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
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 earlier than disease diagnosis in short-tandem-repeat-associated neurological diseases.