Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility.
Kerrison, Nicola D
Gudbjartsson, Daniel F
Chapman, J Ross
Nature Publishing Group
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Wright, D., Day, F., Kerrison, N. D., Zink, F., Cardona, A., Sulem, P., Nunn, D., et al. (2017). Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility.. Nature genetics, 49 674-679. https://doi.org/10.1038/ng.3821
The Y-chromosome is frequently lost in hematopoietic cells, representing the most common somatic mutation in men. However, the mechanisms regulating mosaic loss of chromosomeY (mLOY), and its clinical relevance, are unknown. Using genotype array intensity data and sequence reads in 85,542 men, we identify 19 genomic regions (P<5x10‾⁸) associated with mLOY. Cumulatively, these loci also predicted X-chromosome loss in women (N=96,123, P=4x10‾⁶). Additional epigenome-wide methylation analyses in whole blood highlighted 36 differentially methylated sites associated with mLOY. Identified genes converge on aspects of cell proliferation and cell-cycle regulation, including DNA synthesis (NPAT), DNA damage response (ATM), mitosis (PMF1-CENPN-MAD1L1) and apoptosis (TP53). We highlight shared genetic architecture between mLOY and cancer susceptibility, in addition to inferring a causal effect of smoking on mLOY. Collectively, our results demonstrate that genotype array intensity data enable a measure of cell-cycle efficiency at population scale, identifying genes implicated in aneuploidy, genome instability and cancer susceptibility.
Chromosomes, Human, X, Chromosomes, Human, Y, Humans, Neoplasms, Chromosome Deletion, Genetic Predisposition to Disease, Genomic Instability, Cell Cycle, DNA Methylation, Genotype, Polymorphism, Single Nucleotide, Genome, Human, Female, Male, INDEL Mutation, Genetic Variation, Genome-Wide Association Study
This research has been conducted using the UK Biobank Resource under Application Number 9905. This work was supported by the UK Medical Research Council (Unit Programme numbers MC_UU_12015/1 and MC_UU_12015/2). Research in the S. Jackson laboratory is funded by Cancer Research UK (CRUK; programme grant C6/A18796), with Institute core funding provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S. Jackson receives salary from the University of Cambridge, supplemented by CRUK.
MEDICAL RESEARCH COUNCIL (MR/L00002/1)
Cancer Research UK (A18796)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0512-10135)
Medical Research Council (MC_EX_MR/L100002/1)
Wellcome Trust (092096/Z/10/Z)
Cancer Research UK (A14492)
External DOI: https://doi.org/10.1038/ng.3821
This record's URL: https://www.repository.cam.ac.uk/handle/1810/262877