Genetic predisposition to mosaic Y chromosome loss in blood is associated with genomic instability in other tissues and susceptibility to non-haematological cancers
By
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 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
Posted 08 Jan 2019
bioRxiv DOI: 10.1101/514026
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.
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