Genetic predisposition to mosaic Y chromosome loss in blood

作者：Deborah J. Thompson, The Kidney Cancer GWAS Meta-Analysis Project, 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 Law, Rong Li, Chey Loveday, Jonas Mattisson, Steven A. McCarroll, Yoshinori Murakami, Anna Murray, Paweł Olszewski, Edyta Rychlicka-Buniowska, Robert A. Scott, Unnur Þorsteinsdóttir, Ian Tomlinson, Behrooz Torabi Moghadam, Clare Turnbull, Nicholas J. Wareham, Daníel F. Guðbjartsson, Yoichiro Kamatani, Eva R. Hoffmann, Steve P. Jackson, Kāri Stefánsson, Adam Auton, Ken K. Ong, Mitchell J. Machiela, Po‐Ru Loh, Jan P. Dumanski, Stephen J. Chanock, Lars A. Forsberg, John R. B. Perry · 发表于：Nature · 年份：2019 · DOI：10.1038/s41586-019-1765-3 · 被引用次数：360 · 研究领域：Genetic Associations and Epidemiology、Genomic variations and chromosomal abnormalities、Genetics and Neurodevelopmental Disorders

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. A genome-wide association study of mosaic loss of chromosome Y (LOY) in UK Biobank participants identifies 156 genetic determinants of LOY, showing that LOY is associated with cancer and non-haematological health outcomes.