Journal Article

DZNE-2025-00559

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing.

Pottier, C. ; Küçükali, F. ; Baker, M. ; Batzler, A. ; Jenkins, G. D. ; van Blitterswijk, M. ; Vicente, C. T. ; De Coster, W. ; Wynants, S. ; Van de Walle, P. ; Ross, O. A. ; Murray, M. E. ; Faura, J. ; Haggarty, S. J. ; van Rooij, J. G. ; Mol, M. O. ; Hsiung, G. R. ; Graff, C. ; Öijerstedt, L. ; Neumann, M.DZNE* ; Asmann, Y. ; McDonnell, S. K. ; Baheti, S. ; Josephs, K. A. ; Whitwell, J. L. ; Bieniek, K. F. ; Forsberg, L. ; Heuer, H. ; Lago, A. L. ; Geier, E. G. ; Yokoyama, J. S. ; Oddi, A. P. ; Flanagan, M. ; Mao, Q. ; Hodges, J. R. ; Kwok, J. B. ; Domoto-Reilly, K. ; Synofzik, M.DZNE* ; Wilke, C.DZNE* ; Onyike, C. ; Dickerson, B. C. ; Evers, B. M. ; Dugger, B. N. ; Munoz, D. G. ; Keith, J. ; Zinman, L. ; Rogaeva, E. ; Suh, E. ; Gefen, T. ; Geula, C. ; Weintraub, S. ; Diehl-Schmid, J. ; Farlow, M. R. ; Edbauer, D.DZNE* ; Woodruff, B. K. ; Caselli, R. J. ; Donker Kaat, L. L. ; Huey, E. D. ; Reiman, E. M. ; Mead, S. ; King, A. ; Roeber, S. ; Nana, A. L. ; Ertekin-Taner, N. ; Knopman, D. S. ; Petersen, R. C. ; Petrucelli, L. ; Uitti, R. J. ; Wszolek, Z. K. ; Ramos, E. M. ; Grinberg, L. T. ; Tempini, M. L. G. ; Rosen, H. J. ; Spina, S. ; Piguet, O. ; Grossman, M. ; Trojanowski, J. Q. ; Keene, C. D. ; Jin, L.-W. ; Prudlo, J.DZNE* ; Geschwind, D. H. ; Rissman, R. A. ; Cruchaga, C. ; Ghetti, B. ; Halliday, G. M. ; Beach, T. G. ; Serrano, G. E. ; Arzberger, T.Extern* ; Herms, J.DZNE* ; Boxer, A. L. ; Honig, L. S. ; Vonsattel, J. P. ; Lopez, O. L. ; Kofler, J. ; White, C. L. ; Gearing, M. ; Glass, J. ; Rohrer, J. D. ; Irwin, D. J. ; Lee, E. B. ; Van Deerlin, V. ; Castellani, R. ; Mesulam, M. M. ; Tartaglia, M. C. ; Finger, E. C. ; Troakes, C. ; Al-Sarraj, S. ; Dalgard, C. L. ; Miller, B. L. ; Seelaar, H. ; Graff-Radford, N. R. ; Boeve, B. F. ; Mackenzie, I. R. ; van Swieten, J. C. ; Seeley, W. W. ; Sleegers, K. ; Dickson, D. W. ; Biernacka, J. M. ; Rademakers, R.

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-59216-0

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.

Keyword(s): Humans (MeSH) ; Genome-Wide Association Study (MeSH) ; Whole Genome Sequencing (MeSH) ; Risk Factors (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Male (MeSH) ; Female (MeSH) ; Frontotemporal Lobar Degeneration: genetics (MeSH) ; Frontotemporal Lobar Degeneration: pathology (MeSH) ; DNA-Binding Proteins: genetics (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; Aged (MeSH) ; Middle Aged (MeSH) ; Brain: pathology (MeSH) ; Brain: metabolism (MeSH) ; Protein Serine-Threonine Kinases: genetics (MeSH) ; Cohort Studies (MeSH) ; Nerve Tissue Proteins: genetics (MeSH) ; DNA-Binding Proteins ; Protein Serine-Threonine Kinases ; TARDBP protein, human ; TBK1 protein, human ; Nerve Tissue Proteins

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Contributing Institute(s):

1. Molecular Neuropathology of Neurodegenerative Diseases (AG Neumann)
2. Parkinson Genetics (AG Gasser)
3. Cell Biology of Neurodegeneration (AG Edbauer)
4. Clinical Dementia Research (Rostock /Greifswald) (AG Teipel)
5. Translational Brain Research (AG Herms)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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