Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood

作     者：Jakubek, Yasminka A. Ma, Xiaolong Stilp, Adrienne M. Yu, Fulong Bacon, Jason Wong, Justin W. Aguet, Francois Ardlie, Kristin Arnett, Donna K. Barnes, Kathleen Bis, Joshua C. Blackwell, Tom Becker, Lewis C. Boerwinkle, Eric Bowler, Russell P. Budoff, Matthew J. Carson, April P. Chen, Jiawen Cho, Michael H. Coresh, Josef Cox, Nancy J. de Vries, Paul S. DeMeo, Dawn L. Fardo, David W. Fornage, Myriam Guo, Xiuqing Hall, Michael E. Heard-Costa, Nancy Hidalgo, Bertha Irvin, Marguerite Ryan Johnson, Andrew D. Jorgenson, Eric Kenny, Eimear E. Kessler, Michael D. Levy, Daniel Li, Yun Lima, Joao A.C. Liu, Yongmei Locke, Adam E. Loos, Ruth J.F. Machiela, Mitchell J. Mathias, Rasika A. Mitchell, Braxton D. Murabito, Joanne M. Mychaleckyj, Josyf C. North, Kari E. Orchard, Peter Parker, Stephen C.J. Pershad, Yash Peyser, Patricia A. Pratte, Katherine A. Psaty, Bruce M. Raffield, Laura M. Redline, Susan Rich, Stephen S. Rotter, Jerome I. Shah, Sanjiv J. Smith, Jennifer A. Smith, Aaron P. Smith, Albert Taub, Margaret A. Tiwari, Hemant K. Tracy, Russell Tuftin, Bjoernar Bick, Alexander G. Sankaran, Vijay G. Reiner, Alexander P. Scheet, Paul Auer, Paul L. 

作者机构：Department of Internal Medicine University of Kentucky Lexington KY United States Division of Biostatistics Data Science Institute Medical College of Wisconsin Milwaukee WI United States Department of Biostatistics University of Washington Seattle WA United States Division of Hematology/Oncology Boston Children's Hospital Harvard Medical School Boston MA United States Department of Pediatric Oncology Dana-Farber Cancer Institute Harvard Medical School Boston MA United States Broad Institute of MIT and Harvard Cambridge MA United States GMU-GIBH Joint School of Life Sciences The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases Guangzhou National Laboratory Guangzhou Medical University Guangzhou China Department of Computer Science Department of Biological Sciences University of Wisconsin Milwaukee Milwaukee WI United States Department of Epidemiology University of Texas MD Anderson Cancer Center Houston TX United States Broad Institute Cambridge MA United States University of South Carolina Columbia SC United States Division of Biomedical Informatics and Personalized Medicine School of Medicine School of Medicine University of Colorado Anschutz Medical Campus Aurora CO United States Cardiovascular Health Research Unit Department of Medicine University of Washington Seattle WA United States Department of Biostatistics University of Michigan Ann Arbor MI United States Department of Medicine Division of Cardiology Johns Hopkins Hospital Johns Hopkins University of Medicine Baltimore MD United States Human Genetics Center Department of Epidemiology School of Public Health The University of Texas Health Science Center at Houston Houston TX United States Department of Medicine National Jewish Health Denver CO United States Department of Medicine Division of Cardiology The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center Torrance CA United States Department of Medicine University of Mississippi Medical Center Jackson MS United States Department of Biostatistics University of North Carolina-Chapel Hill Chapel Hill NC United States Channing Division of Network Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA United States NYU Grossman School of Medicine NYU Langone Health New York NY United States Division of Genetic Medicine Vanderbilt University Medical Center Nashville TN United States Department of Biostatistics University of Kentucky Lexington KY United States University of Texas Health Science Center at Houston Houston TX United States Department of Pediatrics The Institute for Translational Genomics and Population Sciences The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center Torrance CA United States Department of Neurology Boston University Chobanian and Avedisian School of Medicine Boston MA United States Department of Epidemiology School of Public Health University of Alabama at Birmingham Birmingham AL United States Framingham Heart Study Framingham MA United States Population Sciences Branch National Heart Lung and Blood Institute National Institutes of Health Bethesda MD United States Regeneron Genetics Center Tarrytown NY United States Institute for Genomic Health Icahn School of Medicine at Mount Sinai New York NY United States Department of Biostatistics Department of Genetics Department of Computer Science University of North Carolina-Chapel Hill Chapel Hill NC United States Duke University School of Medicine Durham NC United States The Charles Bronfman Institute for Personalized Medicine Icahn School of Medicine at Mount Sinai New York NY United States Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark Division of Cancer Epidemiology and Genetics National Cancer Institute Rockville MD United States Division of Allergy and Clinical Immunology Department of Medicine Johns Hopkins University School of Medicine Baltimore MD United States Department of Medicine University of Maryland Baltimore Baltimore MD United States Department of Medicine Boston University Chobanian and Avedisian School of Medicine Boston MA United States Center for Public Health Genomics Department of Public Health Sciences University of Virginia School of Medicine Charlottesville VA United States Department of Epidemiology University of North Carolina-Chapel Hill Chapel Hill NC United States Department of Computational Medicine and Bioinformatics University of Michigan Ann Arbor MI United States Department of Human Genetics University of Michigan Ann Arbor MI United States Department of Epidemiology School of Public Health University of Michigan Ann Arbor MI United States Department of Biostatistics National Jewish Health Denver CO United States Cardiovascular Health Research Unit Department of Medicine Department of Epidemiology Department of Health Systems and Population Health University of Washington Seattle WA United States Department of Genetics University of North Carolina-Chapel Hill Chapel Hill NC United States Division of Sleep Medicine Harvard Medical School Boston MA United States Department of Medicine Division of Cardiology Northwestern University Feinberg School of Medicine Chicago IL United States Institute for Social Research Survey Research Center University of Michigan Ann Arbor MI United States Institute for Biomedical Informatics University of Kentucky Lexington KY United States Department of Biostatistics Johns Hopkins University Baltimore MD United States Department of Biostatistics School of Public Health University of Alabama at Birmingham Birmingham AL United States Departments of Pathology & Laboratory Medicine and Biochemistry Larner College of Medicine at the University of Vermont Colchester VT United States Howard Hughes Medical Institute Boston MA United States Department of Epidemiology University of Washington Seattle WA United States Cancer Center Medical College of Wisconsin Milwaukee WI United States 

出 版 物：《American Journal of Human Genetics》 (Am. J. Hum. Genet.)

年 卷 期：2025年第112卷第2期

页      面：276-290页

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 07[理学] 09[农学] 

基　　金：National Heart, Lung, and Blood Institute, NHLBI National Institutes of Health, NIH U.S. Department of Health and Human Services, HHS 

主　　题：GWAS mosaic loss of chromosome Y multi-ancestry 

摘      要：Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole-genome sequencing (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. We show that haplotype-based calling methods can be used with WGS data to successfully identify mLOY events. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European (EUR) ancestry group compared to other ancestries. We identify multiple loci associated with mLOY susceptibility and show that subsets of human hematopoietic stem cells are enriched for the activity of mLOY susceptibility variants. Finally, we found that certain alleles on chromosome Y are more likely to be lost than others in detectable mLOY clones. © 2024 The Author(s)