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 relationship between inflammatory factors and cerebral small vessel disease: Univariate, multivariate, and summary-data-based mendelian randomization analysis.
To explore the impact of inflammatory factors on the incidence of cerebral small vessel disease (CSVD), we performed a mendelian randomization (MR) study to analyze the causal relationship between multiple inflammatory factors and CSVD imaging markers and utilized summary-data-based mendelian randomization (SMR) analysis to infer whether the impact of instrumental variables (IVs) on disease is mediated by gene expression or DNA methylation.
Using public databases such as UKB and IEU, and original genome-wide association studies, we obtained IVs related to exposure (inflammatory factors) and outcome (CSVD imaging markers). We performed the inverse variance weighted, weighted median, and MR-Egger methods to assess causal effects between exposure and outcome in univariate MR analysis. To evaluate their heterogeneity, a series of sensitivity analyses were conducted, including the Cochrane Q test, MR-Egger intercept test, MR-Presso, and leave-one-out analysis. We also applied mediation and multivariate MR analysis to explore the interactions between positive exposures on the same outcome. Additionally, we conducted the SMR, which utilizes instruments within or near relevant genes in blood or brain tissues, to elucidate the causal associations with CSVD markers.
ABO Univariate MR of multiple cohorts revealed that the risk of small vessel stroke (SVS) increases with elevated levels of TNF-related apoptosis-inducing ligand (TRAIL, OR, 1.23, 95% CI, 1.08-1.39) and interleukin-1 receptor-like 2, (IL-1RL2, OR, 1.29, 95% CI, 1.04-1.61). IL-18 was a potential risk factor for extensive basal ganglia perivascular space burden (BGPVS, OR, 1.02, 95% CI, 1.00-1.05). Moreover, the risk of extensive white matter perivascular space burden (WMPVS) decreased with rising levels of E-selectin (OR, .98, 95% CI, .97-1.00), IL-1RL2 (OR, .97, 95% CI, .95-1.00), IL-3 receptor subunit alpha (IL-3Ra, OR, .98, 95% CI, .97-1.00), and IL-5 receptor subunit alpha (IL-5Ra, OR, .98, 95% CI, .97-1.00). Mediation and multivariate MR analysis indicated that E-selectin and IL-3Ra might interact during the pathogenesis of WMPVS. SMR estimates showed that TRAIL-related IVs rs5030044 and rs2304456 increased the risk of SVS by increasing the expression of gene Kininogen-1 (KNG1) in the cerebral cortex, particularly in the frontal cortex (βsmr = .10, Psmr = .003, FDR = .04). Instruments (rs507666 and rs2519093) related to E-selectin and IL-3Ra could increase the risk of WMPVS by enhancing DNA methylation of the gene ABO in blood tissue (βsmr = .01-.02, Psmr = .001, FDR = .01-.03).
According to MR and SMR analysis, higher levels of TRAIL increased the risk of SVS by upregulating gene expression of KNG1 in brain cortex tissues. In addition, protective effects of E-selectin and IL-3a levels on WMPVS were regulated by increased DNA methylation of gene ABO in blood tissue.
Qiao TC
，Tian HY
，Shan SZ
，Shan LL
，Peng ZY
，Ke J
，Li MT
，Wu Y
，Han Y
... -
《Brain and Behavior》
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
... -
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