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. 2023 Feb 9:14:1068756.
doi: 10.3389/fpsyt.2023.1068756. eCollection 2023.

Mendelian randomization reveals no associations of genetically-predicted obstructive sleep apnea with the risk of type 2 diabetes, nonalcoholic fatty liver disease, and coronary heart disease

Xiaoxu Ding  1 , Lanqing Zhao  1 , Xiangguo Cui  1 , Li Qi  2 , Yu Chen  1
Affiliations

Mendelian randomization reveals no associations of genetically-predicted obstructive sleep apnea with the risk of type 2 diabetes, nonalcoholic fatty liver disease, and coronary heart disease

Xiaoxu Ding et al. Front Psychiatry. .

Abstract

Background: Obstructive sleep apnea (OSA) has been reported to affect cardiometabolic diseases. However, whether such association is causal is still unknown. Here, we attempt to explore the effect of OSA on type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD) and coronary heart disease (CHD).

Methods: Genetic variants associated with OSA were requested from a published genome-wide association study (GWAS) and those qualified ones were selected as instrumental variables (IV). Then, the IV-outcome associations were acquired from T2D, NAFLD and CHD GWAS consortia separately. The Mendelian randomization (MR) was designed to estimate the associations of genetically-predicted OSA on T2D, NAFLD and CHD respectively, using the inverse-variance weighted (IVW) method. We applied the Bonferroni method to adjust the p-value. Besides, MR-Egger regression and weighted median methods were adopted as a supplement to IVW. The Cochran's Q value was used to evaluate heterogeneity and the MR-Egger intercept was utilized to assess horizontal pleiotropy, together with MR-PRESSO. The leave-one-out sensitivity analysis was carried out as well.

Results: No MR estimate reached the Bonferroni threshold (p < 0.017). Although the odds ratio of T2D was 3.58 (95% confidence interval (CI) [1.06, 12.11], IVW-p-value = 0.040) using 4 SNPs, such causal association turned insignificant after the removal of SNP rs9937053 located in FTO [OR = 1.30 [0.68, 2.50], IVW p = 0.432]. Besides, we did not find that the predisposition to OSA was associated with CHD [OR = 1.16 [0.70, 1.91], IVW p = 0.560] using 4 SNPs.

Conclusion: This MR study reveals that genetic liability to OSA might not be associated with the risk of T2D after the removal of obesity-related instruments. Besides, no causal association was observed between NAFLD and CHD. Further studies should be carried out to verify our findings.

Keywords: Mendelian randomization; cardiometabolic diseases; causal inference; obstructive sleep apnea; type 2 diabetes.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The basic assumptions of Mendelian randomization. IV is instrumental variable; OSA is obstructive sleep apnea; T2D is type 2 diabetes; NAFLD is nonalcoholic fatty liver disease; CHD is coronary heart disease.
Figure 2
Figure 2
The forest plot of Mendelian randomization. OSA is obstructive sleep apnea; T2D is type 2 diabetes; NAFLD is nonalcoholic fatty liver disease; CHD is coronary heart disease; OR is odds ratio; 95%LCI is the lower limit of 95% confidence interval of OR; 95%UCI is the upper limit of 95% confidence interval of OR.
Figure 3
Figure 3
(A) The scatterplot of OSA-T2D results. Different colors represent different methods and each point is a single nucleotide polymorphism. The horizontal and vertical lines of each point represent the 95% confidence interval of the effect size. (B) The leave-one-out-sensitivity forest plot of OSA-T2D results.
Figure 4
Figure 4
(A) The scatterplot of OSA-NAFLD results. Different colors represent different methods and each point is a single nucleotide polymorphism. The horizontal and vertical lines of each point represent the 95% confidence interval of the effect size. (B) The leave-one-out-sensitivity forest plot of OSA-NAFLD results.
Figure 5
Figure 5
(A) The scatterplot of OSA-CHD results. Different colors represent different methods and each point is a single nucleotide polymorphism. The horizontal and vertical lines of each point represent the 95% confidence interval of the effect size. (B) The leave-one-out-sensitivity forest plot of OSA-CHD results.
Figure 6
Figure 6
(A) The scatterplot of OSA-T2D results after removal of SNP rs10928560. Different colors represent different methods and each point is a single nucleotide polymorphism. The horizontal and vertical lines of each point represent the 95% confidence interval of the effect size. (B) The scatterplot of OSA-NAFLD results after removal of SNP rs10928560. Different colors represent different methods and each point is a single nucleotide polymorphism. The horizontal and vertical lines of each point represent the 95% confidence interval of the effect size.
Figure 7
Figure 7
(A) The leave-one-out-sensitivity forest plot of OSA-T2D results after removal of SNP rs10928560. (B) The leave-one-out-sensitivity forest plot of OSA-NAFLD results after removal of SNP rs10928560.
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