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Genetic predisposition to mosaic Y chromosome loss in blood is associated with genomic instability in other tissues and susceptibility to non-haematological cancers

Deborah J. Thompson, Giulio Genovese, Jonatan Halvardson, Jacob C. Ulirsch, Daniel J. Wright, Chikashi Terao, Olafur B. Davidsson, Felix R. Day, Patrick Sulem, Yunxuan Jiang, Marcus Danielsson, Hanna Davies, Joe Dennis, Malcolm G. Dunlop, Douglas F. Easton, Victoria A. Fisher, Florian Zink, Richard S. Houlston, Martin Ingelsson, Siddhartha Kar, Nicola D. Kerrison, Ragnar P. Kristjansson, Rong Li, Chey Loveday, Jonas Mattisson, Steven A. McCarroll, Yoshinori Murakami, Anna Murray, Pawel Olszewski, Edyta Rychlicka-Buniowska, Robert A. Scott, Unnur Thorsteinsdottir, Ian Tomlinson, Behrooz Torabi Moghadam, Clare Turnbull, Nicholas J. Wareham, Daniel F. Gudbjartsson, INTEGRAL-ILCCO, The Breast Cancer Association Consortium, CIMBA, The Endometrial Cancer Association Consortium, The Ovarian Cancer Association Consortium, The PRACTICAL Consortium, The Kidney Cancer GWAS Meta-Analysis Project, eQTLGen Consortium, BIOS Consortium, 23andMe Research Team, Yoichiro Kamatani, Hilary K. Finucane, Eva R. Hoffmann, Steve P. Jackson, Kari Stefansson, Adam Auton, Ken K. Ong, Mitchell J. Machiela, Po-Ru Loh, Jan P. Dumanski, Stephen J. Chanock, Lars A. Forsberg, John R. B. Perry
doi: https://doi.org/10.1101/514026
Deborah J. Thompson
1Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, UK
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Giulio Genovese
2Department of Genetics, Harvard Medical School, Boston, MA, USA
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Jonatan Halvardson
5Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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Jacob C. Ulirsch
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
6Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA
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Daniel J. Wright
7MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK
8Open Targets Core Genetics, Wellcome Sanger Institute, Hinxton, UK
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Chikashi Terao
9Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
10Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan
11The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka Japan
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Olafur B. Davidsson
12deCODE Genetics-Amgen, Inc., Reykjavik, Iceland
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Felix R. Day
7MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK
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Patrick Sulem
12deCODE Genetics-Amgen, Inc., Reykjavik, Iceland
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Yunxuan Jiang
1323andMe, Inc., Mountain View, CA, 94041, USA
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Marcus Danielsson
5Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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Hanna Davies
5Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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Joe Dennis
1Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, UK
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Malcolm G. Dunlop
14Colon 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, United Kingdom
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Douglas F. Easton
1Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, UK
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Victoria A. Fisher
15Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
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Florian Zink
12deCODE Genetics-Amgen, Inc., Reykjavik, Iceland
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Richard S. Houlston
16Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK
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Martin Ingelsson
17Department of Public Health and Caring Sciences / Geriatrics, Uppsala University, 751 85 Uppsala, Sweden
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Siddhartha Kar
18Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
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Nicola D. Kerrison
7MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK
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Ragnar P. Kristjansson
12deCODE Genetics-Amgen, Inc., Reykjavik, Iceland
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Rong Li
19Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States
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Chey Loveday
16Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK
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Jonas Mattisson
5Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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Steven A. McCarroll
2Department of Genetics, Harvard Medical School, Boston, MA, USA
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
4Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Yoshinori Murakami
20Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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Anna Murray
21Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK
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Pawel Olszewski
22Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland
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Edyta Rychlicka-Buniowska
5Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
22Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland
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Robert A. Scott
7MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK
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Unnur Thorsteinsdottir
12deCODE Genetics-Amgen, Inc., Reykjavik, Iceland
23Faculty of Medicine, University of Iceland, Reykjavik, Iceland
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Ian Tomlinson
24Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
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Behrooz Torabi Moghadam
5Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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Clare Turnbull
16Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK
25William Harvey Research Institute, Queen Mary University, London, UK
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Nicholas J. Wareham
7MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK
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Daniel F. Gudbjartsson
12deCODE Genetics-Amgen, Inc., Reykjavik, Iceland
26School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland
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Yoichiro Kamatani
9Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
27Kyoto-McGill International Collaborative School in Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
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Hilary K. Finucane
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
28Schmidt Fellows Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Eva R. Hoffmann
29DNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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Steve P. Jackson
30Department of Biochemistry, University of Cambridge, Cambridge, UK
31Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK
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Kari Stefansson
12deCODE Genetics-Amgen, Inc., Reykjavik, Iceland
23Faculty of Medicine, University of Iceland, Reykjavik, Iceland
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Adam Auton
1323andMe, Inc., Mountain View, CA, 94041, USA
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Ken K. Ong
7MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK
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Mitchell J. Machiela
15Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
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Po-Ru Loh
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
32Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
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Jan P. Dumanski
5Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
22Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland
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Stephen J. Chanock
15Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
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Lars A. Forsberg
5Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
33Beijer Laboratory of Genome Research, Uppsala University, Uppsala, Sweden
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John R. B. Perry
7MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK
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Abstract

