A repeat expansion in GOLGA8A is a major risk factor for atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions

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<sup>-21</sup>, 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.

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Journal
Nature Genetics
Published
2026-03-12
DOI
https://doi.org/10.1038/s41588-026-02537-7
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
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article

A repeat expansion in GOLGA8A is a major risk factor for atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions

Julia Kofler, Svenn D’Hert, Natalie Woodman, William P. Cheshire et al.
Nature Genetics
Amyotrophic Lateral Sclerosis Research
article

A repeat expansion in GOLGA8A is a major risk factor for atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions

Julia Kofler, Svenn D’Hert, Natalie Woodman, William P. Cheshire, Mojca Stražišar, Saskia Hutten, Marleen Van den Broeck, Nikhil B Ghayal, Elise Coopman, Anne Sieben, Charles L. White, David Wallon, F. Lebert, Tamar Gefen, Brittany N. Dugger, Bart De Vil, Masud Husain, Merel O. Mol, I. R. A. Mackenzie, Patrick Cras, Sebastiaan Engelborghs, Peter De Rijk, István Bódi, Tim De Pooter, Sarah Wynants, Glenda Margaret Halliday, Annie OF Hiniker, Joanna M. Biernacka, Rafaela Policarpo, Aivi T. Nguyen, Fahri Küçükali, EunRan Suh, Shelley L. Forrest, Julia Keith, Júlia Faura, Jochen Herms, David G. Muñoz, Serge Belliard, Gregory D. Jenkins, Marka van Blitterswijk, Jolien Schaeverbeke, Stephen J. Haggarty, Wolfgang Singer, Olaf Ansorge, Jin Lee-Way, Sara Alidadiani, Jeroen G J van Rooij, Zbigniew K. Wszolek, Mariely DeJesus-Hernandez, Rosa Rademakers, Kathy L. Newell, Manuela Neumann, Ronald C. Petersen, Elizabeth C. Finger, Dorothee Dormann, Margaret Flanagan, Andrew P. King, Edward B. Lee, Geert Joris, Clifton L. Dalgard, Bruce L. Miller, Lea T. Grinberg, Bernardino Ghetti, Anthony Batzler, William W. Seeley, Marla Gearing, Rik Vandenberghe, Dietmar R. Thal, Claire Troakes, Sandra Weintraub, Lee-Cyn Ang, Bradley F. Boeve, Carlos Cruchaga, Gaël Nicolas, Melissa E. Murray, Julie van der Zee, Oscar L. Lopez, Lorne Zinman, Owen A. Ross, Jonathan D. Rohrer, Ekaterina Rogaeva, Alexandra I. Soto-Beasley, Thomas Arzberger, Susana Boluda, John C. van Swieten, Jennifer L. Whitwell, Dennis W. Dickson, Jasper Van Dongen, Wouter De Coster, Gabor G. Kovacs, Marsel M. Mesulam, Raphael J. Gibbs, Jean-Charles Lambert, Safa Al-Sarraj, Qinwen Mao, Vincent Deramecourt, Sonja W. Scholz, Neill R. Graff-Radford, Mathieu Vandenbulcke, Bryan J. Traynor, Rudolph Castellani, Matt Baker, Robert A. Rissman, Tammaryn Lashley, Vivianna M. Van Deerlin, Florent Marguet, Sigrun Roeber, Kristel Sleegers, Florence Pasquier, Keith A. Josephs, Jonathan Glass, Harro Seelaar, Gerard D. Schellenberg, Howard J. Rosen, Adam L. Boxer, Ryan J. Uitti, Nilüfer Ertekin-Taner, R. Ross Reichard, Maria C. Tartaglia, Thomas Kukar, Salvatore Spina, Alissa L. Nana, Cyril Pottier
article en

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<sup>-21</sup>, 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.

Nature Genetics
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), University Health Network (CA), Mayo Clinic (US), Vrije Universiteit Brussel (BE), 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), Inserm (FR), École Pratique des Hautes Études (FR), 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), Johannes Gutenberg University Mainz (DE), Washington University in St. Louis (US), University of Utah (US), Université de Lille (FR), Toronto Western Hospital (CA), Universitair Ziekenhuis Leuven (BE), Institut Pasteur de Lille (FR), London Health Sciences Centre (CA), German Center for Neurodegenerative Diseases (DE), Jacksonville College (US), Erasmus MC (NL), Health Sciences Centre (CA), WinnMed (US), University Medical Center (US), Centre Hospitalier Universitaire de Lille (FR), UNSW Sydney (AU), Sorbonne Université (FR), University of Oxford (GB), Massachusetts General Hospital (US), Lille’s Cardiology Hospital (FR), Assistance Publique – Hôpitaux de Paris (FR), Antwerp University Hospital (BE), Normandie Université (FR), National Institute of Neurological Disorders and Stroke (US), Occupational Cancer Research Centre (CA), King's College Hospital NHS Foundation Trust (GB), Centre Hospitalier Universitaire de Caen Normandie (FR), Hope Center for Neurological Disorders (US), Mayo Clinic in Arizona (US), UK Dementia Research Institute (GB), Universitair Ziekenhuis Brussel (BE), VIB-UAntwerp Center for Molecular Neurology (BE), National Institute on Aging (US), Mayo Clinic in Florida (US), National Hospital for Neurology and Neurosurgery (GB), Institut du Cerveau (FR), VIB-KU Leuven Center for Brain & Disease Research (BE), Centre Hospitalier Universitaire de Rouen (FR), Ontario Brain Institute (CA), University of California Davis Medical Center (US), Institute of Neurobiology (BG), Institute of Molecular Biology (DE), Indiana University School of Medicine, University College London (GB), Bank of England (GB), Indiana University – Purdue University Indianapolis (US), Université de Rouen Normandie (FR), University of Pennsylvania (US), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), The University of Texas Southwestern Medical Center (US), Université de Caen Normandie (FR), KU Leuven (BE)
U.S. Department of Health and Human Services, American Brain Foundation, University of Pennsylvania, Fondation pour l'Aide à la Recherche sur la Sclérose en Plaques, Neuroscience Research Australia, Brain Research UK, Alzheimer's Society, Association de soutien à la Paralysie Supranucléaire Progressive, National Institute for Health and Care Research, Wolfson Foundation, Fonds Wetenschappelijk Onderzoek, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, KU Leuven, China Scholarship Council, Vlaams Instituut voor Biotechnologie, Koning Boudewijnstichting, Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone, Universiteit Antwerpen, Association France Parkinson, Assistance publique-Hôpitaux de Paris, Alzheimer Nederland, Vlaamse regering, Centre hospitalier régional universitaire de Lille, UK Dementia Research Institute, National Institutes of Health, Canadian Institutes of Health Research, Medical Research Council, National Health and Medical Research Council, National Institute on Aging, National Institute of Neurological Disorders and Stroke
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