GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation

Terao, Chikashi; Momozawa, Yukihide; Ishigaki, Kazuyoshi; Kawakami, Eiryo; Akiyama, Masato; Loh, Po−Ru; Genovese, Giulio; Sugishita, Hiroki; Ohta, Toshio; Hirata, Makoto; Perry, John R. B.; Matsuda, Koichi; Murakami, Yoshinori; Kubo, Michiaki; Kamatani, Yoichiro

doi:10.1038/s41467-019-12705-5

Cited by 66 publications

(93 citation statements)

References 49 publications

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“…Our query returned eight GWAS traits associated with variants in LD with rs2887399 ( Supplementary Table S3). As expected, the main trait found to be associated with rs2887399 was mosaic loss of chromosome Y (19,20). Another associated trait included neutrophil count (21), which is interesting in light of recent articles on mosaic Y loss indicating changes in blood cell counts, particularly neutrophil counts (20,22).…”

Section: Resultssupporting

confidence: 56%

LDtrait: An Online Tool for Identifying Published Phenotype Associations in Linkage Disequilibrium

Lin¹,

Brown²,

Machiela³

2020

Cancer Research

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Genome-wide association studies (GWAS) have identified thousands of germline susceptibility loci associated with risk for cancer as well as a wide range of other traits and diseases. An interest of many investigators is identifying traits or diseases that share common susceptibility loci. We developed LDtrait (https://ldlink. nci.nih.gov/?tab¼ldtrait) as an open access web tool for finding germline variation associated with multiple traits. LDtrait searches the NHGRI-EBI GWAS Catalog to identify susceptibility loci in linkage disequilibrium (LD) with a user-provided list of query variants. Options allow for modifying LD thresholds, calculating LD from a diverse set of reference populations, and downloading annotated variant lists. Results from example query searches highlight the utility of LDtrait in uncovering cross-trait associations for cancer risk and other traits. LDtrait accelerates etiologic understanding of cancer genetics by rapidly identifying genetic similarities with other traits or diseases. Significance: The new GWAS search tool LDtrait will expedite discovery of shared genetic components underlying seemingly unrelated diseases and may offer novel insights into cancer research.

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Section: Resultssupporting

confidence: 56%

LDtrait: An Online Tool for Identifying Published Phenotype Associations in Linkage Disequilibrium

Lin¹,

Brown²,

Machiela³

2020

Cancer Research

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“…Their analysis was also a univariable statistical test which did not take into account potential confounding by other factors. A recently published study on 57, 987 men in Biobank Japan also reported associations among mLOY, increased thrombocyte and leukocyte counts 64 . While the authors did not find statistically significant negative associations between erythrocyte counts and continuous mLRR in univariable models, effect estimates indicate men with mLOY trended toward a decreased erythrocyte count.…”

Section: Discussionmentioning

confidence: 86%

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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“…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%

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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GWAS of mosaic loss of chromosome Y highlights genetic effects on blood cell differentiation

Cited by 66 publications

References 49 publications

LDtrait: An Online Tool for Identifying Published Phenotype Associations in Linkage Disequilibrium

LDtrait: An Online Tool for Identifying Published Phenotype Associations in Linkage Disequilibrium

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

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

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