Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility

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.

[1]  D. Compton,et al.  Mechanisms of Chromosomal Instability , 2010, Current Biology.

[2]  Hollis G. Potter,et al.  Author Manuscript , 2013 .

[3]  A. Amon,et al.  Short- and long-term effects of chromosome mis-segregation and aneuploidy , 2015, Nature Reviews Molecular Cell Biology.

[4]  C. Gieger,et al.  Sequence variants at CHRNB 3 – CHRNA 6 and CYP 2 A 6 affect smoking behavior , 2010 .

[5]  Roman Körner,et al.  Human TPX2 is required for targeting Aurora-A kinase to the spindle , 2002, The Journal of cell biology.

[6]  Minoru Kanehisa,et al.  KEGG as a reference resource for gene and protein annotation , 2015, Nucleic Acids Res..

[7]  Abdelghani Mazouzi,et al.  DNA replication stress: causes, resolution and disease. , 2014, Experimental cell research.

[8]  William Wheeler,et al.  Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome , 2016, Nature Communications.

[9]  Ashish Choudhary,et al.  High-throughput RNAi Screening Identifies a Role for TNK1 in Growth and Survival of Pancreatic Cancer Cells , 2011, Molecular Cancer Research.

[10]  Lars Lind,et al.  Smoking is associated with mosaic loss of chromosome Y , 2015, Science.

[11]  C. Gieger,et al.  Sequence variants at CHRNB3–CHRNA6 and CYP2A6 affect smoking behavior , 2010, Nature Genetics.

[12]  Ceramide signaling in apoptosis. , 1997, British medical bulletin.

[13]  Lars Lind,et al.  Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer , 2014, Nature Genetics.

[14]  Rafael A. Irizarry,et al.  Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays , 2014, Bioinform..

[15]  Nazneen Rahman,et al.  Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14 , 2013, Nature Genetics.

[16]  C. Lindgren,et al.  Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease , 2016, American journal of human genetics.

[17]  P. Visscher,et al.  Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets , 2016, Nature Genetics.

[18]  A. Desai,et al.  Molecular architecture of the kinetochore–microtubule interface , 2008, Nature Reviews Molecular Cell Biology.

[19]  D. Reverter,et al.  DYNLL/LC8 Protein Controls Signal Transduction through the Nek9/Nek6 Signaling Module by Regulating Nek6 Binding to Nek9 , 2011, The Journal of Biological Chemistry.

[20]  L. Attardi,et al.  Unravelling mechanisms of p53-mediated tumour suppression , 2014, Nature Reviews Cancer.

[21]  A. Yasui,et al.  The Novel Zinc Finger Protein dASCIZ Regulates Mitosis in Drosophila via an Essential Role in Dynein Light-Chain Expression , 2013, Genetics.

[22]  Joseph T. Glessner,et al.  PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. , 2007, Genome research.

[23]  F. Camargo,et al.  Cytokinesis Failure Triggers Hippo Tumor Suppressor Pathway Activation , 2014, Cell.

[24]  Bjarni V. Halldórsson,et al.  Large-scale whole-genome sequencing of the Icelandic population , 2015, Nature Genetics.

[25]  Jian Gu,et al.  Mosaic loss of chromosome Y is associated with common variation near TCL1A , 2016, Nature Genetics.

[26]  J. Frost,et al.  Controlling the switches: Rho GTPase regulation during animal cell mitosis. , 2014, Cellular signalling.

[27]  Peter E. Czabotar,et al.  Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy , 2013, Nature Reviews Molecular Cell Biology.

[28]  D. Cleveland,et al.  Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis , 2009, Nature Reviews Molecular Cell Biology.

[29]  Nazneen Rahman,et al.  Meta-analysis identifies four new loci associated with testicular germ cell tumor , 2013, Nature Genetics.

[30]  Kari Stefansson,et al.  A germline variant in the TP53 polyadenylation signal confers cancer susceptibility , 2011, Nature Genetics.

[31]  T. Kataoka,et al.  Regulation of mitotic spindle formation by the RhoA guanine nucleotide exchange factor ARHGEF10 , 2009, BMC Cell Biology.

[32]  W. Lamers,et al.  Possible roles of DLK1 in the Notch pathway during development and disease. , 2012, Biochimica et biophysica acta.

[33]  Bonnie Berger,et al.  Efficient Bayesian mixed model analysis increases association power in large cohorts , 2014 .

[34]  G. Davey Smith,et al.  Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator , 2016, Genetic epidemiology.

[35]  K. Helin,et al.  NPAT Expression Is Regulated by E2F and Is Essential for Cell Cycle Progression , 2003, Molecular and Cellular Biology.

[36]  J. Horwood.  UK Biobank Data: Come and Get It , 2014 .

[37]  T. Lehtimäki,et al.  Integrative approaches for large-scale transcriptome-wide association studies , 2015, Nature Genetics.

[38]  P. Elliott,et al.  UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age , 2015, PLoS medicine.

[39]  S. Elledge,et al.  Checking on the fork: the DNA-replication stress-response pathway. , 2002, Trends in cell biology.

