Genetic predisposition to mosaic Y chromosome loss in blood

• Published in: Nature (London) Vol. 575; no. 7784; pp. 652 - 657
• Main Authors: 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, Perry, John R B
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.11.2019
• Subjects: Adult; Age; Age related diseases; Aged; Aging; Analysis; Biomarkers; Blood circulation; Breast cancer; Cancer; Chromosome Deletion; Chromosomes; Chromosomes, Human, Y - genetics; Colorectal cancer; Computational Biology; Computer applications; Confidence intervals; Databases, Genetic; Diagnosis; Female; Gene expression; Gene sequencing; Genes; Genetic aspects; Genetic engineering; Genetic Markers - genetics; Genetic Predisposition to Disease - genetics; Genetic susceptibility; Genomes; Genomic Instability - genetics; Hematology; Humans; Hypotheses; Identification; Leukocytes; Leukocytes - pathology; Male; Medical Genetics; Medicinsk genetik; Men; Middle Aged; Mosaicism; Neoplasms - genetics; Population; Ribonucleic acid; RNA; Tumors; United Kingdom; Y chromosome; Y chromosomes; United Kingdom; United Kingdom > UK
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-019-1765-3

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. 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.