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Mosaic chromosome Y loss is associated with alterations in blood cell counts in UK Biobank men.

ABSTRACT: Mosaic loss of Y chromosome (mLOY) is the most frequently detected somatic copy number alteration in leukocytes of men. In this study, we investigate blood cell counts as a potential mechanism linking mLOY to disease risk in 206,353 UK males. Associations between mLOY, detected by genotyping arrays, and blood cell counts were assessed by multivariable linear models adjusted for relevant risk factors. Among the participants, mLOY was detected in 39,809 men. We observed associations between mLOY and reduced erythrocyte count (-0.009 [-0.014, -0.005] × 10¹² cells/L, p = 2.75 × 10^-5) and elevated thrombocyte count (5.523 [4.862, 6.183] × 10⁹ cells/L, p = 2.32 × 10^-60) and leukocyte count (0.218 [0.198, 0.239] × 10⁹ cells/L, p = 9.22 × 10^-95), particularly for neutrophil count (0.174 × [0.158, 0.190]10⁹ cells/L, p = 1.24 × 10^-99) and monocyte count (0.021 [0.018 to 0.024] × 10⁹ cells/L, p = 6.93 × 10^-57), but lymphocyte count was less consistent (0.016 [0.007, 0.025] × 10⁹ cells/L, p = 8.52 × 10^-4). Stratified analyses indicate these associations are independent of the effects of aging and smoking. Our findings provide population-based evidence for associations between mLOY and blood cell counts that should stimulate investigation of the underlying biological mechanisms linking mLOY to cancer and chronic disease risk.

SUBMITTER: Lin SH

PROVIDER: S-EPMC7046668 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Mosaic chromosome Y loss is associated with alterations in blood cell counts in UK Biobank men.

Lin Shu-Hong SH Loftfield Erikka E Sampson Josh N JN Zhou Weiyin W Yeager Meredith M Freedman Neal D ND Chanock Stephen J SJ Machiela Mitchell J MJ

Scientific reports 20200227 1

Mosaic loss of Y chromosome (mLOY) is the most frequently detected somatic copy number alteration in leukocytes of men. In this study, we investigate blood cell counts as a potential mechanism linking mLOY to disease risk in 206,353 UK males. Associations between mLOY, detected by genotyping arrays, and blood cell counts were assessed by multivariable linear models adjusted for relevant risk factors. Among the participants, mLOY was detected in 39,809 men. We observed associations between mLOY a ...[more]

PMID: 32108144

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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.

Dataset Information

Mosaic chromosome Y loss is associated with alterations in blood cell counts in UK Biobank men.

Publications

Mosaic chromosome Y loss is associated with alterations in blood cell counts in UK Biobank men.

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