Scholarlink

<p>Pathogenic expansions of short tandem repeats (STRs) cause over 70 neurological diseases<sup><CitationRef AdditionalCitationIDS="CR2" CitationID="CR1">1</CitationRef>–<CitationRef CitationID="CR3">3</CitationRef></sup>. 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 loci<sup><CitationRef CitationID="CR4">4</CitationRef>,<CitationRef CitationID="CR5">5</CitationRef></sup>. Associations of repeat length with 7,671 binary traits captured known locus–trait associations, including <i>HTT</i> and Huntington’s disease, <i>DMPK</i> and myotonic disorders and <i>C9orf72</i> 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 <i>HTT</i> expansions exhibited a 22.1% loss of putamen volume, and carriers of <i>CACNA1A</i> 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Population-scale repeat expansions elucidate disease risk and brain atrophy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月8日

查看全文
  • Vijay Kumar Pounraja,
  • Jae Hoon Sul,
  • Joseph Herman,
  • Sean O’Keeffe,
  • Veera Rajagopal,
  • Xiaodong Bai,
  • Michael D. Kessler,
  • Neelroop Parikshak,
  • Karl Landheer,
  • Xingmin Zhang,
  • Sean Yu,
  • Lance Zhang,
  • Michelle G. LeBlanc,
  • Jennifer Rico-Varela,
  • Frederic Grau,
  • Sarah Wolf,
  • Sriramkumar Sundaramoorthy,
  • Farshid Sepehrband,
  • Eli A. Stahl,
  • Yuda Huo,
  • Mohsin Ahmed,
  • Susan Croll,
  • Adam Buchanan,
  • David J. Carey,
  • Christa L. Martin,
  • Michelle Meyer,
  • Kyle Retterer,
  • David Rolston,
  • James R. Cerhan,
  • Fergus J. Couch,
  • Janet E. Olson,
  • Nicholas B. Larson,
  • Zachary S. Fredericksen,
  • Mine Cicek,
  • Joanna M. Biernacka,
  • Victor M. Karpyak,
  • Prashanthi Vemuri,
  • Vijay K. Ramanan,
  • Owen A. Ross,
  • Mark A. Frye,
  • Jeanette E. Eckel Passow,
  • Robert R. Jenkins,
  • Daniel H. Lachance,
  • Kristen L. Drucker,
  • Paul A. Decker,
  • Matthew L. Kosel,
  • Sarah A. McLaughlin,
  • Kathryn J. Ruddy,
  • Nicholas J. Boddicker,
  • Wenan Chen,
  • Suzette J. Bielinski,
  • John C. Lieske,
  • W. Michael Hooten,
  • Lisa A. Boardman,
  • Richard B. Kennedy,
  • Andrew D. Badley,
  • Sean C. Dowdy,
  • Shariska Harrington,
  • Gretchen E. Glaser,
  • Ping Yang,
  • Celine M. Vachon,
  • Stacey 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 C. Harris,
  • Naveen L. Pereira,
  • Nadia N. Laack,
  • Daniel J. Ma,
  • Robert W. Mutter,
  • Jonathan J. Harrington,
  • Jason Torres,
  • Jonathan R. Emberson,
  • Rory Collins,
  • Jaime Berumen,
  • Jesús Alegre-Díaz,
  • Roberto Tapia-Conyer,
  • Pablo Kuri-Morales,
  • Daniel J. Rader,
  • Marylyn D. Ritchie,
  • JoEllen Weaver,
  • Nawar Naseer,
  • Giorgio Sirugo,
  • Afiya Poindexter,
  • Yi-An Ko,
  • Kyle P. Nerz,
  • Jenna Dever,
  • Aidan Harvey,
  • Sydney Linn,
  • Meghan Livingstone,
  • Fred Vadivieso,
  • Stephanie DerOhannessian,
  • Teo Tran,
  • Julia Stephanowski,
  • Salma Santos,
  • Ned Haubein,
  • Joseph Dunn,
  • Anurag Verma,
  • Colleen Morse Kripke,
  • Marjorie Risman,
  • Renae Judy,
  • Colin Wollack,
  • Shefali S. Verma,
  • Scott Damrauer,
  • Yuki Bradford,
  • Scott Dudek,
  • Theodore Drivas,
  • William Salerno,
  • John D. Overton,
  • Jonathan Marchini,
  • Jeffrey Reid,
  • Luca A. Lotta,
  • Aris Baras,
  • Gonçalo Abecasis,
  • Adolfo Ferrando,
  • Andrew Deubler,
  • Luca A. Lotta,
  • John D. Overton,
  • Jeffrey G. Reid,
  • Alan Shuldiner,
  • Katherine Siminovitch,
  • Jason Portnoy,
  • Marcus B. Jones,
  • Lyndon Mitnaul,
  • Alison Fenney,
  • Manuel Allen Revez Ferreira,
  • Maya Ghoussaini,
  • Mona Nafde,
  • Cristen Willer,
  • Lourdes Crane,
  • Niek Verweij,
  • Eric Jorgenson,
  • Joseph Pickrell,
  • Christina Beechert,
  • Erin 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,
  • Manan 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 Zarate,
  • Adam J. Mansfield,
  • Lukas Habegger,
  • Stephen Tahan,
  • Naveen Karumuri,
  • Joshua Backman,
  • Kathryn Burch,
  • Adrian Campos,
  • Liron Ganel,
  • Sheila Gaynor,
  • Benjamin Geraghty,
  • Arkopravo Ghosh,
  • Christopher Gillies,
  • Lauren Gurski,
  • Tyler Joseph,
  • Michael Kessler,
  • Jack Kosmicki,
  • Adam Locke,
  • Priyanka Nakka,
  • Olivier Delaneau,
  • Anthony Marcketta,
  • Joelle Mbatchou,
  • Jonathan Ross,
  • Carlo Sidore,
  • Eli Stahl,
  • Timothy Thornton,
  • Rujin Wang,
  • Kuan-Han Wu,
  • Bin Ye,
  • Blair Zhang,
  • Andrey Ziyatdinov,
  • Yuxin Zou,
  • Jingning Zhang,
  • Kyoko Watanabe,
  • Mira 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,
  • Brian Hobbs,
  • Jon Silver,
  • William Palmer,
  • Rita Guerreiro,
  • Amit Joshi,
  • Antoine Baldassari,
  • Sarah Graham,
  • Ernst Mayerhofer,
  • Erola Pairo Castineira,
  • 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 Otto,
  • Jose Bras,
  • Silvia Alvarez,
  • 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,
  • David Blair,
  • Joshua Motelow,
  • Julie Horowitz,
  • Michelle G. LeBlanc,
  • Nadia Rana,
  • Jennifer Rico Varela,
  • Jaimee Hernandez,
  • Larizbeth Romero,
  • Ashley Paynter,
  • Randi Schwartz,
  • Jody Hankins,
  • Anna Han,
  • Samuel Hart,
  • Ryan Smith,
  • Sarah Murphy,
  • Ann Perez-Beals,
  • Gina Solari,
  • Johannie Rivera-Picart,
  • Michelle Pagan,
  • Sunilbe Siceron,
  • Goncalo R. Abecasis,
  • Giovanni Coppola,
  • Sahar Gelfman

摘要

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.