Abstract 3379: Predictors of mosaic chromosome Y loss and associations with mortality in 223,338 men of the UK Biobank

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Abstract Mosaic loss of the Y chromosome (mLOY) in peripheral leukocytes is an age-related event commonly observed in men older than 50 years of age in which a fraction of leukocytes loses the Y chromosome. In addition to age, previous studies have indicated an association between smoking and increased risk of mLOY. The relationship between mLOY and other health-related exposures (e.g., obesity and alcohol consumption) and with disease outcomes (e.g., cancer risk and overall mortality) remains unclear. We therefore investigated the causes and consequences of mLOY in a large collection of 223,338 men from the UK Biobank. We scanned Y chromosomes for deviations in genotyping array log R ratio intensities for evidence of mLOY. A total of 3,789 (1.7%) men showed evidence for mLOY with median chromosome Y LRR values less than -0.15 and 596 (0.3%) men had high proportions of cells affected with mLOY with median LRR values less than -0.40. Our analysis robustly confirms prior associations of increasing mLOY risk with increasing age (Padj<4.9×10-324). In addition, we observe a strong association between mLOY and smoking (Padj=7.1×10-193), with a higher percentage of current smokers (3.4%) affected by mLOY than former smokers (2.1%) and non-smokers (0.9%). As reported previously for autosomal mosaicism, we observed less mLOY in men of African ancestry (0.4%) compared to men of European ancestry (1.8%, Padj=0.002). Surprisingly, obese men were less likely to have mLOY, with a lower percentage of men with a BMI≥35 having mLOY than men in the normal range (1.3% vs 1.7%, Padj=0.0007). Self-reported health was also associated with mLOY, with a higher percentage of mLOY among men reporting poor health than men reporting excellent health (2.1% vs 1.4%, Padj=0.008). Although no associations were observed between mLOY and prevalent non-melanoma skin cancer (Padj=0.54), suggestive associations were observed with prevalent diabetes (Padj=0.003) and prevalent cardiovascular disease (Padj=0.01). With respect to mortality, we observed an association with mLOY in men with high proportions of cells affected only (LRR<-0.40, Padj=0.002). By cause of death, we noted an association for cancer-specific mortality (HR=1.53, 95% CI=1.13-2.06, Padj=0.0056) in men with high proportions of cells affected, but not for cardiovascular disease mortality, although the number of deaths among men with mLOY was modest (LRR<-0.15= 334 deaths, LRR<-0.40= 75 deaths). Overall, we see evidence for an association of mLOY with several health-related exposures as well as with mortality among men with high proportions of cells affected. Future functional studies related to the physiologic effects of chromosome Y loss in circulating leukocytes are needed to better understand how mLOY may impact disease risk. Citation Format: Erikka Loftfield, Weiyin Zhou, Meredith Yeager, Stephen J. Chanock, Neal D. Freedman, Mitchell J. Machiela. Predictors of mosaic chromosome Y loss and associations with mortality in 223,338 men of the UK Biobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3379.