Genetic predisposition to mosaic Y chromosome loss in blood

Thompson, Deborah J.; Genovese, Giulio; Halvardson, Jonatan; Ulirsch, Jacob C.; Wright, Deil S.; Terao, Chikashi; Davidsson, Olafur B.; Day, Felix R.; Sulem, Patrick; Jiang, Yunxuan; Danielsson, Marcus; Davies, Hanna; Dennis, Joe; Dunlop, Malcolm G.; Easton, Douglas F.; Fisher, Victoria A.; Zink, Florian; Houlston, Richard S.; Ingelsson, Martin; Kar, Siddhartha; Kerrison, Nicola D.; Kinnersley, Ben; Kristjansson, Ragnar P.; Law, Philip; Li, Rong; Loveday, Chey; Mattisson, Jonas; McCarroll, Steven A.; Murakami, Yoshinori; Murray, Anna; Olszewski, Paweł; Rychlicka-Buniowska, Edyta; Scott, Robert A.; Þorsteinsdóttir, Unnur; Tomlinson, Ian; Moghadam, Behrooz Torabi; Turnbull, Clare; Wareham, Nicholas J.; Guðbjartsson, Daníel F.; Kamatani, Yoichiro; Hoffmann, Eva R.; Jackson, Stephen; Stefánsson, Kári; Auton, Adam; Ong, Ken K.; Machiela, Mitchell J.; Loh, Po−Ru; Dumanski, Jan P.; Chanock, Stephen J.; Forsberg, Lars A.; Perry, John R. B.

doi:10.1038/s41586-019-1765-3

Cited by 237 publications

(422 citation statements)

References 90 publications

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“…The molecular mechanisms behind the association of LOY, aging and neoplasia are not completely understood. There is no clear association between LOY and numerical abnormalities of other chromosomes 9,27,53 . LOY does not seem to reflect an overall propensity for loss of small-sized chromosomes 60,61 .…”

Section: Discussionmentioning

confidence: 97%

“…Recently, large genome-wide association studies enrolling >200,000 men in the UK Biobank demonstrated association of germline single nucleotide polymorphisms (SNP) of 156 autosomal loci as well as differential methylation of various genes with LOY 4,[25][26][27] . Whether any of the LOYassociated SNPs or epigenetic changes contribute to hematological neoplasia risk is unclear.…”

Section: Introductionmentioning

confidence: 99%

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Genomic alterations in patients with somatic loss of the Y chromosome as the sole cytogenetic finding in bone marrow cells

et al. 2020

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alterations in patients with somatic loss of the Y chromosome as the sole cytogenetic finding in bone marrow cells. AbstractLoss of the Y chromosome (LOY) is one of the most common somatic genomic alterations in hematopoietic cells in men. However, due to the high prevalence of LOY as the sole cytogenetic finding in the healthy older population, differentiating isolated LOY associated with clonal hematologic processes from aging-associated mosaicism can be difficult in the absence of definitive morphological features of disease. In the past, various investigators have proposed that a high percentage of metaphases with LOY is more likely to represent expansion of a clonal myeloid disease-associated population. It is unknown whether the proportion of metaphases with LOY is associated with the incidence of myeloid neoplasia-associated genomic alterations.To address this question, we identified marrow samples with LOY as isolated cytogenetic finding and used targeted next generation sequencing-based molecular analysis to identify common myeloid neoplasia-associated somatic mutations. Among 73 patients with median age of 75 years (range 29-90), the percentage of metaphases with LOY was <25% in 23 patients, 25-49% in 10, 50-74% in 8 and ≥ 75% in 32. A threshold of ≥ 75% LOY was significantly associated with morphologic diagnosis of myeloid neoplasm (p = 0.004). Further, ≥ 75% LOY was associated with a higher lifetime incidence of diagnosis of myelodysplastic syndromes (MDS; p < 0.0001), and in multivariate analysis ≥ 75% LOY was a statistically significant independent predictor of myeloid neoplasia [OR 6.17;; p = 0.0007]. Higher LOY percentage (≥75%) was associated with greater likelihood of having somatic mutations (p = 0.0009) and a higher number of these mutations (p = 0.0002). Our findings indicate that ≥ 75% LOY in marrow is associated with increased likelihood of molecular alterations in genes commonly seen in myeloid neoplasia and with morphologic features of MDS. These observations suggest that ≥ 75% LOY in bone marrow should be considered an MDS-associated cytogenetic aberration. Main manuscript

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Genomic alterations in patients with somatic loss of the Y chromosome as the sole cytogenetic finding in bone marrow cells

et al. 2020

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“…The current analyses were extension of our previous studies 5,13,14 which included population-based data from 223,336 males between age 37 and 73 recruited between 2007 to 2010 from the UK Biobank 15,16 . After providing informed consent, each participant provided a blood sample, answered a detailed health and lifestyle questionnaire, and had physical measurements taken.…”

