Causal Associations Between Sleep Traits and Delirium: A Bidirectional Two-Sample Mendelian Randomization Study

Abstract

Purpose: Numerous studies have identified a correlation between sleep and delirium; however, the causal relationship remains ambiguous. This bidirectional two-sample Mendelian randomization (MR) study was conducted to examine the possible causal relationships between sleep traits and delirium.

Patients and methods: Utilizing genome-wide association studies (GWAS), we identified ten sleep traits: chronotype, sleep duration, short sleep duration, long sleep duration, daytime napping, daytime sleepiness, insomnia, number of sleep episodes (NSE), sleep efficiency, and rapid eye movement sleep behavior disorder (RBD). In this MR study, genetic variants independently associated with exposures were selected as instrumental variables (IVs). To establish causal inferences, three regression models were employed-inverse variance weighted (IVW), MR Egger, and weighted median (WM) -and conducted sensitivity analyses to assess the robustness of our findings.

Results: Our results suggest no significant causal association between the ten sleep traits and the risk of delirium. The reverse MR analysis revealed that delirium is associated with an increased propensity for morning chronotype [OR_IVW, 1.025; 95% CI, 1.012-1.036; p = 1.50E-05; adjusted p values (p_adjusted)= 1.35E-04] and a decreased risk of long sleep duration [OR_IVW, 0.996; 95% CI, 0.993-0.999; p = 0.013; p_adjusted= 0.059]. However, no robust evidence currently exists to substantiate a causal relationship between delirium and other sleep traits.

Conclusion: Our bidirectional, two-sample MR analysis study did not provide definitive evidence that sleep traits may augment the susceptibility to delirium. However, the reverse MR results indicate that delirium may predispose patients to an earlier sleep-wake cycle. Additional large-scale investigations are necessary to examine the bidirectional causality between delirium and sleep traits.

Keywords: Mendelian randomization analysis; delirium; genome-wide association studies; sleep traits.

Figure 1

MR model of exposure and risk of delirium. The design of this study was based on the following hypotheses: genetic variants are associated with exposure but not with confounders; genetic variants affect delirium only through exposure.

Figure 2

Forest plots utilized Three methods to visualize the causal effects of Sleep traits on Delirium risk.

Figure 3

Forest plots utilized Three methods to visualize the causal effects of Delirium on Sleep traits risk.

Figure 4

Visualization of the MR analysis of the effect of Delirium on Chronotype and Long sleep duration. (A) Scatter plot of the MR analysis and Leave-one-out sensitivity analysis of the effect of Delirium on Chronotype; (B) Scatter plot of the MR analysis and Leave-one-out sensitivity analysis of the effect of Delirium on Long sleep duration.