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. 2023 Apr 21;9(16):eade9746.
doi: 10.1126/sciadv.ade9746. Epub 2023 Apr 21.

Age-related loss of chromosome Y is associated with levels of sex hormone binding globulin and clonal hematopoiesis defined by TET2, TP53, and CBL mutations

Ahmed A Z Dawoud  1   2 , William J Tapper  1 , Nicholas C P Cross  1   2
Affiliations

Age-related loss of chromosome Y is associated with levels of sex hormone binding globulin and clonal hematopoiesis defined by TET2, TP53, and CBL mutations

Ahmed A Z Dawoud et al. Sci Adv. .

Abstract

Mosaic loss of the Y-chromosome (LOY) in peripheral blood leukocytes is the most common somatic alteration in men and linked to wide range of malignant and nonmalignant conditions. LOY is associated with age, smoking, and constitutional genetics. Here, we aimed to assess the relationships between LOY, serum biomarkers, and clonal hematopoiesis (CH). LOY in U.K. Biobank was strongly associated with levels of sex hormone binding globulin (SHBG), a key regulator of testosterone bioavailability. Mendelian randomization suggested a causal effect of SHBG on LOY but there was no evidence for an effect of LOY on SHBG. In contrast, age-related CH defined by somatic driver mutations was not associated with SHBG but was associated with LOY at clonal fractions above 30%. TET2, TP53, and CBL mutations were enriched in LOY cases, but JAK2 V617F was depleted. Our findings thus identify independent relationships between LOY, sex hormone levels, and CH.

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Figures

Fig. 1.
Fig. 1.. The relationship between LOY and biochemistry markers.
The relationship between LOY and each of 31 biomarkers (29 measured and 2 calculated) was tested using multivariable linear regression in R in 222,835 UKB males. (A) basic models: each linear model considered age, age squared, smoking status, smoking intensity, 10 PC, and multiple testing; (B) sensitivity model: hypertension, insulin-dependent diabetes, non–insulin-dependent diabetes, and BMI were added to each basic model.
Fig. 2.
Fig. 2.. The relationship between LOY and levels of sex hormones.
The box plots summarize serum sex hormone measurements in participants without LOY (n = 178,277) and with LOY (n = 4458). SHBG: median nM = 41.54 versus 35.86, P < 0.001; TT: median nM = 11.74 versus 11.58, P < 0.001; FT: median nM = 0.19 versus 0.20, P < 0.001; BAT: median nM = 4.78 versus 5.18, P < 0.001.
Fig. 3.
Fig. 3.. MR using an IVW model to estimate the causal relationship between SHBG and LOY.
(A) Analysis using eight independent SNPs associated with SHBG (genome-wide significant or derived from conditional analysis) from multiple cohorts of men and women (42) used as instrumental variables in BBJ. The IVW test estimated a significant positive effect of SHBG on LOY (P = 6.58 × 10−4). (B) Conservative analysis using a subset of four SNPs associated with SHBG at genome-wide significance in men (P = 7.28 × 10−4). (C) Analysis using 40 independent SNPs associated with LOY in BBJ assessed as instrumental variables in UKB. The IVW test estimated no effect of LOY on SHBG (P = 0.21). The line of regression is indicated in blue, and the axes show β coefficients for SNP effects on SHBG and LOY. rs7910927 at 10q21.3 within JMJD1C is highlighted with a red circle in (A) and (B) but not in (C) as it was not associated with LOY at a genome-wide significant level in BBJ.
Fig. 4.
Fig. 4.. The relationship between the predicted expression of 13 genes and each of LOY and SHBG.
eQTL SNPs were used as proxies for gene expression and assessed as predictors for LOY (A) and the eight significant SNPs were compared to SHBG levels (B) incorporating age, age squared, smoking history and intensity, and 10 PC as covariates.
Fig. 5.
Fig. 5.. The relationship between LOY and CH.
LOY was stratified according to the clonal size and the proportion of participants with CH within each group was compared with controls. (A) myeloid CH, (B) lymphoid CH, and (C) unknown driver CH.
Fig. 6.
Fig. 6.. The relationship between LOY clonal size and CH VAFs.
Boxplots summarizing the distribution of VAFs of somatic mutations in controls and cases with LOY broken down by clone size. (A) myeloid CH, (B) lymphoid CH, and (C) unknown driver CH. The red lines connect median values.
Fig. 7.
Fig. 7.. The distribution of BAFs and estimated clone sizes for the 44,558 detected LOY events.
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