title: Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility.
abstract: The Y chromosome is frequently lost in hematopoietic cells, which represents the most common somatic alteration in men. However, the mechanisms that regulate mosaic loss of chromosome Y (mLOY), and its clinical relevance, are unknown. We used genotype-array-intensity data and sequence reads from 85,542 men to identify 19 genomic regions (P < 5 × 10-8) that are associated with mLOY. Cumulatively, these loci also predicted X chromosome loss in women (n = 96,123; P = 4 × 10-6). Additional epigenome-wide methylation analyses using whole blood highlighted 36 differentially methylated sites associated with mLOY. The genes identified converge on aspects of cell proliferation and cell cycle regulation, including DNA synthesis (NPAT), DNA damage response (ATM), mitosis (PMF1, CENPN and MAD1L1) and apoptosis (TP53). We highlight the 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 enables a measure of cell cycle efficiency at population scale and identifies genes implicated in aneuploidy, genome instability and cancer susceptibility.
authors.affiliation: MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Daniel J
authors.identifier: http://orcid.org/0000-0003-3983-2093
authors.initials: DJ
authors.lastname: Wright
authors.affiliation: MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Felix R
authors.identifier: http://orcid.org/0000-0003-3789-7651
authors.initials: FR
authors.lastname: Day
authors.affiliation: MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Nicola D
authors.initials: ND
authors.lastname: Kerrison
authors.affiliation: deCODE Genetics-Amgen, Inc., Reykjavik, Iceland.
authors.forename: Florian
authors.initials: F
authors.lastname: Zink
authors.affiliation: MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Alexia
authors.initials: A
authors.lastname: Cardona
authors.affiliation: deCODE Genetics-Amgen, Inc., Reykjavik, Iceland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.affiliation: Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Deborah J
authors.identifier: http://orcid.org/0000-0003-1465-5799
authors.initials: DJ
authors.lastname: Thompson
authors.affiliation: deCODE Genetics-Amgen, Inc., Reykjavik, Iceland.
authors.forename: Svanhvit
authors.initials: S
authors.lastname: Sigurjonsdottir
authors.affiliation: deCODE Genetics-Amgen, Inc., Reykjavik, Iceland.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.affiliation: deCODE Genetics-Amgen, Inc., Reykjavik, Iceland.
authors.forename: Agnar
authors.initials: A
authors.lastname: Helgason
authors.affiliation: Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: J Ross
authors.identifier: http://orcid.org/0000-0002-6477-4254
authors.initials: JR
authors.lastname: Chapman
authors.affiliation: Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.|Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: Steve P
authors.initials: SP
authors.lastname: Jackson
authors.affiliation: MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.affiliation: MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.affiliation: MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Scott
authors.affiliation: deCODE Genetics-Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteindottir
authors.affiliation: MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.|Department of Pediatrics, University of Cambridge, Cambridge, UK.
authors.forename: Ken K
authors.initials: KK
authors.lastname: Ong
authors.affiliation: deCODE Genetics-Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.affiliation: MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
authors.forename: John R B
authors.initials: JRB
authors.lastname: Perry
mesh_terms: D002453:Cell Cycle / Q000235:genetics*; D002872:Chromosome Deletion; D041321:Chromosomes, Human, X / Q000235:genetics; D041322:Chromosomes, Human, Y / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods / Q000706:statistics & numerical data; D042822:Genomic Instability; D005838:Genotype; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide