Department of Neurology, The First Affiliated Hospital of Jinan University, No. 601 West Huangpu Avenue, Tianhe District, Guangzhou 510630, China; Department of Neurology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, Guangdong 518000, China.
Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
J Stroke Cerebrovasc Dis. 2024 Nov;33(11):107948. doi: 10.1016/j.jstrokecerebrovasdis.2024.107948. Epub 2024 Aug 15.
Previous 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.
Genetic 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.
We 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.
This 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.
先前的队列研究表明，脑小血管疾病（cSVD）与“不明原因的头晕”之间存在关联。这种关联的因果关系尚不确定，但考虑到大量出现不明原因头晕的患者数量庞大，这具有重要的临床意义。我们旨在通过孟德尔随机化方法研究与 cSVD 相关表型对不明原因头晕的因果影响。
通过大规模全基因组关联研究，确定了与 cSVD 相关表型（脑白质高信号（WMH）体积、腔隙性卒（LS）、血管周围间隙（PVS）和脑微出血（CMBs））以及不明原因头晕相关的遗传工具。我们进行了 2 样本孟德尔随机化分析。主要分析采用随机效应逆方差加权（IVW）方法。对于敏感性分析，我们使用加权中位数、MR-Egger、MR 偏倚残差总和和异常值（MR-PRESSO），并实施了逐一缺失分析方法进行敏感性分析。
我们成功地发现 WMH 体积与不明原因头晕之间存在显著的因果关系（优势比[95%CI]，1.12[1.01-1.23]）。然而，我们未能检测到其他与 cSVD 相关的表型对不明原因头晕的任何显著因果影响，LS 的优势比[95%CI]为 1.03[0.98-1.09]，白质 PVS 为 0.75[0.55-1.02]，基底节 PVS 为 1.02[0.68-1.52]，海马 PVS 为 0.80[0.43-1.51]，脑叶 CMBs 为 0.95[0.90-1.00]，混合 CMBs 为 0.97[0.92-1.01]。敏感性分析的结果与主要分析基本一致。
这项 MR 研究支持 WMH（一种与 cSVD 相关的表型）与不明原因头晕风险之间存在因果关系，但不支持其他与 cSVD 相关的表型与不明原因头晕之间存在这种关系。这些发现需要通过随机对照试验、更大的队列研究以及基于更广泛 GWAS 的 MR 研究进一步验证。
