BAPTA-AM br method SE YX br SYG SXG bYG
method11: SE YX
SYG 2 ðSXG bYG Þ2 , where S and
b XG b 4
SYG are the corresponding SEs. We also performed mendelian randomization–Egger regression analysis to estimate the potential pleiotropic effect of the mLOY-related genetic variants.13 A multivariate Cox propor-tional hazards regression model was used to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs), adjusting for age, pack-years of smoking, and tumor stage. General statistical analyses were performed with R software (version 3.2.2). Two-sided p values less than 0.05 were considered statistically significant.
Genetically Predicted mLOY Is Associated with mLRR-Y
A total of 14 mLOY-related SNPs were included in the analysis after exclusion of five variants with MAF less than 0.05 in the Chinese population. We created a wGRS to predict mLOY by summing the dosage of 14 inde-pendent mLOY-increasing BAPTA-AM (see Supplementary Table 2).
We first estimated mLRR-Y as a proxy of the copy number of the Y chromosome in 810 healthy male participants; the association between 14 reported mLOY-related SNPs and mLRR-Y is shown in Supplementary Table 3. A significant negative correla-tion between genetically predicted mLOY and mLRR-Y was observed, whereas individuals carrying greater numbers of mLOY-increasing alleles had a significantly lower mLRR-Y (b ¼ –0.58, p ¼ 3.38 10 2) (Fig. 1 and Supplementary Fig. 1), suggesting that the predicted mLOY from the 14 mLRR-Y signals identified in Wright
et al.5 is a good indicator of the individual quantitative level of Y chromosome loss. Additionally, consistent with previous results, the individual mLRR-Y level was significantly greater in lifelong nonsmokers than in smokers (p ¼ 1.52 10–2) and the younger population (p ¼ 3.28 10–5) (Supplementary Fig. 2A and B).
Genetically Predicted mLOY Is Associated with a Decreased Lung Cancer Risk
We provide the 14 mLOY-related genetic variants and their effect on lung cancer risk from our lung cancer GWAS data in Supplementary Table 3. We performed a logistic regression analysis to evaluate the association between genetically predicted mLOY and lung cancer risk in 3797 males (1711 case patients and 2086 con-trols). After controlling for age, smoking status, and the first PC, we found that increased genetically predicted mLOY was significantly associated with a decreased risk of lung cancer (per SD increase in the wGRS: OR ¼ 0.92, 95% CI: 0.86–0.98, p ¼ 1.30 10–2) (see Fig. 1 and Supplementary Fig. 3). The more interesting result was that the protective effect was observed in lifelong nonsmokers but not in smokers (lifelong nonsmokers: OR ¼ 0.80, 95% CI: 0.69–0.93, p ¼ 4.03 10–3; smokers: OR ¼ 0.96, 95% CI: 0.89–1.04, p ¼ 2.90 10–1; pHeterogeneity ¼ 3.83 10–2) (Table 1), suggesting that smoking behavior dramatically abolished the protective effect of mLOY against lung cancer.
Because smoking behavior and increasing age contribute to the generation of mLOY and the risk of lung cancer, we further investigated whether mLOY caused by damaging environmental factors was different from genetically defined mLOY. As expected, we observed that genetically predicted mLOY was not associated with smoking status or age (Supplementary Fig. 2C and D), whereas the individual mLRR-Y level was significantly greater in lifelong nonsmokers and the younger popu-lation than in smokers and the older population (see Supplementary Fig. 2A and B). More interestingly, whereas genetically predicted mLOY was linearly asso-ciated with a decreased lung cancer risk (p for linearity
Table 1. Stratified Analyses of the Association between mLOY and Lung Cancer Risk