Abstract
PURPOSE: This study utilizes bidirectional Mendelian randomization (MR) to examine the causal relationships between white matter hyperintensity (WMH) phenotypes-namely, WMH volume, fractional anisotropy (FA), and mean diffusivity (MD)-and cognitive abilities, including cognitive performance, intelligence, and overall cognitive function. METHODS: This study leverages genetic variation data from genome-wide association study (GWAS) datasets and employs a bidirectional two-sample MR analysis. The analysis incorporates MR Egger, weighted median, weighted mode, and inverse variance weighted (IVW) methods to assess the bidirectional causal relationship between cognitive abilities and WMH volume, FA, and MD. RESULTS: This study employed MR to explore the causal relationships between WMH volume, FA, MD, and cognitive outcomes. Most MR methods yielded nonsignificant p values (>0.05) and wide confidence intervals. Heterogeneity tests indicated no significant heterogeneity or pleiotropy between WMH volume and cognitive performance or intelligence. However, significant heterogeneity was found between WMH volume and cognitive function, FA with cognitive performance and intelligence, and MD with cognitive performance and intelligence. Reverse analysis also revealed no significant causal relationships. CONCLUSIONS: This study suggests that the bidirectional causal effects between cognitive abilities and WMH volume, FA, and MD are minimal or nonsignificant and highlights data heterogeneity as a concern.