Predictors of mosaic chromosome Y loss and associations with mortality in the UK Biobank

Abstract

Mosaic loss of the Y chromosome (mLOY) is the most commonly reported large structural somatic event. Previous studies have indicated age and cigarette smoking increase the risk of mLOY, but the relationship of other exposures with mLOY and mLOY with disease has not been adequately investigated. We characterized mLOY in a large cohort of 223,338 men from the UK Biobank by scanning for deviations in genotyping array median log2 intensity ratios (mLRR) of the Y chromosome using a standard algorithm. A total of 3,789 (1.7%) men showed evidence for mLOY (mLRR < −0.15). In multivariable-adjusted logistic regression models, we found that mLOY increases exponentially with age (overall P-value < 4.9 × 10−324; p-value for the quadratic term = 2.1 × 10−7), and observed a strong association with current smoking (P-value = 7.8 × 10−184). We observed less mLOY in men of African ancestry (0.4%) compared to men of European ancestry (1.8%, P-value = 0.003). Although mLOY was not associated with prevalent cancer (P-value = 0.61), associations were observed for diabetes (P-value = 0.003) and cardiovascular disease (P-value = 0.01). Using Cox proportional hazards regression models, mLOY was associated with all-cause mortality among men with a high proportion of cells affected (mLRR < −0.40; HR = 1.35, 95% CI = 1.08–1.70, P-value = 0.009). In conclusion, mLOY was associated with several health-related factors as well as with all-cause mortality. Further functional studies are warranted to understand how and in what way mLOY could influence adult male health.

Genetic predisposition to mosaic Y chromosome loss in blood is associated with genomic instability in other tissues and susceptibility to non-haematological cancers

“…Additionally, the LOY-associated genes encoding cyclins and cyclindependent kinases, CCND3, CDKN1B and CDKN1C, are also implicated in pancreatic β-cell growth and maturation. We hypothesise that the previously reported association between clonal mosaicism in blood and T2D 15,46 may reflect a common susceptibility to cell cycle dysregulation and genome instability, which lead to both increased clonal mosaicism and reduced pancreatic β -cell mass.…”

“…We developed a new statistical approach for identifying male individuals with LOY based on allelespecific genotyping intensities in the pseudoautosomal region (PAR) of the sex chromosomes. In contrast to previous work that has quantified Y chromosome loss based on median genotyping intensity over the non-pseudoautosomal region of the Y chromosome (mLRR-Y) [12][13][14][15] , our approach leverages the diploid nature of the PAR to ascertain mosaic Y loss based on differences between maternal (X PAR) vs. paternal (Y PAR) allelic intensities at heterozygous sites: mosaic Y loss causes Y PAR intensities to decrease relative to X PAR intensities. This intuition can be harnessed even in population cohorts in which absolute phase information (i.e., information about maternal vs. paternal inheritance of alleles) is unavailable: we can overcome this obstacle by performing statistical phasing and subsequently identifying evidence of an imbalance in allelic intensities between the two statistically phased haplotypes (accounting for the possibility of phase switch errors) 5,6 .…”

“…Previous studies have demonstrated robust associations with age, sex (clonal mosaicism is more frequent in males), smoking and inherited germline genetic predisposition 2,4,[10][11][12][13][14][15] . Recent epidemiological studies have challenged the view that LOY in the hematopoietic system is a phenotypically neutral event, with epidemiological associations observed with various forms of cancer 13,[16][17][18][19][20] , autoimmune conditions 21,22 , age-related macular degeneration 23 , cardiovascular disease 24 , Alzheimer's disease 25 , type 2 diabetes 15 , obesity 15 , and all-cause mortality 15,16 . The extent to which such observations represent a causal association, reverse causality or confounding is unclear.…”

Immune cells lacking Y chromosome have widespread dysregulation of autosomal genes

“…We provide the first mechanistic explanation for the associations between LOY in blood and risk for disease in other organs.Recent epidemiological analyses have challenged the view that LOY in blood cells is phenotypically neutral. Studies have identified increased risks for men with LOY in connection with all-cause mortality [8,9], Alzheimer's disease [10], various forms of cancer [8,[11][12][13], autoimmune conditions [14,15], age-related macular degeneration [16], cardiovascular disease [17], type 2 diabetes and obesity [9]. Furthermore, it has been known for centuries that males have a shorter life expectancy [18][19][20].…”

MADloy: Robust detection of mosaic loss of chromosome Y from genotype-array-intensity data

“…The most common somatic mutation in humans is the mosaic loss of chromosome Y (mLOY) in men. Recent evidence suggests the important role of mLOY in numerous diseases, being a biological factor that contributes to overall male mortality (1,2) and, therefore, is likely to play an important role in male-specific treatments of disease. In particular, mLOY in blood cells increases with age, and is associated with smoking and with the risk of several age-related disorders, including hematological and non-hematological cancers, macular degeneration (3), Alzheimer's disease (4), major cardiovascular events (5) and suicidal behaviors (6).…”