Population-scale repeat expansions elucidate disease risk and brain atrophy

作者：Vijay Kumar Pounraja, Jae Hoon Sul, Joseph L. Herman, Sean O’Keeffe, Veera M. Rajagopal, Xiaodong Bai, Michael D. Kessler, Neelroop Parikshak, Karl Landheer, Xingmin Zhang, Sean Yu, L Zhang, Michelle G. LeBlanc, Jennifer Rico-Varela, Frederic R. Grau, Sarah E. Wolf, Sriramkumar Sundaramoorthy, Farshid Sepehrband, Eli Stahl, Yuda Huo, Mohsin Ahmed, Susan D. Croll, Adam Buchanan, David J. Carey, Christa Lese Martin, Michelle Meyer, Kyle Retterer, David D.K. Rolston, Mayo-RGC Project Generation, PG Leadership Team, James R. Cerhan, Fergus J. Couch, Janet E. Olson, Bioinformatics Statistical Genetics, Nicholas B. Larson, Zachary S. Fredericksen, Mine S. Cicek, Registry Principal Investigators, Joanna M. Biernacka, Victor M. Karpyak, Prashanthi Vemuri, Vijay K. Ramanan, Owen A. Ross, M. Frye, Jeanette E. Eckel Passow, R. R. Jenkins, Daniel H. Lachance, Kristen Drucker, Paul A. Decker, Matthew L. Kosel, Sarah A. McLaughlin, Kathryn J. Ruddy, Nicholas Boddicker, Wenan Chen, Suzette J. Bielinski, John C. Lieske, W. Michael Hooten, Lisa A. Boardman, Richard B. Kennedy, Andrew D. Badley, Sean C. Dowdy, S W Harrington, Gretchen E. Glaser, Ping Yang, C. M. Vachon, Stacey J. Winham, Angela Dispenzieri, Samuel O. Antwi, Ann L. Oberg, Kari G. Rabe, Scott H. Kaufmann, Ellen L. Goode, William A. Cliby, Jamie Bakkum-Gamez, Sun-Hee Lee, J. Eric Ahlskog, James H. Bower, Peter Harris, Naveen L. Pereira, Nadia N. Laack, Daniel J, Robert W. Mutter, Management, Jonathan J. Harrington, Mexico City Prospective Study, Jason Torres, J Emberson, Rory Collins, Jaime Berumen, Jesús Alegre-Díaz, Roberto Tapia-Conyer, Pablo Kuri-Morales, Penn Medicine BioBank, PMBB Leadership Team, Daniel J. Rader, Marylyn D. Ritchie, Regulatory Oversight Patient Recruitment, JoEllen Weaver, Nawar Naseer, Giorgio Sirugo, Afiya Poindexter, Yi-An Ko, Kyle P. Nerz, Jenna Dever, Aidan Harvey, Sydney Linn, Lab Operations, Meghan Livingstone, Fred Vadivieso, Stephanie DerOhannessian, Teo Tran, Julia Stephanowski, Salma Santos, Ned C. Haubein, Joseph Dunn, Anurag Verma, Colleen Morse Kripke, Marjorie Risman, Renae Judy, Colin Wollack, Genome Informatics, Shefali S. Verma, Scott M. Damrauer, Yuki Bradford, Scott Dudek, Theodore G. Drivas, William Salerno, John D. Overton, Jonathan Marchini, Jeffrey G. Reid, Luca Lotta, Aris Baras, Leadership Team RGC Management, Gonçalo R. Abecasis, Adolfo A. Ferrando, Andrew Deubler, Luca Lotta, John D. Overton, Jeffrey G. Reid, Alan R. Shuldiner, Katherine Siminovitch, Jason Portnoy, Marcus B. Jones, Lyndon Mitnaul, Alison Fenney, Manuel Allen Revez Ferreira, Maya Ghoussaini, Mona Nafde, Cristen J. Willer, Lourdes Crane, Niek Verweij, Eric Jorgenson, Joseph Pickrell, Lab Operations Sequencing, Christina Beechert, Erin D. Fuller, Laura M. Cremona, Eugene Kalyuskin, Hang Du, Caitlin Forsythe, Zhenhua Gu, Kristy Guevara, Michael Lattari, Alexander Lopez, Kia Manoochehri, Prathyusha Challa, Manasi Pradhan, Raymond Reynoso, Ricardo Schiavo, Maria Sotiropoulos Padilla, Chenggu Wang, Sarah E. Wolf, Data Engineering Genome Informatics, Manan Mohan Goyal, George Mitra, Rouel Lanche, Vrushali Mahajan, Sai Lakshmi Vasireddy, Gisu Eom, Krishna Pawan Punuru, Sujit Gokhale, Shehroze Aamer, Pooja Mule, Mudasar Sarwar, Muhammad Aqeel, Razvan Panea, Evan Edelstein, Devika Torvi, Ayesha Rasool, Evan K. Maxwell, Boris Boutkov, Alexander Gorovits, Ju Guan, Alicia Hawes, Olga Krasheninina, Samantha Rodríguez