Mosaic chromosome Y loss is associated with alterations in blood cell counts in UK Biobank men.
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ABSTRACT:
SUBMITTER: Lin SH
PROVIDER: S-EPMC7046668 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC6098142 | biostudies-literature
Project description:BackgroundAge-related macular degeneration (AMD) is the leading cause of severe vision loss in patients over 55 years old in the industrialized world. In the past 20 years, approximately 288 million patents have been affected by this disease. Despite this high prevalence, the molecular mechanism for AMD remains unclear, and there remains no effective treatment for this disease. The mosaic loss of Y chromosome (mLOY) has been identified as a common phenomenon in multiple age-related disease (i.e., oncogenesis and cardiovascular disease) has recently been identified by genome-wide analysis to be linked to AMD as well. As the Y chromosome mainly possesses three genomic functions, sister chromatin cohesion, cell cycle mitosis, and apoptotic signaling, here we characterize the Y chromosome euchromatic genes and non-chromosome AMD genes in relevance to cellular proliferation and apoptotic signaling of leukocytes.ResultsUsing STRING, a publically available database of all protein-protein interaction, Grassmann et al. found the genes on the Y chromosome is mainly believed to take part in three major cellular genomic functions- sister chromatin cohesion, cell cycle mitosis, and apoptotic signaling. Based on data from the Ensembl Genome database, we focus on our discussion on coding genes found in the euchromatins but not the PAR1 and PAR2 regions of the Y chromosomes. All 14 known euchromatic genes on the Y chromosome short arm and all 31 known euchromatic genes on the Y chromosome long arm (Yq) are directly or indirectly involved in the cell cycle (meiosis and mitosis) and proliferation. We sorted non-Y chromosome AMD associated genes into these three categories to identify signaling pathways that may compound with cellular dysregulation due to mLOY. Of the genes associated with AMD, complement pathway genes such as C2, C9 and CFH/ARMD4 are associated with proliferation, receptor-mediated endocytosis genes such as APOE, DAB2 and others associated with apoptotic signaling. Because nucleated cells found in peripheral circulation are mainly composed of leukocytes with reduced expression of CD99, a protein essential for leukocytes adhesion, translocation, and function, mLOY in these cells likely affect retinal degeneration through altered immunological surveillance. In fact, there is precedence that circulating macrophage can stabilize and modify the cardiac rhythm and contractility post ischemic damage. Therefore, the most likely mechanism through which peripheral mLOY affects AMD development in men is through the role affected leukocytes play in retinal proliferation and apoptosis.ConclusionsmLOY in peripheral blood is newly discovered in AMD by Grassmann et al. as it is a common phenomenon in oncogenesis and cardiac dysfunction. Here the recent data conclude the possible mechanism for the newly identified link between mLOY and AMD, and provide support that mLOY in circulating macrophage-monocyte of affected male patients promotes AMD by targeting the retina and causing macular degeneration.
| S-EPMC9153148 | biostudies-literature
Project description:RationaleAsthma is a complex, heterogeneous disease strongly associated with type 2 inflammation, and blood eosinophil counts guide therapeutic interventions in moderate and severe asthma. Eosinophils are leukocytes involved in type 2 immune responses. Despite these critical associations between asthma and blood eosinophil counts, the shared genetic architecture of these two traits remains unknown. The objective of the present study was to characterise the genetic architecture of blood eosinophil counts and asthma in the UK Biobank.MethodsWe performed genome-wide association studies (GWAS) of doctor-diagnosed asthma, blood eosinophil, neutrophil, lymphocyte and monocyte counts in the UK Biobank. Genetic correlation analysis was performed on GWAS results and validated in the Trans-National Asthma Genetic Consortium (TAGC) study of asthma.ResultsGWAS of doctor-diagnosed asthma and blood eosinophil counts in the UK Biobank identified 585 and 3429 significant variants, respectively. STAT6, a transcription factor involved in interleukin-4 signalling, was a key shared pathway between asthma and blood eosinophil counts. Genetic correlation analysis demonstrated a positive correlation between doctor-diagnosed asthma and blood eosinophil counts (r=0.38±0.10, correlation±se; p=4.7×10-11). As a validation of this association, we found a similar correlation between TAGC and blood eosinophil counts in the UK Biobank (0.37±0.08, correlation±se; p=1.2×10-6).ConclusionsThese findings define the shared genetic architecture between blood eosinophil counts and asthma risk in subjects of European ancestry and point to a genetic link to the STAT6 signalling pathway in these two traits.
| S-EPMC10463033 | biostudies-literature
Project description:Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.
| S-EPMC4908225 | biostudies-literature
Project description:Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.
| S-EPMC6887549 | biostudies-literature
Project description:Tobacco smoking is a risk factor for numerous disorders, including cancers affecting organs outside the respiratory tract. Epidemiological data suggest that smoking is a greater risk factor for these cancers in males compared with females. This observation, together with the fact that males have a higher incidence of and mortality from most non-sex-specific cancers, remains unexplained. Loss of chromosome Y (LOY) in blood cells is associated with increased risk of nonhematological tumors. We demonstrate here that smoking is associated with LOY in blood cells in three independent cohorts [TwinGene: odds ratio (OR) = 4.3, 95% confidence interval (CI) = 2.8 to 6.7; Uppsala Longitudinal Study of Adult Men: OR = 2.4, 95% CI = 1.6 to 3.6; and Prospective Investigation of the Vasculature in Uppsala Seniors: OR = 3.5, 95% CI = 1.4 to 8.4] encompassing a total of 6014 men. The data also suggest that smoking has a transient and dose-dependent mutagenic effect on LOY status. The finding that smoking induces LOY thus links a preventable risk factor with the most common acquired human mutation.
