Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing
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.
Authors
- Julia Kofler (ORCID: https://orcid.org/0000-0003-4298-7328)
- Andrew King (ORCID: https://orcid.org/0000-0003-0481-3490)
- Pieter Van de Walle (ORCID: https://orcid.org/0000-0002-6020-7885)
- Sandra Weıntraub (ORCID: https://orcid.org/0000-0003-2605-5205)
- Lawrence S. Honig (ORCID: https://orcid.org/0000-0002-9703-2265)
- Lea T. Grinberg (ORCID: https://orcid.org/0000-0002-6809-0618)
- Margaret E. Flanagan (ORCID: https://orcid.org/0009-0008-7078-3545)
- John Cornelis Van Swieten (ORCID: https://orcid.org/0000-0001-6278-6844)
- Rudolph J. Castellani (ORCID: https://orcid.org/0000-0002-5414-3184)
- Hilary W. Heuer (ORCID: https://orcid.org/0000-0002-3776-1685)
- Keith A. Josephs (ORCID: https://orcid.org/0000-0003-2930-8634)
- Clifton L. Dalgard (ORCID: https://orcid.org/0000-0003-2025-8239)
- Ryan J. Uitti (ORCID: https://orcid.org/0000-0001-8113-4710)
- Dennis W. Dickson (ORCID: https://orcid.org/0000-0001-7189-7917)
- Safa Al‐Sarraj (ORCID: https://orcid.org/0000-0002-6783-3571)
- John B. Kwok (ORCID: https://orcid.org/0000-0001-9574-6195)
- Caroline Graff (ORCID: https://orcid.org/0000-0002-9949-2951)
- Ekaterina A. Rogaeva (ORCID: https://orcid.org/0000-0002-2852-0329)
- Alissa L. Nana (ORCID: https://orcid.org/0000-0003-3474-8044)
- Dieter Edbauer (ORCID: https://orcid.org/0000-0002-7186-4653)
- Cyril P. Pottier (ORCID: https://orcid.org/0000-0002-3049-9346)
- Kristel Sleegers (ORCID: https://orcid.org/0000-0002-0283-2332)
- Maria Carmela Tartaglia (ORCID: https://orcid.org/0000-0002-5944-8497)
- Jennifer Whitwell
- Daniel H. Geschwind (ORCID: https://orcid.org/0000-0003-2896-3450)
- Robert A. Rissman (ORCID: https://orcid.org/0000-0001-9245-8278)
- Adam L. Boxer (ORCID: https://orcid.org/0000-0002-1215-5064)
- Cristina T. Vicente (ORCID: https://orcid.org/0000-0002-7882-9543)
- John Q. Trojanowski (ORCID: https://orcid.org/0000-0002-9239-8794)
- Kevin F. Bieniek (ORCID: https://orcid.org/0000-0003-4922-864X)
- Yan W. Asmann (ORCID: https://orcid.org/0000-0002-8896-2647)
- Zbigniew K. Wszołek (ORCID: https://orcid.org/0000-0001-5487-1053)
- Anthony Batzler
- Charles L. White (ORCID: https://orcid.org/0000-0002-3870-2804)
- Salvatore Spina (ORCID: https://orcid.org/0000-0003-3570-9143)
- Kimiko Domoto‐Reilly (ORCID: https://orcid.org/0000-0002-7396-1633)
- Claire Troakes (ORCID: https://orcid.org/0000-0002-1790-7376)
- C. Dirk Keene (ORCID: https://orcid.org/0000-0002-5291-1469)
- Matthis Synofzik (ORCID: https://orcid.org/0000-0002-2280-7273)
- Changiz Geula (ORCID: https://orcid.org/0000-0002-9311-3295)
- Jeroen van Rooij (ORCID: https://orcid.org/0000-0001-9754-073X)
- Tamar Gefen (ORCID: https://orcid.org/0000-0002-2380-3100)
- Linn Öijerstedt (ORCID: https://orcid.org/0000-0003-0635-6377)
- Brittany N. Dugger (ORCID: https://orcid.org/0000-0003-2141-8855)
- Qinwen Mao (ORCID: https://orcid.org/0000-0001-7876-2046)
- Merel O. Mol (ORCID: https://orcid.org/0000-0003-2533-2530)
- Carlos C Cruchaga (ORCID: https://orcid.org/0000-0002-0276-2899)
- Vivianna M. Van Deerlin (ORCID: https://orcid.org/0000-0002-7400-9097)
- Sarah Wynants (ORCID: https://orcid.org/0000-0003-2376-6722)
- Ronald Carl Petersen (ORCID: https://orcid.org/0000-0002-8178-6601)
