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

被引:114
|
作者
Wright, Daniel J. [1 ]
Day, Felix R. [1 ]
Kerrison, Nicola D. [1 ]
Zink, Florian [2 ]
Cardona, Alexia [1 ]
Sulem, Patrick [2 ]
Thompson, Deborah J. [3 ]
Sigurjonsdottir, Svanhvit [2 ]
Gudbjartsson, Daniel F. [2 ]
Helgason, Agnar [2 ]
Chapman, J. Ross [4 ]
Jackson, Steve P. [5 ,6 ]
Langenberg, Claudia [1 ]
Wareham, Nicholas J. [1 ]
Scott, Robert A. [1 ]
Thorsteindottir, Unnur [2 ,7 ]
Ong, Ken K. [1 ,8 ]
Stefansson, Kari [2 ,7 ]
Perry, John R. B. [1 ]
机构
[1] Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England
[2] Amgen Inc, deCODE Genet, Reykjavik, Iceland
[3] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England
[4] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England
[5] Univ Cambridge, Wellcome Trust & Canc Res UK Gurdon Inst, Cambridge, England
[6] Univ Cambridge, Dept Biochem, Cambridge, England
[7] Univ Iceland, Fac Med, Reykjavik, Iceland
[8] Univ Cambridge, Dept Pediat, Cambridge, England
基金
英国医学研究理事会; 英国惠康基金;
关键词
PROTEIN; LOCI; IDENTIFICATION; MECHANISMS; RISK; METAANALYSIS; RESOLUTION; EXPRESSION; APOPTOSIS; RESOURCE;
D O I
10.1038/ng.3821
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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 x 10-8) that are associated with mLOY. Cumulatively, these loci also predicted X chromosome loss in women (n = 96,123; P = 4 x 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.
引用
收藏
页码:674 / +
页数:8
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