Thyroid Function in Causal Relation to MRI Markers of Cerebral Small Vessel Disease: A Mendelian Randomization Analysis

Observational studies have provided insufficient information on the association between thyroid function and the risk of cerebral small vessel disease (CSVD); moreover, the causality of this link is still unclear.This study aims to investigate whether genetically predicted variation within thyroid function is causally associated with the risk of CSVD using 2-sample Mendelian randomization (MR) analysis.In this 2-sample MR study with genome-wide association variants, we estimated the causal effects of genetically predicted thyrotropin (thyroid-stimulating hormone, TSH; n = 54 288), free thyroxine (FT4; n = 49 269), hypothyroidism (n = 51 823), and hyperthyroidism (n = 51 823) on 3 neuroimaging markers of CSVD, including white matter hyperintensity (WMH; n = 42 310), mean diffusivity (MD; n = 17 467), and fractional anisotropy (FA, n = 17 663). The primary analysis was conducted by the inverse variance-weighted MR method, followed by sensitivity analyses using MR-PRESSO, MR-Egger, weighted median, and weighted mode methods.Genetically increased TSH was associated with increased MD (β = .311, 95% CI 0.0763, 0.548, P = .01). Genetically increased FT4 was associated with increased FA (β = .540, 95% CI 0.222, 0.858, P < .001). Sensitivity analyses using different MR methods showed similar directions but lower precision. No significant associations of hypothyroidism or hyperthyroidism with WMH, MD, or FA were found (all P > .05).This study indicated that genetically predicted increased TSH was associated with increased MD, as well as increased FT4 with increased FA, implying the causal effect of thyroid dysfunction on white matter microstructural injury. There were no significant causal relationships of hypothyroidism or hyperthyroidism with CSVD. Further investigations should verify these findings and clarify the underlying pathophysiological mechanisms.