- Bruce L. Miller (ORCID: https://orcid.org/0000-0002-2152-4220)
- Lorne Zinman (ORCID: https://orcid.org/0000-0002-8096-8366)
- Melissa E. Murray (ORCID: https://orcid.org/0000-0001-7379-2545)
- Chiadi U. Onyike (ORCID: https://orcid.org/0000-0003-2255-4437)
- Murray Grossman (ORCID: https://orcid.org/0000-0002-7447-6218)
- Glenda Margaret Halliday (ORCID: https://orcid.org/0000-0003-0422-8398)
- Eric M. Reiman (ORCID: https://orcid.org/0000-0002-0705-3696)
- Bernardino Ghetti (ORCID: https://orcid.org/0000-0002-1842-8019)
- Rosa Rademakers (ORCID: https://orcid.org/0000-0002-4049-0863)
- Harro Seelaar (ORCID: https://orcid.org/0000-0003-1989-7527)
- Joanna M. Biernacka (ORCID: https://orcid.org/0000-0001-9350-4440)
- Geidy E. Serrano (ORCID: https://orcid.org/0000-0002-9527-2011)
- Matt Baker
- Ian R. Mackenzie (ORCID: https://orcid.org/0000-0003-3875-2972)
- Olivier Piguet (ORCID: https://orcid.org/0000-0002-6696-1440)
- Fahri Küçükali (ORCID: https://orcid.org/0000-0002-3835-9639)
- Alexis P. Oddi (ORCID: https://orcid.org/0000-0001-9151-889X)
- Leonard Petrucelli (ORCID: https://orcid.org/0000-0003-2959-129X)
- Sigrun Roeber
- EunRan Suh
- David S. Knopman (ORCID: https://orcid.org/0000-0002-6544-066X)
- Ging‐Yuek Robin Hsiung (ORCID: https://orcid.org/0000-0002-8017-0856)
- Jennifer S. Yokoyama (ORCID: https://orcid.org/0000-0001-7274-2634)
- Edward B. Lee (ORCID: https://orcid.org/0000-0002-4589-1180)
- Julia Keith (ORCID: https://orcid.org/0000-0003-1519-6731)
- Bradley F. Boeve (ORCID: https://orcid.org/0000-0002-4153-8187)
- Bryan K. Woodruff (ORCID: https://orcid.org/0000-0002-4728-7294)
- Júlia Faura (ORCID: https://orcid.org/0000-0002-8436-1377)
- Jochen Herms (ORCID: https://orcid.org/0000-0002-6201-1042)
- Wouter De Coster (ORCID: https://orcid.org/0000-0002-5248-8197)
- Jonathan D. Rohrer (ORCID: https://orcid.org/0000-0002-6155-8417)
- Jonathan D. Glass (ORCID: https://orcid.org/0000-0002-3295-4971)
- Johannes Prudlo (ORCID: https://orcid.org/0000-0002-7932-5929)
- Martin R. Farlow (ORCID: https://orcid.org/0000-0001-7897-5471)
- Howard J. Rosen (ORCID: https://orcid.org/0000-0001-9281-7402)
- David G. Muñoz (ORCID: https://orcid.org/0000-0003-0957-6244)
- Elizabeth C. Finger (ORCID: https://orcid.org/0000-0003-4461-7427)
- Thomas G. Beach (ORCID: https://orcid.org/0000-0003-3296-6128)
- Richard J. Caselli (ORCID: https://orcid.org/0000-0001-5784-2987)
- Owen A. Ross (ORCID: https://orcid.org/0000-0003-4813-756X)
- William W. Seeley (ORCID: https://orcid.org/0000-0003-1410-2027)
- Gregory D. Jenkins (ORCID: https://orcid.org/0000-0001-6408-6227)
- Bret M. Evers (ORCID: https://orcid.org/0000-0001-5686-0315)
- Carlo Wilke (ORCID: https://orcid.org/0000-0002-7250-8597)
- Ethan G. Geier
- Leah K. Forsberg (ORCID: https://orcid.org/0000-0003-4086-9598)
- Janine Diehl‐Schmid (ORCID: https://orcid.org/0000-0002-7745-1382)
- Marka van Blitterswijk (ORCID: https://orcid.org/0000-0002-3054-7053)
- Nilüfer Ertekin‐Taner (ORCID: https://orcid.org/0000-0003-4436-8889)
- Edward D. Huey (ORCID: https://orcid.org/0000-0002-8295-5884)
- David J. Irwin (ORCID: https://orcid.org/0000-0002-5599-5098)
- Stephen J. Haggarty (ORCID: https://orcid.org/0000-0002-7872-168X)
- Simon Mead (ORCID: https://orcid.org/0000-0002-4326-1468)
- Bradford Clark Dickerson (ORCID: https://orcid.org/0000-0002-5958-3445)
