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

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.