[40]  P. Yen,et al.  DAZAP1, an hnRNP protein, is required for normal growth and spermatogenesis in mice. , 2008, RNA.

[41]  R. Mott,et al.  A Genome-Wide Association Study for Regulators of Micronucleus Formation in Mice , 2016, G3: Genes, Genomes, Genetics.

[42]  J. Laine,et al.  The protooncogene TCL1 is an Akt kinase coactivator. , 2000, Molecular cell.

[43]  M. Christmann,et al.  Transcriptional regulation of human DNA repair genes following genotoxic stress: trigger mechanisms, inducible responses and genotoxic adaptation , 2013, Nucleic acids research.

[44]  G. Sluder,et al.  Prolonged Prometaphase Blocks Daughter Cell Proliferation Despite Normal Completion of Mitosis , 2010, Current Biology.

[45]  D. Adelson,et al.  HENMT1 and piRNA Stability Are Required for Adult Male Germ Cell Transposon Repression and to Define the Spermatogenic Program in the Mouse , 2015, PLoS genetics.

[46]  Ellen T. Gelfand,et al.  The Genotype-Tissue Expression (GTEx) project , 2013, Nature Genetics.

[47]  M. Yamashita,et al.  Stress-induced ceramide generation and apoptosis via the phosphorylation and activation of nSMase1 by JNK signaling , 2014, Cell Death and Differentiation.

[48]  L. Schermelleh,et al.  Dynein light chain 1 and a spindle-associated adaptor promote dynein asymmetry and spindle orientation , 2012, The Journal of cell biology.

[49]  Haroon Naeem,et al.  Reducing the risk of false discovery enabling identification of biologically significant genome-wide methylation status using the HumanMethylation450 array , 2014, BMC Genomics.

[50]  N. Day,et al.  EPIC-Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer. , 1999, British journal of cancer.

[51]  Liang Niu,et al.  ENmix: a novel background correction method for Illumina HumanMethylation450 BeadChip , 2015, Nucleic acids research.

[52]  M. Peters,et al.  Systematic identification of trans eQTLs as putative drivers of known disease associations , 2013, Nature Genetics.

[53]  Devin C. Koestler,et al.  DNA methylation arrays as surrogate measures of cell mixture distribution , 2012, BMC Bioinformatics.

[54]  Peter Kraft,et al.  A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer , 2014, Nature Genetics.

[55]  Ali Amin Al Olama,et al.  The genetic epidemiology of prostate cancer and its clinical implications , 2014, Nature Reviews Urology.

[56]  G. Kroemer,et al.  Apoptosis and genomic instability , 2004, Nature Reviews Molecular Cell Biology.

[57]  J. Heierhorst,et al.  ATM Substrate Chk2-interacting Zn2+ Finger (ASCIZ) Is a Bi-functional Transcriptional Activator and Feedback Sensor in the Regulation of Dynein Light Chain (DYNLL1) Expression* , 2011, The Journal of Biological Chemistry.

[58]  Kaanan P. Shah,et al.  A gene-based association method for mapping traits using reference transcriptome data , 2015, Nature Genetics.

[59]  P. Elliott,et al.  A coherent approach for analysis of the Illumina HumanMethylation450 BeadChip improves data quality and performance in epigenome-wide association studies , 2015, Genome Biology.

[60]  William Wheeler,et al.  Detectable clonal mosaicism and its relationship to aging and cancer , 2012, Nature Genetics.

[61]  K. Cimprich,et al.  Causes and consequences of replication stress , 2013, Nature Cell Biology.

[62]  Manolis Kellis,et al.  HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants , 2011, Nucleic Acids Res..

[63]  Ayellet V. Segrè,et al.  Common Inherited Variation in Mitochondrial Genes Is Not Enriched for Associations with Type 2 Diabetes or Related Glycemic Traits , 2010, PLoS genetics.

[64]  Alexander R. Pico,et al.  Analysis of 60 Reported Glioma Risk SNPs Replicates Published GWAS Findings but Fails to Replicate Associations From Published Candidate‐Gene Studies , 2013, Genetic epidemiology.

[65]  H. Hakonarson,et al.  Rare variants in TP53 and susceptibility to neuroblastoma. , 2014, Journal of the National Cancer Institute.

[66]  Susan L. Kline,et al.  The human Mis12 complex is required for kinetochore assembly and proper chromosome segregation , 2006, The Journal of cell biology.

[67]  A. Hofman,et al.  Disease variants alter transcription factor levels and methylation of their binding sites , 2016, Nature Genetics.

[68]  M. Daly,et al.  An Atlas of Genetic Correlations across Human Diseases and Traits , 2015, Nature Genetics.

[69]  R. Bowser,et al.  The septin CDCrel-1 binds syntaxin and inhibits exocytosis , 1999, Nature Neuroscience.

[70]  G. Velimezi,et al.  ATMIN is required for the ATM-mediated signaling and recruitment of 53BP1 to DNA damage sites upon replication stress , 2014, DNA repair.

[71]  Peter Kraft,et al.  Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types. , 2016, Cancer discovery.