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

Greater white matter hyperintensities (WMH) in older adults have been associated with reduced bone mineral density (BMD) and increased fractures and falls. However, it is unclear whether there is a causal relationship between BMD reduction and WMH. In this study, Mendelian randomization (MR) was used to find the causality between WMH and estimated BMD (eBMD).

We performed a two-sample bidirectional MR analysis using statistical data obtained from publicly available genome-wide association studies (GWAS). The main method of MR analysis is the inverse-variance weighted (IVW) method. To identify and account for the impact of horizontal pleiotropy, we also employed MR-Egger regression, MR pleiotropy residual sum, and outlier (MR-PRESSO).

MR analysis found a causal relationship between eBMD and WMH (IVW OR = 0.938, 95 % CI: 0.889-0.990, p = 0.020). Our causal estimates are unlikely to be distorted by horizontal pleiotropy according to heterogeneity test (both p > 0.05) and MR-Egger regression (p > 0.05). However, in the reverse MR analysis, there was no evidence that WMH was causally correlated with eBMD (IVW OR = 0.979, 95 % CI: 0.954-1.005, p = 0.109).

Our results suggest that low eBMD increased the risk of WMH; conversely, no evidence that WMH causally affects eBMD was found.