Estimated bone mineral density and white matter hyperintensities: A bidirectional Mendelian randomization study

Area of Science:

• Neuroscience
• Gerontology
• Genetics

Background:

• White matter hyperintensities (WMH) are associated with reduced bone mineral density (BMD) and increased fracture risk in older adults.
• The causal relationship between BMD and WMH remains unclear.
• Mendelian randomization (MR) is a robust method for investigating causality between traits.

Purpose of the Study:

• To investigate the potential causal relationship between estimated BMD (eBMD) and WMH using a bidirectional Mendelian randomization (MR) approach.
• To determine if reduced BMD leads to WMH or if WMH influences BMD.

Main Methods:

• A two-sample bidirectional MR analysis was conducted using publicly available genome-wide association study (GWAS) data.
• The inverse-variance weighted (IVW) method was the primary analytical approach.
• MR-Egger regression and MR-PRESSO were used to assess and correct for horizontal pleiotropy.

Main Results:

• MR analysis revealed a causal effect of eBMD on WMH (IVW OR = 0.938, p = 0.020), indicating that lower eBMD increases WMH risk.
• No significant causal effect of WMH on eBMD was detected in the reverse MR analysis (IVW OR = 0.979, p = 0.109).
• Tests for heterogeneity and pleiotropy (MR-Egger, MR-PRESSO) suggested that the causal estimates were robust.

Conclusions:

• Low estimated BMD is a causal risk factor for white matter hyperintensities in older adults.
• There is no evidence to support a causal role of white matter hyperintensities in affecting bone mineral density.