Section: Methodsmentioning

confidence: 99%

“…Men with mLRR > 0.15 could possibly have a mosaic gain of Y chromosome or a constitutional extra copy of the Y chromosome (XYY syndrome) and were removed (205 men, 0.09%). We also apply the methods proposed by Thompson et al 14 to call dichotomized mLOY. For clarity, we use the term mLOY for dichotomized mLOY calls by Thompson et al Our final analytical set included 206,353 self-reported men who reported no prior cancer history at recruitment (n = 14,356 excluded), did not have X chromosome heterozygosity (n = 167 excluded), had consistent smoking data (n = 2 excluded), were without evidence of copy number gains of Y chromosome (n = 205 excluded) and passed quality control during the dichotomized mLOY detection step (n = 2,394 excluded) as shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

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

Lin

Loftfield

Sampson

et al. 2020

Sci Rep

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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] × 10 12 cells/L, p = 2.75 × 10 −5) and elevated thrombocyte count (5.523 [4.862, 6.183] × 10 9 cells/L, p = 2.32 × 10 −60) and leukocyte count (0.218 [0.198, 0.239] × 10 9 cells/L, p = 9.22 × 10 −95), particularly for neutrophil count (0.174 × [0.158, 0.190]10 9 cells/L, p = 1.24 × 10 −99) and monocyte count (0.021 [0.018 to 0.024] × 10 9 cells/L, p = 6.93 × 10 −57), but lymphocyte count was less consistent (0.016 [0.007, 0.025] × 10 9 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. Recently, large molecular epidemiology studies have shown that hematopoietic cells can undergo postzygotic mutations resulting in somatic copy number alterations, which can give rise to daughter cells with the same genomic aberration. Clonal expansion of cells bearing a somatic mutation results in clonal mosaicism 1. Clonal mosaicism can be driven by somatic mutations affecting genes frequently mutated in myelodysplastic disease (referred to as clonal hematopoiesis of indeterminate potential (CHIP)) 2 or be the result of acquired copy number aberrations. The most frequently detected somatic copy number alteration in circulating leukocytes is mosaic loss of the Y chromosome (mLOY) in males 3-5. The prevalence of mLOY is age-related, increasing substantially after age 50 in men. Likewise, CHIP is common in the elderly, with recent evidence suggesting CHIP and mLOY may co-occur 6. Exposure to cigarette smoking 4,7 has also been well established as a risk factor for mLOY and recently, early evidence suggests that air pollution could also be associated with mLOY 8. Epidemiologic studies have uncovered potential associations between mLOY and increased risk of cancer 3-5 , neurodegenerative diseases 9 , and cardiovascular diseases 10,11. Similarly, CHIP has been associated with select cancers and cardiovascular disease 2. Although common germline variants near important cell-cycle regulation and cancer susceptibility genes have been identified through genome-wide association studies of mLOY 4,12 , the underlying biologic mechanisms linking mLOY to chronic disease risk are likely complex. We investigated possible associations between mLOY and clinical measures, here the composition of the classical h...

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“…LOY is an age related phenomenon that has been associated with a wide spectrum of human diseases including cancer, Alzheimer's disease, cardiovascular disease, and reduced overall life expectancy in men. [11][12][13][14] Genetic variation in multiple loci is involved in the inherited susceptibility to LOY, which can also be driven by smoking and other environmental exposures. 15 LOY is the most common copy number alteration in male leukocytes, estimated to occur in <2% men under 60 years of age, but exponentially increasing with aging to 15-40% in 70-85 year-old males and >50% at 93 years of age.…”

Section: Introductionmentioning

confidence: 99%

Clonal chromosomal mosaicism and loss of chromosome Y in men are risk factors for SARS-CoV-2 vulnerability in the elderly

Pérez-Jurado

Cáceres

Esko

et al. 2020

Preprint

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The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, has an estimated overall case fatality ratio of 1.38% in China, being 53% higher in males and increasing exponentially with age. Mosaicism for X chromosome monosomy (XCM) shows a similar increase in aging population mostly driven by loss of chromosome Y in males (LOY), and is associated with a raise in all-cause mortality. Using comparative transcriptomic data, we have defined that XCM/LOY is associated with abnormal peripheral blood cell counts with decreased progenitor cells and multiple biomarkers of immune system dysfunction, pro-coagulation activity and increased cardiovascular risk. Several differentially down-regulated genes in XCM/LOY individuals are involved in the initial immune response to SARS-CoV-2 (OR of enrichment=7.23, p=1.5x10 -7 ), mainly interferon-induced genes that code for inhibitors of viral processes. Thus, our data suggest that XCM mosaicism underlies at least part of the sex-biased severity and mortality of COVID-19 in aging patients.Given its potential relevance for modulating prognosis and therapeutic response, we propose that evaluation of LOY and XCM by currently established methods should be implemented as biomarkers in infected patients, including currently ongoing clinical trials with different medications and vaccines for COVID-19. Testing for LOY/XCM at large scale among elderly people may also be helpful to identify still unexposed people who may be especially vulnerable to severe Covid-19 disease.

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Genetic predisposition to mosaic Y chromosome loss in blood

Cited by 237 publications

References 90 publications

Genomic alterations in patients with somatic loss of the Y chromosome as the sole cytogenetic finding in bone marrow cells

Genomic alterations in patients with somatic loss of the Y chromosome as the sole cytogenetic finding in bone marrow cells

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

Clonal chromosomal mosaicism and loss of chromosome Y in men are risk factors for SARS-CoV-2 vulnerability in the elderly

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