Genetic predisposition to mosaic Y chromosome loss in blood

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, Ben Kinnersley, Ragnar P. Kristjansson, Philip J. Law, 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, Yoichiro Kamatani, 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 and John R. B. Perry ()
Additional contact information
Deborah J. Thompson: University of Cambridge
Giulio Genovese: Harvard Medical School
Jonatan Halvardson: Uppsala University
Jacob C. Ulirsch: Broad Institute of MIT and Harvard
Daniel J. Wright: University of Cambridge
Chikashi Terao: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences
Olafur B. Davidsson: deCODE Genetics, Amgen
Felix R. Day: University of Cambridge
Patrick Sulem: deCODE Genetics, Amgen
Yunxuan Jiang: 23andMe
Marcus Danielsson: Uppsala University
Hanna Davies: Uppsala University
Joe Dennis: University of Cambridge
Malcolm G. Dunlop: University of Edinburgh, Western General Hospital
Douglas F. Easton: University of Cambridge
Victoria A. Fisher: National Cancer Institute
Florian Zink: deCODE Genetics, Amgen
Richard S. Houlston: The Institute of Cancer Research
Martin Ingelsson: Uppsala University
Siddhartha Kar: University of Cambridge
Nicola D. Kerrison: University of Cambridge
Ben Kinnersley: The Institute of Cancer Research
Ragnar P. Kristjansson: deCODE Genetics, Amgen
Philip J. Law: The Institute of Cancer Research
Rong Li: Johns Hopkins University School of Medicine
Chey Loveday: The Institute of Cancer Research
Jonas Mattisson: Uppsala University
Steven A. McCarroll: Harvard Medical School
Yoshinori Murakami: University of Tokyo
Anna Murray: University of Exeter
Pawel Olszewski: Medical University of Gdansk
Edyta Rychlicka-Buniowska: Uppsala University
Robert A. Scott: University of Cambridge
Unnur Thorsteinsdottir: deCODE Genetics, Amgen
Ian Tomlinson: University of Birmingham
Behrooz Torabi Moghadam: Uppsala University
Clare Turnbull: The Institute of Cancer Research
Nicholas J. Wareham: University of Cambridge
Daniel F. Gudbjartsson: deCODE Genetics, Amgen
Yoichiro Kamatani: Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences
Eva R. Hoffmann: University of Copenhagen
Steve P. Jackson: University of Cambridge
Kari Stefansson: deCODE Genetics, Amgen
Adam Auton: 23andMe
Ken K. Ong: University of Cambridge
Mitchell J. Machiela: National Cancer Institute
Po-Ru Loh: Broad Institute of MIT and Harvard
Jan P. Dumanski: Uppsala University
Stephen J. Chanock: National Cancer Institute
Lars A. Forsberg: Uppsala University
John R. B. Perry: University of Cambridge

Nature, 2019, vol. 575, issue 7784, 652-657

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1765-3

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