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Genetic predisposition to mosaic Y chromosome loss in blood.
Thompson, Deborah J; Genovese, Giulio; Halvardson, Jonatan; Ulirsch, Jacob C; Wright, Daniel J; Terao, Chikashi; Davidsson, Olafur B; Day, Felix R; Sulem, Patrick; Jiang, Yunxuan; Danielsson, Marcus; Davies, Hanna; Dennis, Joe; Dunlop, Malcolm G; Easton, Douglas F; Fisher, Victoria A; Zink, Florian; Houlston, Richard S; Ingelsson, Martin; Kar, Siddhartha; Kerrison, Nicola D; Kinnersley, Ben; Kristjansson, Ragnar P; Law, Philip J; Li, Rong; Loveday, Chey; Mattisson, Jonas; McCarroll, Steven A; Murakami, Yoshinori; Murray, Anna; Olszewski, Pawel; Rychlicka-Buniowska, Edyta; Scott, Robert A; Thorsteinsdottir, Unnur; Tomlinson, Ian; Moghadam, Behrooz Torabi; Turnbull, Clare; Wareham, Nicholas J; Gudbjartsson, Daniel F; Kamatani, Yoichiro; Hoffmann, Eva R; Jackson, Steve P; Stefansson, Kari; Auton, Adam; Ong, Ken K; Machiela, Mitchell J; Loh, Po-Ru; Dumanski, Jan P; Chanock, Stephen J; Forsberg, Lars A.
Affiliation
  • Thompson DJ; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Genovese G; Department of Genetics, Harvard Medical School, Boston, MA, USA.
  • Halvardson J; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ulirsch JC; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Wright DJ; Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Terao C; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Davidsson OB; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
  • Day FR; MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
  • Sulem P; Open Targets Core Genetics, Wellcome Sanger Institute, Hinxton, UK.
  • Jiang Y; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
  • Danielsson M; Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.
  • Davies H; Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
  • Dennis J; Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
  • Dunlop MG; deCODE Genetics, Amgen, Reykjavík, Iceland.
  • Easton DF; MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
  • Fisher VA; Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
  • Zink F; deCODE Genetics, Amgen, Reykjavík, Iceland.
  • Houlston RS; 23andMe, Mountain View, CA, USA.
  • Ingelsson M; Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Kar S; Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Kerrison ND; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Kinnersley B; Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit and CRUK Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
  • Kristjansson RP; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Law PJ; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
  • Li R; deCODE Genetics, Amgen, Reykjavík, Iceland.
  • Loveday C; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Mattisson J; Geriatrics Research Group, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
  • McCarroll SA; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
  • Murakami Y; MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
  • Murray A; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Olszewski P; deCODE Genetics, Amgen, Reykjavík, Iceland.
  • Rychlicka-Buniowska E; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Scott RA; Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Thorsteinsdottir U; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Tomlinson I; Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Moghadam BT; Department of Genetics, Harvard Medical School, Boston, MA, USA.
  • Turnbull C; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Wareham NJ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Gudbjartsson DF; Division of Molecular Pathology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
  • Kamatani Y; William Harvey Research Institute, Queen Mary University, London, UK.
  • Hoffmann ER; MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
  • Jackson SP; deCODE Genetics, Amgen, Reykjavík, Iceland.
  • Stefansson K; School of Engineering and Natural Sciences, University of Iceland, Reykjavík, Iceland.
Nature ; 575(7784): 652-657, 2019 11.
Article in En | MEDLINE | ID: mdl-31748747
ABSTRACT
Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Chromosome Deletion / Genetic Predisposition to Disease / Chromosomes, Human, Y / Genomic Instability / Leukocytes / Mosaicism Limits: Adult / Aged / Female / Humans / Male / Middle aged Country/Region as subject: Europa Language: En Journal: Nature Year: 2019 Type: Article Affiliation country: United kingdom
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Chromosome Deletion / Genetic Predisposition to Disease / Chromosomes, Human, Y / Genomic Instability / Leukocytes / Mosaicism Limits: Adult / Aged / Female / Humans / Male / Middle aged Country/Region as subject: Europa Language: En Journal: Nature Year: 2019 Type: Article Affiliation country: United kingdom