- Shannon K. McDonnell (ORCID: https://orcid.org/0000-0001-6201-369X)
- Neill R. Graff‐Radford (ORCID: https://orcid.org/0000-0001-9847-9096)
- Laura L. Donker Kaat
- Oscar L. López (ORCID: https://orcid.org/0000-0002-8546-8256)
- Manuela Neumann (ORCID: https://orcid.org/0000-0002-6232-4057)
- John R. Hodges (ORCID: https://orcid.org/0000-0002-1370-5160)
- Eliana Marisa Ramos (ORCID: https://orcid.org/0009-0003-7982-4415)
- M. Marcel Mesulam
- Marla Gearing
- Argentina Lario Lago
- Thomas Arzberger
- Lee‐Way Jin
- Saurabh Baheti (ORCID: https://orcid.org/0000-0002-3564-7627)
- Maria Luisa Gorno Tempini
- Jean Paul Vonsattel
Institutions
- Northwestern University (US)
- University of Southern California (US)
- Western University (CA)
- The University of Sydney (AU)
- St. Michael's Hospital (CA)
- Sunnybrook Health Science Centre (CA)
- Mayo Clinic (US)
- Karolinska University Hospital (SE)
- Harvard University (US)
- University of British Columbia (CA)
- Johns Hopkins University (US)
- Uniformed Services University of the Health Sciences (US)
- University of Antwerp (BE)
- Emory University (US)
- University of California, Los Angeles (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of Pittsburgh (US)
- University of California, San Francisco (US)
- King's College London (GB)
- University of Toronto (CA)
- University of Washington (US)
- Washington University in St. Louis (US)
- University of Utah (US)
- Brown University (US)
- Columbia University Irving Medical Center (US)
- Discovery Centre (CA)
- German Center for Neurodegenerative Diseases (DE)
- Jacksonville College (US)
- Erasmus MC (NL)
- Harborview Medical Center (US)
- Health Sciences Centre (CA)
- WinnMed (US)
- Karolinska Institutet (SE)
- Massachusetts General Hospital (US)
- King's College Hospital NHS Foundation Trust (GB)
- Inn-Salzach-Klinikum (DE)
- Mayo Clinic in Arizona (US)
- UK Dementia Research Institute (GB)
- VIB-UAntwerp Center for Molecular Neurology (BE)
- MRC Prion Unit (GB)
- Prevent Alzheimer’s Disease 2020 (US)
- Hertie Institute for Clinical Brain Research (DE)
- Banner Sun Health Research Institute (US)
- Mayo Clinic in Florida (US)
- University of California Davis Medical Center (US)
- Banner Alzheimer’s Institute
- Indiana University School of Medicine
- University College London (GB)
- University of Rostock (DE)
- Indiana University – Purdue University Indianapolis (US)
- Case Western Reserve University (US)
- Technical University of Munich (DE)
- Columbia University (US)
- University of Pennsylvania (US)
- University of Tübingen (DE)
- Ludwig-Maximilians-Universität München (DE)
- Neuroscience Research Australia (AU)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-25
- DOI
- https://doi.org/10.1038/s41467-025-59216-0
- Citations
- 12
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 15.28
Funders
- University of Pittsburgh
- EU Joint Programme – Neurodegenerative Disease Research
- Consortium canadien en neurodégénérescence associée au vieillissement
- National Institute for Health and Care Research
- Karolinska Institutet
- Stockholms Läns Landsting
- Vetenskapsrådet
- Swedish Brain Power
- Universiteit Antwerpen
- Vlaamse regering
- Canadian Institutes of Health Research
- Medical Research Council
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke
- National Center for Advancing Translational Sciences