Bi-directional and multivariate mendelian randomization analysis of the relationship between circulating 25-hydroxyvitamin D concentration and obstructive sleep apnea

Background 25-hydroxyvitamin D [25(OH)D] deficiency in patients with Obstructive Sleep Apnea (OSA) has long been noted, but identifying the exact causal relationship remains hard. Investigation of the causality between 25(OH)D deficiency and OSA would help facilitate disease prevention. Methods We conducted a two-sample bi-directional Mendelian randomization (MR) study. For forward analysis, 237 newly identified genetic variants are used as proxies for 25(OH)D to estimate the unconfounded effect on OSA among 16,761 OSA cases and 201,194 controls of European ancestry. Reverse analysis was performed to detect the causal impact of OSA on 25(OH)D levels. The inverse variance weighted (IVW) method was used as the primary analysis. Sensitivity analysis was performed to evaluate the robustness of our results. Multivariate MR analysis was conducted to evaluate the direct link between 25(OH)D and OSA after accounting for body mass index (BMI). Results IVW indicated that OSA causally associated with a lower level of 25(OH)D ((beta = -0.03, 95% CI = -0.06 similar to -0.007, P = 0.01). No evidence of the causal link from 25(OH)D to OSA was detected (OR = 0.99, 95% CI = 0.88 similar to 1.12, P = 0.85). Sensitivity analysis suggested the MR estimates were not biased. Multivariate MR analysis indicated the effect of OSA on 25(OH)D vanished upon accounting for BMI (beta = -0.011, 95% CI = -0.028 similar to 0.007, P = 0.23). Conclusion This MR study provided evidence that OSA was causally associated with a lower level of 25(OH)D, which might be driven by BMI. Obesity management should be enhanced in patients with OSA to prevent 25(OH)D deficiency.