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

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.

Liu X ，Li X ，Wang X ，Xu A ... -  《-》

Causal Effect of the 25-Hydroxyvitamin D Concentration on Cerebral Small Vessel Disease: A Mendelian Randomization Study.

Lee KJ ，Kim H ，Lee SJ ，Duperron MG ，Debette S ，Bae HJ ，Sung J ... -  《-》

Correlation between obstructive sleep apnea and cerebral small vessel disease: a mendelian randomization study.

Whether obstructive sleep apnea (OSA) is causally associated with an increased risk of cerebral small vessel disease (CSVD) remains controversial. We conducted a two-sample Mendelian randomization (MR) study to clarify the causal relationship between OSA and CSVD risk. Single-nucleotide polymorphisms associated with OSA at the genome-wide significance level (P < 5 × 10- 8) in the FinnGen consortium were selected as instrumental variables. Summary-level data for white matter hyperintensities (WMHs), lacunar infarctions (LIs), cerebral microbleeds (CMBs), fractional anisotropy (FA), and mean diffusivity (MD) were obtained from three meta-analyses of genome-wide association studies (GWASs). The random-effects inverse-variance weighted (IVW) method was selected for the major analysis. Weighted-median, MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out analysis methods were implemented for the sensitivity analyses. Genetically predicted OSA was not associated with LIs (odds ratio [OR] = 1.10, 95% confidence interval [CI] = 0.86-1.40), WMHs (OR = 0.94, 95% CI = 0.83-1.07), FA (OR = 1.33, 95% CI = 0.75-2.33), MD (OR = 0.93, 95% CI = 0.58-1.47), CMBs (OR = 1.29, 95% CI = 0.86-1.94), mixed CMBs (OR = 1.17, 95% CI = 0.63-2.17), and lobar CMBs (OR = 1.15, 95% CI = 0.75-1.76) in IVW method. The results of the sensitivity analyses were generally consistent with the major analyses. This MR study does not support causal associations between OSA and the risk of CSVD in individuals of European ancestry. These findings need to be further validated in randomized controlled trials, larger cohort studies, and MR studies based on larger GWASs.

Wu B ，Liu F ，Sun G ，Wang S ... -  《-》

The possible causal relationship between COVID-19 and imaging markers of cerebral small vessel disease: a Mendelian randomization study.

Song J ，Zhou D ，Jia L ，Wang M ，Lan D ，Li J ，Hamit FZH ，Ding Y ，Ji X ，Meng R ... -  《-》

Cerebral small vessel disease increases risk for epilepsy: a Mendelian randomization study.

Despite previous research suggesting a potential association between cerebral small vessel disease (CSVD) and epilepsy, the precise causality and directionality between cerebral small vessel disease (CSVD) and epilepsy remain incompletely understood. We aimed to investigate the causal link between CSVD and epilepsy. A bidirectional two-sample Mendelian randomization (MR) analysis was performed to evaluate the causal relationship between CSVD and epilepsy. The analysis included five dimensions of CSVD, namely small vessel ischemic stroke (SVS), intracerebral hemorrhage (ICH), white matter damage (including white matter hyperintensity [WMH], fractional anisotropy, and mean diffusivity), lacunar stroke, and cerebral microbleeds. We also incorporated epilepsy encompassing both focal epilepsy and generalized epilepsy. Inverse variance weighted (IVW) was used as the primary estimate while other four MR techniques were used to validate the results. Pleiotropic effects were controlled by adjusting vascular risk factors through multivariable MR. The study found a significant association between SVS (odds ratio [OR] 1.117, PFDR = 0.022), fractional anisotropy (OR 0.961, PFDR = 0.005), mean diffusivity (OR 1.036, PFDR = 0.004), and lacunar stroke (OR 1.127, PFDR = 0.007) with an increased risk of epilepsy. The aforementioned correlations primarily occurred in focal epilepsy rather than generalized epilepsy on subgroup analysis and retained their significance in the multivariable MR analysis. Our study demonstrated that genetic susceptibility to CSVD independently elevates the risk of epilepsy, especially focal epilepsy. Diffusion tensor imaging may help screen patients at high risk for epilepsy in CSVD. Improved management of CSVD may be a significant approach in reducing the overall prevalence of epilepsy.

Wang Y ，Zuo H ，Li W ，Wu X ，Zhou F ，Chen X ，Liu F ，Xi Z ... -  《-》