Age-related loss of the Y chromosome is associated with sex hormone binding globulin and selected drivers of clonal hematopoiesis

Abstract

Mosaic loss of the Y-chromosome (LOY) is the most common somatic alteration in men. We aimed to assess the relationship between LOY and serum biomarkers in UK Biobank and explore the interaction with constitutional and somatic genetics. LOY was strongly associated with levels of sex hormone binding globulin (SHBG, beta=0.12, PFDR= P = 7.44x10-36, adjusted for age, age squared, gender, smoking status, smoking intensity and principal genetic components), a key regulator of testosterone bioavailability associated with diverse disorders including cancer and autoimmune diseases. Furthermore, LOY was associated with total testosterone (TT, beta=0.09, PFDR=2.23 x 10-20), but not bioavailable testosterone (PFDR=0.46) or free testosterone (PFDR=0.75). These relationships remained significant after sensitivity analysis that included comorbidities and body mass index (SHBG, beta = 0.08, PFDR = 4.61x10-21; TT, beta=0.05, PFDR=4.13 x 10-9). Mendelian randomisation suggested a causal effect of SHBG on LOY in BioBank Japan (P=6.58x10-4) but there was no evidence for an effect of LOY on SHBG (P=0.46). Assessment of cis-eQTLs for 13 genes associated with LOY identified two SNPs that were also associated with levels of SHBG, however only rs7141210 (imprinted DLK1-MEG3 locus) modified the relationship between SHBG and LOY (rs7141210-T/T; Pinteraction=0.04) with low levels of SHBG seen specifically in men without LOY (beta=-0.02, P=0.001), but not those with LOY (P=0.41). Age-related clonal hematopoiesis (CH) defined by somatic driver mutations was not associated with sex hormone levels but was associated with LOY at clonal fractions >30% (OR=1.52, P=2.92x10-4). TET2, TP53, and CBL mutations were enriched in high level LOY cases, but not DNMT3A or ASXL1. Our findings thus identify independent relationships between LOY, sex hormones and CH.