Genetic predisposition to mosaic Y chromosome loss in blood.

Thompson DJ, Genovese G, Halvardson J, Ulirsch JC, Wright DJ, Terao C, Davidsson OB, Day FR, Sulem P, Jiang Y, Danielsson M, Davies H, Dennis J, Dunlop MG, Easton DF, Fisher VA, Zink F, Houlston RS, Ingelsson M, Kar S, Kerrison ND, Kinnersley B, Kristjansson RP, Law PJ, Li R, Loveday C, Mattisson J, McCarroll SA, Murakami Y, Murray A, Olszewski P, Rychlicka-Buniowska E, Scott RA, Thorsteinsdottir U, Tomlinson I, Moghadam BT, Turnbull C, Wareham NJ, Gudbjartsson DF, International Lung Cancer Consortium (INTEGRAL-ILCCO) , Breast Cancer Association Consortium , Consortium of Investigators of Modifiers of BRCA1/2 , Endometrial Cancer Association Consortium , Ovarian Cancer Association Consortium , Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) Consortium , Kidney Cancer GWAS Meta-Analysis Project , eQTLGen Consortium , Biobank-based Integrative Omics Study (BIOS) Consortium , 23andMe Research Team , Kamatani Y, Hoffmann ER, Jackson SP, Stefansson K, Auton A, Ong KK, Machiela MJ, Loh PR, Dumanski JP, Chanock SJ, Forsberg LA, Perry JRB

Nature 575 (7784) 652-657 [2019-11-00; online 2019-11-20]

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism 1-5, 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.

NGI Uppsala (SNP&SEQ Technology Platform) [Service]

National Genomics Infrastructure [Service]

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PubMed 31748747

DOI 10.1038/s41586-019-1765-3

Crossref 10.1038/s41586-019-1765-3

pii: 10.1038/s41586-019-1765-3
pmc: PMC6887549
mid: EMS84547