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] × 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...

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

“…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).…”

Germline risk of clonal haematopoiesis

“…Environmental exposures that increase somatic variant acquisition are significantly correlated with CH prevalence. In particular, smoking is robustly associated with CHIP 8 , 27 , 32 and mLOY 11 , 13 – 16 , 33 , 34 . In the case of cytotoxic chemotherapy and radiation therapy, the mutational spectrum exhibits a marked enrichment of mutations in DNA damage response pathway genes 32 , 35 , 36 .…”

Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sex chromosome encoded genes

“…LOY has been reported in ~93% of esophageal adenocarcinomas 26 , ~12% of male breast cancers 27 and ~23% of urothelial bladder cancer samples 28 . Mosaic loss of chrY has also been observed outside of the oncology context, where it has been correlated with increased age [29][30][31] . LOY has been associated with a number of pathophysiological conditions, including clonal hematopoiesis and Alzheimer's disease 32,33 .…”