Zárate, Adam J. Mansfield, Lukas Habegger, Stephen Tahan, Naveen Karumuri, Data Science Analytical Genetics, Joshua Backman, Kathryn Burch, Adrián Campos, Liron Ganel, Sheila Gaynor, Benjamin Geraghty, Arkopravo Ghosh, Christopher Gillies, Lauren Gurski, Tyler Joseph, Michael D. Kessler, Jack A. Kosmicki, Adam E. Locke, Priyanka Nakka, Olivier Delaneau, Anthony Marcketta, Joelle Mbatchou, Jonathan Ross, Carlo Sidore, Eli Stahl, Timothy A. Thornton, Rujin Wang, Kuan-Han Wu, Bin Ye, Blair Zhang, Andrey Ziyatdinov, Yuxin Zou, Jingning Zhang, Kyoko Watanabe, Mira Y. Tang, Frank Wendt, Suganthi Balasubramanian, Suying Bao, Kathie Sun, Chuanyi Zhang, Aaron Zhang, David Corrigan, Dhruv Shidhaye, Chen Wang, Keyrun Adhikari, Alexander Lachmann, Anna Alkelai, Mark Weiner, Julian Stamp, Therapeutic Area Genetics, Brian Hobbs, Jon Silver, William Palmer, Rita Guerreiro, Amit D. Joshi, Antoine Baldassari, Sarah E. Graham, Ernst Mayerhofer, Erola Pairó Castiñeira, Mary Haas, George Hindy, Jonas Bovijn, Tanima De, Luanluan Sun, Olukayode Sosina, Arthur Gilly, Peter Dornbos, Moeen Riaz, Manav Kapoor, Gannie Tzoneva, Vijay Kumar, Jacqueline M. Otto, José Brás, Silvia Álvarez, Jessie Brown, Hossein Khiabanian, Joana Revez, Kimberly Skead, Jae Soon Sul, Lei Chen, Sam Choi, Amy Damask, Nan Lin, Charles Paulding, Sameer Malhotra, Jacob McPadden, D. G. Blair, Joshua Motelow, Julie Horowitz, Michelle G. LeBlanc, Nadia Rana, Jennifer Rico Varela, Jaimee Hernandez, Larizbeth A. Romero, Ashley Paynter, Business Operations Senior Partnerships, Randi Schwartz, Jody L. Hankins, Anna Han, Samuel Hart, Ryan Smith, Sarah E. Murphy, Administrative Coordinators Business Operations, Ann Perez-Beals, Gina Solari, Johannie Rivera-Picart, Michelle Pagan, Sunilbe Siceron, Gonçalo R. Abecasis, Giovanni Coppola, Sahar Gelfman · 发表于：Nature · 年份：2026 · DOI：10.1038/s41586-026-10345-6 · 被引用次数：1 · 研究领域：Genetic Neurodegenerative Diseases、Amyotrophic Lateral Sclerosis Research、Parkinson's Disease Mechanisms and Treatments

Pathogenic expansions of short tandem repeats (STRs) cause over 70 neurological diseases1–3. Here we performed a population-scale survey of pathogenic repeat expansions by analysing repeat length in 37 disease-associated STR loci in a diverse set of 1,020,833 samples using short-read sequencing whole-exome and whole-genome data. Consistent with previous findings, we found that the frequency of pathogenic repeats is higher than the prevalence of corresponding diseases for most loci4,5. Associations of repeat length with 7,671 binary traits captured known locus–trait associations, including HTT and Huntington’s disease, DMPK and myotonic disorders and C9orf72 and motor neuron disease, among others. Finally, we found that, even before disease diagnosis, repeat expansions in several loci strongly associate with increased levels of neurofilament light chain (NfL) and a loss of brain volume in specific disease-associated regions. For example, carriers of HTT expansions exhibited a 22.1% loss of putamen volume, and carriers of CACNA1A expansions showed a 24.6% loss of cerebellar volume. These observations suggest that both decreased brain volumes and increased NfL levels occur earlier than disease diagnosis. This study demonstrates the use of characterizing repeat expansions from short-read sequencing data in diverse population-scale cohorts and its application to epidemiology and clinical biomarker development. Decreased brain volumes and increased NfL levels can be observed earlie...