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 ... -  《-》

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 associations between obstructive sleep apnea and COVID-19: A bidirectional Mendelian randomization study.

The COVID-19 pandemic has caused significant impact on human health. Whether obstructive sleep apnea (OSA) increases the risk of COVID-19 remains unclear. We sought to clarify this issue using two-sample Mendelian randomization (TSMR) analysis in large cohorts. Bidirectional two-sample Mendelian randomization (MR) was used to evaluate the potential causality between OSA and COVID-19 by selecting single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) from genome-wide association studies (GWAS). The inverse-variance weighted (IVW) method was selected as the main approach for data analysis to estimate the possible causal effects. Alternative methods such as MR-Egger, the MR pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out analysis methods were implemented as sensitivity analysis approaches to ensure the robustness of the results. All forward MR analyses consistently indicated the absence of a causal relationship between OSA and any COVID-19 phenotype. In the reverse MR analysis, the IVW mode demonstrated that severe respiratory confirmed COVID-19 was correlated with a 4.9% higher risk of OSA (OR, 1.049; 95%CI, 1.018-1.081; P = 0.002), consistent in MR-PRESSO (OR = 1.049, 95%CI 1.018-1.081, P = 0.004), weighted median (OR = 1.048, 95%CI 1.003-1.095, P = 0.035), and MR-Egger (OR = 1.083, 95%CI 1.012-1.190, P = 0.041) methods. There is no significant evidence supporting a causal association between OSA and any COVID phenotype, while we identified potential evidence for a causal effect of severe COVID-19 on an increased risk of OSA.

Gao X ，Wei T ，Wang H ，Sui R ，Liao J ，Sun D ，Han D ... -  《-》

Causal Effect of Obstructive Sleep Apnea on Atrial Fibrillation: A Mendelian Randomization Study.

Chen W ，Cai X ，Yan H ，Pan Y ... -  《Journal of the American Heart Association》

Causal Impact of Type 2 Diabetes Mellitus on Cerebral Small Vessel Disease: A Mendelian Randomization Analysis.

The relationship between type 2 diabetes mellitus (T2D) and cerebral small vessel disease (CSVD) is unclear. We aimed to examine the causal effect of T2D, fasting glucose levels, and higher insulin resistance on CSVD using Mendelian randomization. Five CSVD phenotypes were studied; 2 were clinical outcomes associated with CSVD (lacunar stroke: n=2191/27 297 and intracerebral hemorrhage [ICH]: n=2254/8195 [deep and lobar ICH]), whereas 3 were radiological markers of CSVD (white matter hyperintensities: n=8429; fractional anisotropy [FA]: n=8357; and mean diffusivity: n=8357). We applied 2 complementary analyses to evaluate the association of T2D with CSVD. First, we used summarized data from genome-wide association study to calculate the effects of T2D-related variants on CSVD with inverse-variance weighted and weighted median approaches. Second, we performed a genetic risk score approach to test the effects of T2D-associated variants on white matter hyperintensities, FA, and mean diffusivity using individual-level data in UK Biobank. T2D was associated with higher risk of lacunar stroke (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.04-1.28; P=0.007) and lower mean FA (OR, 0.78; 95% CI, 0.66-0.92; P=0.004) but not white matter hyperintensities volume (OR, 1.01; 95% CI, 0.97-1.04; P=0.626), higher mean diffusivity (OR, 1.04; 95% CI, 0.89-1.23; P=0.612), ICH (OR, 1.07; 95% CI, 0.95-1.20; P=0.269), lobar ICH (OR, 1.07; 95% CI, 0.89-1.28; P=0.466), or deep ICH (OR, 1.16; 95% CI, 0.99-1.36; P=0.074). Weighted median and penalized median weighted analysis showed similar effect estimates of T2D on lacunar stroke and FA, but with wider CIs, meaning they were not significant. The genetic score on individual-level data was significantly associated with FA (OR, 0.63; 95% CI, 0.45-0.89; P=0.008) after adjusting for potential confounders. Our Mendelian randomization study provides evidence to suggest that T2D may be causally associated with CSVD, in particular with lacunar stroke and FA.

Liu J ，Rutten-Jacobs L ，Liu M ，Markus HS ，Traylor M ... -  《-》