Causal effects of basal metabolic rate and adiposity on obstructive sleep apnea: univariable, multivariable, and bidirectional Mendelian randomization evidence.

BACKGROUND

Obstructive sleep apnea (OSA) is a common disorder strongly associated with obesity, yet the causal contribution of basal metabolic rate to OSA and the directionality of the OSA-metabolism relationship remain unclear. The objective of this study was to evaluate the independent and potential bidirectional causal relationships between basal metabolic rate and adiposity-related traits with obstructive sleep apnea using Mendelian randomization.

METHODS

Two-sample Mendelian randomization (MR) was performed using genome-wide association study data from predominantly European populations to evaluate the causal effects of basal metabolic rate, body mass index, and whole-body fat mass on OSA risk and to assess the reverse effects of genetic liability to OSA on basal metabolic rate. Genetic instruments were derived from the UK Biobank genome-wide association study, and the OSA outcome was obtained from a large meta-analysis genome-wide association study. Univariable MR, multivariable MR, reverse MR, and extensive sensitivity analyses (MR-Egger, weighted median, MR-PRESSO, and leave-one-out analyses) were performed.

RESULTS

Univariable MR showed that higher genetically predicted basal metabolic rate, body mass index, and whole-body fat mass were each associated with increased OSA risk (IVW odds ratio per SD: basal metabolic rate 1.85, 95% CI 1.62-2.10; body mass index 2.27, 95% CI 2.07-2.49; whole-body fat mass 2.05, 95% CI 1.85-2.28; all p < 0.05). In multivariable MR, the association between basal metabolic rate and OSA was fully attenuated after adjusting for adiposity (p > 0.05), whereas body mass index and whole-body fat mass retained strong independent causal effects (both p < 0.05), indicating that the apparent basal metabolic rate-OSA association is entirely mediated by fat mass. Reverse MR suggested that genetic liability to OSA modestly increases basal metabolic rate (OR = 1.08, 95% CI 1.04-1.12, p < 0.05), although this estimate showed partial sensitivity to pleiotropy.

CONCLUSION

Elevated adiposity is the primary causal driver of OSA. Although basal metabolic rate does not independently influence OSA risk, OSA may increase resting energy expenditure, suggesting a bidirectional relationship. These findings highlight adiposity reduction as a central target for preventing and treating OSA.