We sought to determine the significance of myeloid clonal hematopoiesis (CH) in the UK Biobank cohort (n=502,524, median age=58 years). Utilizing SNP array (n=486,941) and whole exome sequencing data (n=49,956), we identified 1166 participants with myeloid CH, defined by myeloid-associated mosaic chromosome abnormalities (mCA) and/or likely somatic driver mutations in DNMT3A, TET2, ASXL1, JAK2, SRSF2 or PPM1D. Myeloid CH increased by 1.1-fold per annum (myeloid mCA, P=1.57x10 -38 ; driver mutations, P=5.89x10 - 47). Genome-wide association analysis identified two distinct signals within TERT that predisposed to myeloid CH, plus a weaker signal corresponding to the JAK2 46/1 haplotype. Specific subtypes of myeloid CH were associated with several blood features and clinical phenotypes, including TET2 mutations and chronic obstructive pulmonary disease. Smoking history was significantly associated with myeloid CH: 53% of myeloid CH cases were smokers compared to 44% of controls (P=3.38x10 -6 ), a difference principally due to current (OR=1.10; P=6.14x10 -6 ) rather than past smoking (P=0.08). Breakdown of CH by specific mutation type revealed that ASXL1 loss of function mutations were most strongly associated with current smoking status (OR=1.07; P=1.92x10 -5 ), and the only abnormality associated with past smoking (OR=1.04; P=0.0026). We suggest that the inflammatory environment induced by smoking may promote the outgrowth of ASXL1-mutant clones.

We sought to determine the relationship between age-related clonal hematopoiesis (CH) and chronic kidney disease (CKD). CH, defined as mosaic chromosome abnormalities (mCA) and/or driver mutations was identified in 5449 (2.9%) eligible UK Biobank participants (n = 190,487 median age = 58 years). CH was negatively associated with glomerular filtration rate estimated from cystatin-C (eGFR.cys; β = −0.75, P = 2.37 × 10–4), but not with eGFR estimated from creatinine, and was specifically associated with CKD defined by eGFR.cys < 60 (OR = 1.02, P = 8.44 × 10–8). In participants without prevalent myeloid neoplasms, eGFR.cys was associated with myeloid mCA (n = 148, β = −3.36, P = 0.01) and somatic driver mutations (n = 3241, β = −1.08, P = 6.25 × 10–5) associated with myeloid neoplasia (myeloid CH), specifically mutations in CBL, TET2, JAK2, PPM1D and GNB1 but not DNMT3A or ASXL1. In participants with no history of cardiovascular disease or myeloid neoplasms, myeloid CH increased the risk of adverse outcomes in CKD (HR = 1.6, P = 0.002) compared to those without myeloid CH. Mendelian randomisation analysis provided suggestive evidence for a causal relationship between CH and CKD (P = 0.03). We conclude that CH, and specifically myeloid CH, is associated with CKD defined by eGFR.cys. Myeloid CH promotes adverse outcomes in CKD, highlighting the importance of the interaction between intrinsic and extrinsic factors to define the health risk associated with CH.

Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzing 1,035 individuals with KIT D816V positive disease and 17,960 healthy control individuals from five European populations. After quality control, we tested 592,007 SNPs at stage 1 and 75 SNPs at stage 2 for association by using logistic regression and performed a fixed effects meta-analysis to combine evidence across the two stages. From the meta-analysis, we identified three intergenic SNPs associated with mastocytosis that achieved genome-wide significance without heterogeneity between cohorts: rs4616402 (p meta ¼ 1.37 3 10 À15 , OR ¼ 1.52), rs4662380 (p meta ¼ 2.11 3 10 À12 , OR ¼ 1.46), and rs13077541 (p meta ¼ 2.10 3 10 À9 , OR ¼ 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (p eQTL ¼ 2.3 3 10 À14 ), a gene encoding a transcription factor known to play a critical role in myelopoiesis. The role of the other two SNPs is less clear: rs4662380 is associated with expression of the long non-coding RNA gene TEX41 (p eQTL ¼ 2.55 3 10 À11 ), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (b)-like 1 X-linked receptor 1 (p eQTL ¼ 5.70 3 10 À8 ). In individuals with available data and non-advanced disease, rs4616402 was associated with age at presentation (p ¼ 0.009; beta ¼ 4.41; n ¼ 422). Additional focused analysis identified suggestive associations between mastocytosis and genetic variation at TERT, TPSAB1/TPSB2, and IL13. These findings demonstrate that multiple germline variants predispose to KIT D816V positive mastocytosis and provide novel avenues for functional investigation.

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.

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.