A Mendelian randomized analysis of the association between breast cancer and bone mineral density

The number of SNPs selected as instrumental variables significantly correlated with exposure ranged from 4 to 1079. Their explained variance varied from 2.5 to 31.7%.The F-statistic for each SNP and the general F-statistic were all above 10 (see table 1).

Two-way MR analysis

MR analysis from breast cancer to BMD showed an inverse causality between breast cancer and its ER+ subtype, HE-BMD. Breast cancer may reduce her HE-BMD, a recognized risk factor for osteoporosis (OR 0.980, 95% CI 0.970–0.990, FDR = 1.51 × 10⁻⁴) Similar to ER+ subtype (OR 0.979, 95% CI 0.969–0.989, FDR = 1.51 × 10⁻⁴) (figure. 2A, Supplementary table S1). ER- subtype was not associated with HE-BMD (OR 1.034, 95% CI 0.998–1.072, FDR = 7.69 × 10⁻²). No causal relationship was found between breast cancer, its subtypes and BMD at other sites (LS, FN, FA). Heterogeneity was found in Mendelian randomization of breast cancer, ER+ subtype to HE-BMD, LS-BMD, and FN-BMD. When heterogeneity was present in the sensitivity analysis, the weighted median method statistic was in the same direction as that of the IVW model, and the weighted median method was chosen as the main statistical effect. Horizontal pleiotropy was found in the ER- subtype for HE-BMD. The MR-Egger results were taken as the main effect size.The original IVW, weighted median and MR-Egger results between breast cancer and BMD are presented in the Supplementary Table S2together with heterogeneity and multifaceted tests.

Forest plot of two-way Mendelian randomization results. (Ah) are Mendelian randomization results of the association between breast cancer and its subtypes and bone mineral density at different sites. (B.) are Mendelian randomization results of the association between bone density at various sites and breast cancer and its subtypes.

MR analysis from BMD to breast cancer showed no significant association (FDR > 0.05, Fig. 2B). There was heterogeneity in the MR statistical analysis of HE-BMD in breast cancer and its ER+ and ER− subtypes. MR analysis did not show horizontal pleiotropy in BMD in any region of breast cancer.Supplementary table S3 presents IVW, weighted median and MR-Egger results between BMD and breast cancer, together with tests for heterogeneity and pleiotropy.

Multivariate-mediated MR analysis

MR analysis of hormone levels for BMD showed a positive causal relationship between FT, TT and HE-BMD. Higher FT may increase HE-BMD and was considered a protective factor in osteoporosis (OR 1.116, 95% CI 1.086–1.147, FDR = 1.04 × 10⁻¹⁴); similar results are seen for TT (OR 1.039, 95% CI 1.013–1.066, FDR = 2.60 × 10⁻⁴) (figure. 3Supplementary table S1). FT and TT had no causal relationship with LS-BMD, FN-BMD, or FA-BMD. Heterogeneity was found in MR analysis of FT, TT to HE-BMD, LS-BMD, FN-BMD, and FA-BMD. Weighted median was adopted as the main method. MR analysis showed no horizontal pleiotropy in any of the hormone levels for BMD.The original results of IVW, weighted median and MR-Egger between hormone levels and BMD are given in the Supplementary Table S4, together with heterogeneity and multifaceted tests. Multivariate MR analysis suggested that elevated FT might be an independent protective factor in HE-BMD (adjusted OR = 1.076, P = 0.033), whereas TT was not significant in the multivariate MR model. was not (adjusted OR = 1.023, P = 0.520). Results mediating MR analysis suggested that FT mediates 71.5% of the causality between TT and HE-BMD. There was a causal relationship between breast cancer, its ER+ subtype, FT, and HE-BMD. Multivariate MR analysis showed that FT mediator-corrected breast cancer had no significant adverse effect on HE-BMD (adjusted OR = 0.982, P = 0.077), and both ER+ type and FT were independent of HE-BMD. was shown to be a factor (ER+: adjusted OR = 0.977, P = 0.021; FT: adjusted OR = 1.111, P = 6.88 × 10⁻⁶). Mediation MR analysis showed that FT mediated the causality between breast cancer and HE-BMD by 2.9%. The effect of breast cancer and its ER+ subtype-adjusted FT on HE-BMD was shown in Figure 1. Four.

Forest plot of Mendelian randomization results between testosterone levels and bone mineral density at various sites.

Forest plot before and after FT adjustment of heel bone density and mediated ratios of breast cancer and its ER+ subtype.

MR analysis of hormone levels in breast cancer showed a positive causal relationship between FT and TT and breast cancer and its ER+ subtype. Higher FT may increase breast cancer risk (OR 1.137, 95% CI 1.054–1.226, FDR = 1.21 × 10⁻³) TT (OR 1.130, 95% CI 1.040–1.227, FDR = 5.81 × 10⁻³) (figure. FiveSupplementary table S1). Similarly, higher FT may increase the risk of ER+ subtype (OR 1.235, 95% CI 1.136–1.344, FDR = 2.51 × 10⁻⁶) TT (OR 1.213, 95% CI 1.096–1.343, FDR = 5.55 × 10⁻⁴) (figure. FiveSupplementary table S1). FT and TT had no causal relationship with the ER- subtype of breast cancer (FDR > 0.05, Fig. Five). Heterogeneity was found in his FT and TT MR analyzes of breast cancer and its ER+/ER− subtypes, so the weighted median result was taken as the main effect. MR analysis showed no horizontal pleiotropy in any of the breast cancer hormone levels.The original results of IVW, weighted median and MR-Egger between hormone levels and breast cancer are presented in the Supplementary Table S5together with heterogeneity and multifaceted tests.

Forest plot of Mendelian randomization results between testosterone levels and breast cancer.

The statistical power of exposure to FT and TT for HE-BMD, breast cancer, and ER+ outcomes were all 100%. However, the statistical power of exposure to breast cancer and ER+ on HE-BMD outcomes was 74% and 69%, respectively.