A positive correlation between genetically predicted T-scores and Z-scores is associated with increased breast cancer risk.
Genetically predicted increases in bone mineral density T-scores and Z-scores may elevate the risk of breast cancer.
The causal relationship observed was confirmed through meta-analysis and found to be robust against various sensitivity analyses.
No evidence was found for a reverse causal relationship between breast cancer and bone mineral density.
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BACKGROUND: Breast cancer (BC) poses significant burdens on women globally. While past research suggests a potential link between (BMD) and BC risk, findings remain inconsistent. Our study aims to elucidate the causal relationship between BMD and BC in East Asians using bidirectional (MR).
METHODS: Genetic association data for bone mineral density T-scores (BMD-T) and Z-scores (BMD-Z) (Sample size = 92,615) and BC 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 (IVs) were used, with BC 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 IVs. 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. Besides, the Bonferroni correction was also used to adjust the significance threshold. 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 ([Formula: see text], [Formula: see text], [Formula: see text]) and BMD-Z ([Formula: see text],[Formula: see text], [Formula: see text]) with increased BC risk. The Cochran's [Formula: see text] test and 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 the causal relationship between BMD and BC risk in East Asian populations, suggesting that BMD screening is of great significance in detecting and preventing BC.
Key numbers
1.22
Increase in BC Risk
Odds ratio for -T related to BC risk.
92,615
Sample Size for -T
Total sample size for -T analysis.
95,283
Sample Size for BC
Total sample size for breast cancer analysis.
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