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

作者：Wouter De Coster, Marleen Van den Broeck, Matt Baker, Nikhil B Ghayal, Sarah Wynants, Anthony Batzler, Cyril Pottier, Sara Alidadiani, Fahri Küçükali, Gregory D. Jenkins, Rafaela Policarpo, Marka van Blitterswijk, Mariely DeJesus-Hernandez, Alexandra I. Soto-Beasley, Júlia Faura, Elise Coopman, Saskia Hutten, Merel O. Mol, David Wallon, Anne Sieben, Elizabeth C. Finger, Melissa E. Murray, Shelley L. Forrest, Maria C. Tartaglia, Claire Troakes, Jeroen G J van Rooij, Aivi T. Nguyen, R. Ross Reichard, Natalie Woodman, Alissa L. Nana, Sandra Weintraub, Tamar Gefen, Bart De Vil, István Bódi, Oscar L. Lopez, Susana Boluda, Serge Belliard, Florence Lebert, Florent Marguet, Qinwen Mao, Marsel M. Mesulam, Adam L. Boxer, Mathieu Vandenbulcke, EunRan Suh, Jolien Schaeverbeke, Jean‐Charles Lambert, Sonja W. Scholz, Clifton L. Dalgard, Bryan J. Traynor, Raphael J. Gibbs, Gerard D. Schellenberg, Dorothee Dormann, Geert Joris, Tim De Pooter, Peter De Rijk, Svenn D’Hert, Jasper Van Dongen, Julie van der Zee, Mojca Stražišar, Marla Gearing, Thomas Kukar, Margaret Flanagan, Sebastiaan Engelborghs, Bernardino Ghetti, Kathy L. Newell, Andrew P. King, Sigrun Roeber, Howard J. Rosen, Salvatore Spina, Patrick Cras, Nilüfer Ertekin-Taner, Zbigniew K. Wszolek, Ryan J. Uitti, William P. Cheshire, Wolfgang Singer, Jochen Herms, Keith A. Josephs, Jennifer L. Whitwell, Ronald C. Petersen, Florence Pasquier, Gaël Nicolas, Rudolph Castellani, Jonathan Glass, Bruce L. Miller, Gabor G. Kovacs, Robert A. Rissman, Annie Hiniker, Vincent Deramecourt, Lee-Cyn Ang, Jin Lee-Way, Vivianna M. Van Deerlin, Brittany N. Dugger, Dietmar R. Thal, Lea T. Grinberg, Carlos Cruchaga, Thomas Arzberger, David G. Muñoz, Julia Keith, Lorne Zinman, Ekaterina Rogaeva, Edward B. Lee, Stephen J. Haggarty, Olaf Ansorge, Masud Husain, Glenda M. Halliday, Safa Al-Sarraj, Owen A. Ross, Kristel Sleegers, Rik Vandenberghe, Bradley F. Boeve, Neill R. Graff-Radford, Julia Kofler, Charles L. White, Tammaryn Lashley, Manuela Neumann, Joanna M. Biernacka, William W. Seeley, Harro Seelaar, John C. van Swieten, Jonathan D. Rohrer, Dennis W. Dickson, I. R. A. Mackenzie, Rosa Rademakers · 发表于：Nature Genetics · 年份：2026 · DOI：10.1038/s41588-026-02537-7 · 研究领域：Amyotrophic Lateral Sclerosis Research、Genetic Neurodegenerative Diseases、Genomics and Rare Diseases

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.