| S-EPMC4356728 | biostudies-literature
Project description:Mosaic loss of chromosome Y (LOY) is the most common somatic genetic aberration and is associated with increased risk for all-cause mortality, various forms of cancer and Alzheimer's disease, as well as other common human diseases. By tracking LOY frequencies in subjects from which blood samples have been serially collected up to five times during up to 22 years, we observed a pronounced intra-individual variation of changes in the frequency of LOY within individual men over time. We observed that in some individuals the frequency of LOY in blood clearly progressed over time and that in other men, the frequency was constant or showed other types of longitudinal development. The predominant method used for estimating LOY is calculation of the median Log R Ratio of probes located in the male specific part of chromosome Y (mLRRY) from intensity data generated by SNP-arrays, which is difficult to interpret due to its logarithmic and inversed scale. We present here a formula to transform mLRRY-values to percentage of LOY that is a more comprehensible unit. The formula was derived using measurements of LOY from matched samples analysed using SNP-array, whole genome sequencing and a new AMELX/AMELY-based assay for droplet digital PCR. The methods described could be applied for analyses of the vast amount of SNP-array data already generated in the scientific community, allowing further discoveries of LOY associated diseases and outcomes.
| S-EPMC7028735 | biostudies-literature
Project description:Incidence and mortality for sex-unspecific cancers are higher among men, a fact that is largely unexplained. Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells, but the phenotypic consequences of LOY have been elusive. From analysis of 1,153 elderly men, we report that LOY in peripheral blood was associated with risks of all-cause mortality (hazards ratio (HR) = 1.91, 95% confidence interval (CI) = 1.17-3.13; 637 events) and non-hematological cancer mortality (HR = 3.62, 95% CI = 1.56-8.41; 132 events). LOY affected at least 8.2% of the subjects in this cohort, and median survival times among men with LOY were 5.5 years shorter. Association of LOY with risk of all-cause mortality was validated in an independent cohort (HR = 3.66) in which 20.5% of subjects showed LOY. These results illustrate the impact of post-zygotic mosaicism on disease risk, could explain why males are more frequently affected by cancer and suggest that chromosome Y is important in processes beyond sex determination. LOY in blood could become a predictive biomarker of male carcinogenesis.
| S-EPMC5536222 | biostudies-literature
Project description:Mosaic loss of Y chromosome (LOY) is the most common somatic change that occurs in circulating white blood cells of older men. LOY in leukocytes is associated with increased risk for all-cause mortality and a range of common disease such as hematological and non-hematological cancer, Alzheimer's disease, and cardiovascular events. Recent genome-wide association studies identified up to 156 germline variants associated with risk of LOY. The objective of this study was to use these variants to calculate a novel polygenic risk score (PRS) for LOY, and to assess the predictive performance of this score in a large independent population of older men. We calculated a PRS for LOY in 5131 men aged 70 years and older. Levels of LOY were estimated using microarrays and validated by whole genome sequencing. After adjusting for covariates, the PRS was a significant predictor of LOY (odds ratio [OR] = 1.74 per standard deviation of the PRS, 95% confidence intervals [CI] 1.62-1.86, p < 0.001). Men in the highest quintile of the PRS distribution had > fivefold higher risk of LOY than the lowest (OR = 5.05, 95% CI 4.05-6.32, p < 0.001). Adding the PRS to a LOY prediction model comprised of age, smoking and alcohol consumption significantly improved prediction (AUC = 0.628 [CI 0.61-0.64] to 0.695 [CI 0.67-0.71], p < 0.001). Our results suggest that a PRS for LOY could become a useful tool for risk prediction and targeted intervention for common disease in men.
| S-EPMC8667399 | biostudies-literature
Project description:Mosaic loss of chromosome Y (mLOY) is frequently observed in the leukocytes of ageing men. However, the genetic architecture and biological mechanisms underlying mLOY are not fully understood. In a cohort of 95,380 Japanese men, we identify 50 independent genetic markers in 46 loci associated with mLOY at a genome-wide significant level, 35 of which are unreported. Lead markers overlap enhancer marks in hematopoietic stem cells (HSCs, P ≤ 1.0 × 10-6). mLOY genome-wide association study signals exhibit polygenic architecture and demonstrate strong heritability enrichment in regions surrounding genes specifically expressed in multipotent progenitor (MPP) cells and HSCs (P ≤ 3.5 × 10-6). ChIP-seq data demonstrate that binding sites of FLI1, a fate-determining factor promoting HSC differentiation into platelets rather than red blood cells (RBCs), show a strong heritability enrichment (P = 1.5 × 10-6). Consistent with these findings, platelet and RBC counts are positively and negatively associated with mLOY, respectively. Collectively, our observations improve our understanding of the mechanisms underlying mLOY.
| S-EPMC6797717 | biostudies-literature