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Causal Association between Whole Body Water Mass and Sleep Apnea: A Mendelian Randomization Study.

RATIONALE
Growing evidence has suggested that body water content plays a critical role in sleep apnea. However, their causal relationship has not been established.


OBJECTIVE
This study is aimed to investigate whether increased whole body water mass is causally associated with a higher risk of sleep apnea using two-sample Mendelian randomization (MR) analysis.


METHODS
Body water mass-associated genetic instruments were extracted from a genome-wide association study conducted by Neale Lab, which incorporates 331, 315 individuals of European ancestry. Genetic variants for sleep apnea were derived from FinnGen dataset. MR analysis was performed using inverse variance-weighted and weight median methods, respectively. MR-Egger regression and MR-PRESSO (Pleiotropy Residual Sum and Outlier) test were applied to evaluate the directional pleiotropy. In addition, we performed a multivariable MR analysis that includes BMI, snoring, and waist-to-hip ratio as covariate exposures to address their confounding effects. To elucidate mechanisms of the association between body water mass and sleep apnea, we further conducted MR analysis on common edematous diseases.


RESULTS
MR estimates showed that per standard deviation increase in body water mass led to an increase in the risk of sleep apnea by 49% (OR 1.490; 95% CI 1.308-1.696; P = 1.75×10-9). The result after MR-PRESSO correction further supports their causal association (OR 1.414; 95% CI 1.253-1.595; P = 1.76×10-8). Additionally, the multivariable MR analysis indicates a significant causal association between a higher BWM and increased risk of sleep apnea (OR 1.204; 95% CI 1.031-1.377; P = 0.036). Genetic predisposition to a higher body water mass was also causally related with increased risk of edematous diseases.


CONCLUSIONS
Our results suggested that increased body water mass is a potential risk factor for sleep apnea. Pathologic edema is a possible intermediate factor mediating this causal association.