Causal effect of cerebral small vessel disease on unexplained dizziness: A Mendelian randomization study

Abstract

BackgroundPrevious cohort studies have suggested an association between cerebral small vessel disease (cSVD) and “unexplained dizziness”. The causality of this link remains uncertain, but it would be of significant clinical importance, considering the substantial number of patients presenting with unexplained dizziness is large. We aimed to investigate the causal effect of cSVD-related phenotypes on unexplained dizziness using a Mendelian randomization approach. MethodsGenetic instruments for each cSVD-related phenotype - white matter hyperintensity (WMH) volume, lacunar stroke (LS), perivascular spaces (PVS), and cerebral microbleeds (CMBs) - as well as unexplained dizziness were identified through large-scale genome-wide association studies. We conducted 2-sample Mendelian randomization analyses. The random-effects inverse-variance weighted (IVW) method was chosen for the primary analysis. For sensitivity analyses, we employed the weighted-median, MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out analysis methods were implemented for the sensitivity analyses. ResultsWe successfully identified a significant causal effect of WMH volume on unexplained dizziness (odds ratio [95% CI], 1.12 [1.01–1.23]). However, we were unable to detect any significant causal effects of the other cSVD-related phenotypes on unexplained dizziness, with odds ratios [95% CI] of 1.03 [0.98–1.09] for LS, 0.75 [0.55–1.02] for white matter PVS, 1.02 [0.68–1.52] for basal ganglia PVS, 0.80 [0.43–1.51] for hippocampal PVS, 0.95 [0.90–1.00] for lobar CMBs, and 0.97 [0.92–1.01] for mixed CMBs respectively. The results from the sensitivity analyses were generally consistent with those of the primary analyses. ConclusionsThis MR study supports a causal relationship between WMH, a phenotype associated with cSVD, and the risk of unexplained dizziness, but does not support such a relationship between other cSVD-related phenotypes and unexplained dizziness. These findings require further validation through randomized controlled trials, larger cohort studies, and MR studies based on more extensive GWASs.