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.

Figure 1. Estimated X and Y chromosome loss with age in the Icelandic deCODE study.

(A) Y chromosome copy number estimated in 8703 males from whole genome sequencing. (B) X chromosome copy-number for 9280 females. In each case, the black line indicates the line of best fit with age at blood collection as a linear predictor.

Figure 2. Association of 19 SNP mLOY genetic risk score on X loss in women.

The genetic risk score is additive, based on mLRR-Y increasing allele dosage.

Figure 3. Overview of identified genes implicated in Y chromosome loss.

Genes falling within GWAS loci are shown in blue, those implicated by methylation analyses in green. Grey boxes highlight specific checkpoints, signalling cascades, or enzymes of note. Green arrows denote activation of a target by phosphorylation, blue arrows a signalling cascade and its ultimate effect.