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism, yet our knowledge of the causes and consequences of this is limited. Using a newly developed approach, we estimate that 20% of the UK Biobank male population (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 involved in cell-cycle regulation, cancer susceptibility, somatic drivers of tumour growth and cancer therapy targets. Genetic susceptibility to LOY is associated with non-haematological health outcomes in both men and women, supporting the hypothesis that clonal haematopoiesis is a biomarker of genome instability in other tissues. Single-cell RNA sequencing identifies dysregulated autosomal gene expression in leukocytes with LOY, providing insights into how LOY may confer cellular growth advantage. Collectively, these data highlight the utility of studying clonal mosaicism to uncover fundamental mechanisms underlying cancer and other ageing-related diseases.

Footnotes

  • ↵# Consortium membership is listed in the supplementary section

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Genetic predisposition to mosaic Y chromosome loss in blood is associated with genomic instability in other tissues and susceptibility to non-haematological cancers
Deborah J. Thompson, Giulio Genovese, Jonatan Halvardson, Jacob C. Ulirsch, Daniel J. Wright, Chikashi Terao, Olafur B. Davidsson, Felix R. Day, Patrick Sulem, Yunxuan Jiang, Marcus Danielsson, Hanna Davies, Joe Dennis, Malcolm G. Dunlop, Douglas F. Easton, Victoria A. Fisher, Florian Zink, Richard S. Houlston, Martin Ingelsson, Siddhartha Kar, Nicola D. Kerrison, Ragnar P. Kristjansson, Rong Li, Chey Loveday, Jonas Mattisson, Steven A. McCarroll, Yoshinori Murakami, Anna Murray, Pawel Olszewski, Edyta Rychlicka-Buniowska, Robert A. Scott, Unnur Thorsteinsdottir, Ian Tomlinson, Behrooz Torabi Moghadam, Clare Turnbull, Nicholas J. Wareham, Daniel F. Gudbjartsson, INTEGRAL-ILCCO, The Breast Cancer Association Consortium, CIMBA, The Endometrial Cancer Association Consortium, The Ovarian Cancer Association Consortium, The PRACTICAL Consortium, The Kidney Cancer GWAS Meta-Analysis Project, eQTLGen Consortium, BIOS Consortium, 23andMe Research Team, Yoichiro Kamatani, Hilary K. Finucane, Eva R. Hoffmann, Steve P. Jackson, Kari Stefansson, Adam Auton, Ken K. Ong, Mitchell J. Machiela, Po-Ru Loh, Jan P. Dumanski, Stephen J. Chanock, Lars A. Forsberg, John R. B. Perry
bioRxiv 514026; doi: https://doi.org/10.1101/514026
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Genetic predisposition to mosaic Y chromosome loss in blood is associated with genomic instability in other tissues and susceptibility to non-haematological cancers
Deborah J. Thompson, Giulio Genovese, Jonatan Halvardson, Jacob C. Ulirsch, Daniel J. Wright, Chikashi Terao, Olafur B. Davidsson, Felix R. Day, Patrick Sulem, Yunxuan Jiang, Marcus Danielsson, Hanna Davies, Joe Dennis, Malcolm G. Dunlop, Douglas F. Easton, Victoria A. Fisher, Florian Zink, Richard S. Houlston, Martin Ingelsson, Siddhartha Kar, Nicola D. Kerrison, Ragnar P. Kristjansson, Rong Li, Chey Loveday, Jonas Mattisson, Steven A. McCarroll, Yoshinori Murakami, Anna Murray, Pawel Olszewski, Edyta Rychlicka-Buniowska, Robert A. Scott, Unnur Thorsteinsdottir, Ian Tomlinson, Behrooz Torabi Moghadam, Clare Turnbull, Nicholas J. Wareham, Daniel F. Gudbjartsson, INTEGRAL-ILCCO, The Breast Cancer Association Consortium, CIMBA, The Endometrial Cancer Association Consortium, The Ovarian Cancer Association Consortium, The PRACTICAL Consortium, The Kidney Cancer GWAS Meta-Analysis Project, eQTLGen Consortium, BIOS Consortium, 23andMe Research Team, Yoichiro Kamatani, Hilary K. Finucane, Eva R. Hoffmann, Steve P. Jackson, Kari Stefansson, Adam Auton, Ken K. Ong, Mitchell J. Machiela, Po-Ru Loh, Jan P. Dumanski, Stephen J. Chanock, Lars A. Forsberg, John R. B. Perry
bioRxiv 514026; doi: https://doi.org/10.1101/514026

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