A causal relationship between bone mineral density and breast cancer risk: a Mendelian randomization study based on East Asian population

Abstract

Background Breast cancer (BC) poses significant burdens on women globally. While past research suggests a potential link between bone mineral density (BMD) and BC risk, findings remain inconsistent. Our study aims to elucidate the causal relationship between BMD and BC in East Asians using bidirectional Mendelian randomization (MR) and reverse MR analyses. Methods Genetic association data for bone mineral density T-scores (BMD-T) and Z-scores (BMD-Z) (Sample size = 92,615) and breast cancer from two different sources (Sample size1 = 98,283; Sample size2 = 79,550) were collected from publicly available genome-wide association studies (GWAS). Single-nucleotide polymorphisms (SNPs) associated with BMD-T and BMD-Z as phenotype-related instrumental variables were used, with breast cancer as the outcome. As the primary means of causal inference, the inverse variance weighted (IVW) approach was employed. Heterogeneity analysis was conducted using Cochran's Q test, while MR-Egger regression analysis was implemented to assess the pleiotropic effects of the instrumental variables. Sensitivity analyses were performed using methods such as MR-Egger, weighted median, and weighted mode to analyze the robustness and reliability of the results. The MR-PRESSO method and the RadialMR were used to detect and remove outliers. The PhenoScanner V2 website was utilized to exclude confounding factors shared between BMD and BC. Then, the meta-analysis method was applied to combine the MR analysis results from the two BC sources. Finally, a reverse MR analysis was conducted. Results The results of the IVW method were consolidated through meta-analysis, revealing a positive correlation between genetically predicted BMD-T (OR = 1.22, 95% CI: 1.13–1.33, P < 0.001) and BMD-Z(OR = 1.17, 95% CI: 1.09–1.26, P < 0.001)with increased BC risk.The MR-Egger regression suggested that neither of these causal relationships was affected by heterogeneity or horizontal pleiotropy. The sensitivity analyses supported the IVW results, indicating the robustness of the findings. Reverse MR analysis showed no causal relationship between BC and BMD. Conclusion Our MR study results provide evidence for a causal relationship between BMD and BC risk, which suggests the significance of BMD screening in detecting and preventing BC.