rooij
- Department of Neurology, Erasmus Medical Center
- Merel O. Mol
- Department of Neurology, Erasmus Medical Center
- Ging-Yuek R. Hsiung
- Department of Medicine, Division of Neurology, University of British Columbia
- Caroline Graff
- Division of Neurogeriatrics, Karolinska Institutet
- Linn Öijerstedt
- Division of Neurogeriatrics, Karolinska Institutet
- Manuela Neumann
- German Center for Neurodegenerative Diseases (DZNE)
- Yan Asmann
- Department of Health Sciences Research, Mayo Clinic
- Shannon K. McDonnell
- Department of Quantitative Health Sciences, Mayo Clinic
- Saurabh Baheti
- Department of Quantitative Health Sciences, Mayo Clinic
- Keith A. Josephs
- Department of Neurology, Mayo Clinic
- Jennifer L. Whitwell
- Department of Radiology, Mayo Clinic
- Kevin F. Bieniek
- Department of Neuroscience, Mayo Clinic
- Leah Forsberg
- Department of Neurology, Mayo Clinic
- Hilary Heuer
- Department of Neurology, UCSF Weill Institute for Neurosciences, University of California
- Argentina Lario Lago
- Department of Neurology, UCSF Weill Institute for Neurosciences, University of California
- Ethan G. Geier
- Department of Neurology, UCSF Weill Institute for Neurosciences, University of California
- Jennifer S. Yokoyama
- Department of Neurology, UCSF Weill Institute for Neurosciences, University of California
- Alexis P. Oddi
- Department of Neurology, UCSF Weill Institute for Neurosciences, University of California
- Margaret Flanagan
- University of Texas Health Science Center San Antonio
- Qinwen Mao
- Department of Pathology, University of Utah
- John R. Hodges
- Central Clinical School and Brain and Mind Centre, University of Sydney
- John B. Kwok
- University of Sydney
- Kimiko Domoto-Reilly
- Department of Neurology, University of Washington
- Matthis Synofzik
- German Center for Neurodegenerative Diseases (DZNE)
- Carlo Wilke
- German Center for Neurodegenerative Diseases (DZNE)
- Chiadi Onyike
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University
- Bradford C. Dickerson
- Department of Neurology, Case Western Reserve University
- Bret M. Evers
- Division of Neuropathology, University of Texas Southwestern Medical Center
- Brittany N. Dugger
- Department of Pathology and Laboratory Medicine, University of California, Davis Medical Center
- David G. Munoz
- St. Michael’s Hospital
- Julia Keith
- Department of Laboratory Medicine and Pathobiology, University of Toronto
- Lorne Zinman
- Sunnybrook Health Sciences Centre
- Ekaterina Rogaeva
- Krembil Discovery Tower, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto
- EunRan Suh
- Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania
- Tamar Gefen
- Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University
- Changiz Geula
- Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University
- Sandra Weintraub
- Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University
- Janine Diehl-Schmid
- Department of Psychiatry and Psychotherapy, Technical University of Munich
- Martin R. Farlow
- Department of Neurology, Indiana University School of Medicine
- Dieter Edbauer
- German Center for Neurodegenerative Diseases (DZNE)
- Bryan K. Woodruff
- Department of Neurology, Mayo Clinic
- Richard J. Caselli
- Department of Neurology, Mayo Clinic
- Laura L. Donker Kaat
- Department of Clinical Genetics, Erasmus Medical Center
- Edward D. Huey
- Department of Psychiatry and Human Behavior, Brown Alpert Medical School, Brown University
- Eric M. Reiman
- Banner Alzheimer’s Institute
- Simon Mead
- MRC Prion Unit at University College London, Institute of Prion Diseases
- Andrew King
- Department of Basic and Clinical Neuroscience, London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Sigrun Roeber
- Centre for Neuropathology and Prion Research, Ludwig-Maximilians-University of Munich
- Alissa L. Nana
- Department of Neurology, UCSF Weill Institute for Neurosciences, University of California
- Nilufer Ertekin-Taner
- Department of Neuroscience, Mayo Clinic
- David S. Knopman
- Department of Neurology, Mayo Clinic
- Ronald C. Petersen
- Department of Neurology, Mayo Clinic
- Leonard Petrucelli
- Department of Neuroscience, Mayo Clinic
- Ryan J. Uitti
- Department of Neurology, Mayo Clinic
- Zbigniew K. Wszolek
- Department of Neurology, Mayo Clinic
- Eliana Marisa Ramos
- Department of Neurology, David Geffen School of Medicine, University of California
- Lea T. Grinberg
- Department of Neurology, UCSF Weill Institute for Neurosciences, University of California
- Maria Luisa Gorno Tempini
- Department of Neurology, UCSF Weill Institute for Neurosciences, University of California
