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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Cerebral small vessel disease; Epidemiology; Mendelian randomization; Neuroimaging; Obstructive sleep apnea; Risk factor.