Bone mineral density and cardiovascular diseases: a two-sample Mendelian randomization study

Area of Science:

• Genetics
• Cardiovascular Medicine
• Bone Metabolism

Background:

• Observational studies show inconsistent links between bone mineral density (BMD) and cardiovascular disease (CVD).
• The causality of the relationship between BMD and CVD remains debated.
• Robust methodologies are needed to clarify this association.

Purpose of the Study:

• To evaluate the causal relationship between genetically predicted BMD and seven major CVDs.
• To investigate potential shared genetic factors influencing bone mineral density and cardiovascular health.
• To differentiate direct causal effects from confounding factors in the BMD-CVD association.

Main Methods:

• Two-sample Mendelian randomization (MR) using publicly available genome-wide association studies (GWAS) data.
• Utilized UK Biobank (primary) and FinnGen (validation) cohorts for cardiovascular outcomes.
• Employed inverse variance weighted (IVW), weighted median, weighted mode, and MR-Egger regression models, with MR-Egger Pleiotropy RESidual Sum and Outlier test for pleiotropy assessment.

Main Results:

• No statistically significant causal relationship was found between genetically predicted BMD and atrial fibrillation, angina, ischemic heart disease, heart failure, hypertension, myocardial infarction, or non-ischemic cardiomyopathy.
• Results were consistent across multiple MR analytical methods (IVW, weighted median, weighted mode, MR-Egger).
• Validation analysis using the FinnGen cohort confirmed the primary findings, showing no causal link.

Conclusions:

• This comprehensive MR study provides no evidence for a causal effect of BMD on major CVDs.
• Observed associations in prior studies are likely due to shared underlying risk factors.
• The findings suggest that bone density does not directly cause cardiovascular disease.