- Howard J. Rosen
- Department of Pathology, UCSF Weill Institute for Neurosciences, University of California
- Salvatore Spina
- Department of Neurology, UCSF Weill Institute for Neurosciences, University of California
- Olivier Piguet
- School of Psychology and Brain and Mind Centre, University of Sydney
- Murray Grossman
- Department of Neurology, Penn Frontotemporal Degeneration Center, Perelman School of Medicine at the University of Pennsylvania
- John Q. Trojanowski
- Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania
- C. Dirk Keene
- University of Washington BioRepository and Integrated Neuropathology (BRaIN) lab, Harborview Medical Center
- Lee-Way Jin
- M.I.N.D. Institute Laboratory, University of California, Davis Medical Center
- Johannes Prudlo
- German Center for Neurodegenerative Diseases (DZNE)
- Daniel H. Geschwind
- Department of Neurology, David Geffen School of Medicine, University of California
- Robert A. Rissman
- Alzheimer’s Therapeutic Research Institute, Keck School of Medicine of the University of Southern California
- Carlos Cruchaga
- Department of Psychiatry, Knight Alzheimer Disease Research Center, Washington University School of Medicine
- Bernardino Ghetti
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine
- Glenda M. Halliday
- University of Sydney
- Thomas G. Beach
- Civin Laboratory for Neuropathology, Banner Sun Health Research Institute
- Geidy E. Serrano
- Civin Laboratory for Neuropathology, Banner Sun Health Research Institute
- Thomas Arzberger
- Centre for Neuropathology and Prion Research, Ludwig-Maximilians-University of Munich
- Jochen Herms
- German Center for Neurodegenerative Diseases (DZNE)
- Adam L. Boxer
- Department of Neurology, UCSF Weill Institute for Neurosciences, University of California
- Lawrence S. Honig
- Department of Neurology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center
- Jean P. Vonsattel
- Department of Pathology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center
- Oscar L. Lopez
- Department of Neurology, University of Pittsburgh
- Julia Kofler
- Department of Pathology, University of Pittsburgh
- Charles L. White
- Division of Neuropathology, University of Texas Southwestern Medical Center
- Marla Gearing
- Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University
- Jonathan Glass
- Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University
- Jonathan D. Rohrer
- Department of Neurodegenerative Disease, Dementia Research Centre, University College London, Queen Square Institute of Neurology
- David J. Irwin
- Department of Neurology, Penn Frontotemporal Degeneration Center, Perelman School of Medicine at the University of Pennsylvania
- Edward B. Lee
- Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania
- Vivianna Van Deerlin
- Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania
- Rudolph Castellani
- Department of Pathology, Feinberg School of Medicine, Northwestern University
- Marsel M. Mesulam
- Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University
- Maria C. Tartaglia
- Krembil Discovery Tower, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto
- Elizabeth C. Finger
- Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario
- Claire Troakes
- Department of Basic and Clinical Neuroscience, London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Safa Al-Sarraj
- Department of Basic and Clinical Neuroscience, London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King’s College London
- Clifton L. Dalgard
- Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences
- Bruce L. Miller
- Department of Neurology, UCSF Weill Institute for Neurosciences, University of California
- Harro Seelaar
- Department of Neurology, Erasmus Medical Center
- Neill R. Graff-Radford
- Department of Neurology, Mayo Clinic
- Bradley F. Boeve
- Department of Neurology, Mayo Clinic
- Ian RA. Mackenzie
- Department of Pathology and Laboratory Medicine, University of British Columbia
- John C. van Swieten
- Department of Neurology, Erasmus Medical Center
- William W. Seeley
- Department of Neurology, UCSF Weill Institute for Neurosciences, University of California
- Kristel Sleegers
- Department of Biomedical Sciences, University of Antwerp
- Dennis W. Dickson
- Department of Neuroscience, Mayo Clinic
- Joanna M. Biernacka
- Department of Quantitative Health Sciences, Mayo Clinic
- Rosa Rademakers
- Department of Neuroscience, Mayo Clinic
- DOI
- https://doi.org/10.1038/s41467-025-59216-0
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 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.
