Journal Article

DZNE-2026-00415

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A repeat expansion in GOLGA8A is a major risk factor for atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions.

De Coster, W. ; Van den Broeck, M. ; Baker, M. ; Ghayal, N. B. ; Wynants, S. ; Batzler, A. ; Pottier, C. ; Alidadiani, S. ; Küçükali, F. ; Jenkins, G. D. ; Policarpo, R. ; van Blitterswijk, M. ; DeJesus-Hernandez, M. ; Soto-Beasley, A. I. ; Faura, J. ; Coopman, E. ; Hutten, S. ; Mol, M. O. ; Wallon, D. ; Sieben, A. ; Finger, E. C. ; Murray, M. E. ; Forrest, S. L. ; Tartaglia, M. C. ; Troakes, C. ; van Rooij, J. G. J. ; Nguyen, A. T. ; Reichard, R. R. ; Woodman, N. L. ; Nana, A. L. ; Weintraub, S. ; Gefen, T. ; De Vil, B. ; Bodi, I. ; Lopez, O. L. ; Boluda, S. ; Belliard, S. ; Lebert, F. ; Marguet, F. ; Mao, Q. ; Mesulam, M. M. ; Boxer, A. L. ; Vandenbulcke, M. ; Suh, E. ; Schaeverbeke, J. ; Lambert, J.-C. ; Scholz, S. W. ; Dalgard, C. L. ; Traynor, B. J. ; Gibbs, R. J. ; Schellenberg, G. D. ; Dormann, D. ; Joris, G. ; De Pooter, T. ; De Rijk, P. ; D'Hert, S. ; Van Dongen, J. ; van der Zee, J. ; Strazisar, M. ; Gearing, M. ; Kukar, T. ; Flanagan, M. ; Engelborghs, S. ; Ghetti, B. ; Newell, K. L. ; King, A. ; Roeber, S. ; Rosen, H. J. ; Spina, S. ; Cras, P. ; Ertekin-Taner, N. ; Wszolek, Z. K. ; Uitti, R. J. ; Cheshire, W. P. ; Singer, W. ; Herms, J.DZNE* ; Josephs, K. A. ; Whitwell, J. L. ; Petersen, R. C. ; Pasquier, F. ; Nicolas, G. ; Castellani, R. ; Glass, J. ; Miller, B. L. ; Kovacs, G. G. ; Rissman, R. A. ; Hiniker, A. ; Deramecourt, V. ; Ang, L.-C. ; Lee-Way, J. ; Van Deerlin, V. M. ; Dugger, B. N. ; Thal, D. R. ; Grinberg, L. T. ; Cruchaga, C. ; Arzberger, T.Extern* ; Munoz, D. G. ; Keith, J. ; Zinman, L. ; Rogaeva, E. ; Lee, E. B. ; Haggarty, S. J. ; Ansorge, O. ; Husain, M. ; Halliday, G. M. ; Al-Sarraj, S. ; Ross, O. A. ; Sleegers, K. ; Vandenberghe, R. ; Boeve, B. F. ; Graff-Radford, N. R. ; Kofler, J. ; White, C. L. ; Lashley, T. ; Neumann, M.DZNE* ; Biernacka, J. M. ; Seeley, W. W. ; Seelaar, H. ; van Swieten, J. C. ; Rohrer, J. D. ; Dickson, D. W. ; Mackenzie, I. R. A. ; Rademakers, R.

2026
Macmillan Publishers Limited, part of Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41588-026-02537-7

Abstract: Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is neuropathologically characterized by aggregation of the FET family of proteins and clinically manifests as sporadic young-onset frontotemporal dementia. Here we describe a major risk locus on chr15q14 identified through a genome-wide association study in 59 pathologically confirmed aFTLD-U cases and 3,153 controls (lead single nucleotide polymorphism rs549846383, P = 5.85 × 10-21, odds ratio 26.7). When combined with data from 28 additional aFTLD-U cases, 3,712 controls and 3,215 individuals with other neurodegenerative diseases and by leveraging in-house and public long-read genome sequencing data from 1,715 individuals, we identified a tandem repeat expansion on the associated haplotypes in an intron of GOLGA8A. We found variation in repeat length, motif length, and motif sequence, with long CT-dimer expansions strongly associated with aFTLD-U. Although the functional consequence of this repeat remains unknown, its presence in nearly 60% of aFTLD-U cases points to a fundamental role in disease pathogenesis.

Keyword(s): Humans (MeSH) ; Frontotemporal Lobar Degeneration: genetics (MeSH) ; Frontotemporal Lobar Degeneration: pathology (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Risk Factors (MeSH) ; Genome-Wide Association Study (MeSH) ; Ubiquitin: metabolism (MeSH) ; Ubiquitin: genetics (MeSH) ; Male (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Female (MeSH) ; Membrane Proteins: genetics (MeSH) ; Inclusion Bodies: metabolism (MeSH) ; Inclusion Bodies: pathology (MeSH) ; Inclusion Bodies: genetics (MeSH) ; DNA Repeat Expansion: genetics (MeSH) ; Middle Aged (MeSH) ; Haplotypes (MeSH) ; Case-Control Studies (MeSH) ; Aged (MeSH) ; Ubiquitin ; Membrane Proteins

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Contributing Institute(s):

1. Translational Brain Research (AG Herms)
2. Molecular Neuropathology of Neurodegenerative Diseases (AG Neumann)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2026

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