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The Association between Obstructive Sleep Apnea and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study

Zhihai Huang; Emergency Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Zhenzhen Zheng; Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Lingpin Pang; Emergency Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Kaili Fu; Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Junfen Cheng; Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Ming Zhong; Emergency Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Lingyue Song; Emergency Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Dingyu Guo; Emergency Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Qiaoyun Chen; Emergency Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Yanxi Li; Emergency Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Yongting Lv; Emergency Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Riken Chen; Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China; Xishi Sun; Emergency Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China

Background Despite previous observational studies linking obstructive sleep apnea (OSA) to venous thromboembolism (VTE), these findings remain controversial. This study aimed to explore the association between OSA and VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT), at a genetic level using a bidirectional two-sample Mendelian randomization (MR) analysis. Methods Utilizing summary-level data from large-scale genome-wide association studies in European individuals, we designed a bidirectional two-sample MR analysis to comprehensively assess the genetic association between OSA and VTE. The inverse variance weighted was used as the primary method for MR analysis. In addition, MR–Egger, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) were used for complementary analyses. Furthermore, a series of sensitivity analyses were performed to ensure the validity and robustness of the results. Results The initial and validation MR analyses indicated that genetically predicted OSA had no effects on the risk of VTE (including PE and DVT). Likewise, the reverse MR analysis did not find substantial support for a significant association between VTE (including PE and DVT) and OSA. Supplementary MR methods and sensitivity analyses provided additional confirmation of the reliability of the MR results. Conclusion Our bidirectional two-sample MR analysis did not find genetic evidence supporting a significant association between OSA and VTE in either direction.

Introduction

Obstructive sleep apnea (OSA) is a prevalent sleep disorder characterized by the recurrent partial or complete obstruction and collapse of the upper airway during sleep, leading to episodes of apneas and hypoventilation. 1 2 Research studies have reported that the prevalence of OSA in the adult population ranges from 9 to 38%, with a higher prevalence observed in males (13–33%) compared to females (6–19%). Moreover, the prevalence of OSA tends to increase with age and is closely associated with the prevalence of obesity. 3 4

There is mounting evidence indicating that OSA serves as an independent risk factor for several cardiovascular diseases, including hypertension, 5 stroke, 6 pulmonary hypertension, 7 and heart failure. 8 Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is recognized as the third most common cardiovascular disease worldwide. 9 There is evidence suggesting that OSA may also be linked to an increased risk of VTE. 10 For instance, a prospective study involving 15,664 subjects (1,424 subjects with OSA) observed a twofold higher incidence of VTE in patients with OSA compared to non-OSA patients. 11 Similarly, findings from a national retrospective cohort study conducted by Peng and his colleagues indicated that patients with OSA had a 3.50-fold higher risk of DVT and a 3.97-fold higher risk of PE compared to the general population. 12 However, the results of observational studies remain somewhat controversial. A 5-year prospective study involving 2,109 subjects concluded that OSA did not increase the risk of VTE recurrence. 13 Another retrospective analysis involving 1,584 patients, of which 848 were women, revealed an intriguing discovery suggesting that OSA may serve as an independent risk factor for VTE solely in women, rather than in men. 14 Moreover, patients with VTE were found to have a higher prevalence of OSA, 15 suggesting a potential bidirectional relationship.

Although previous observational studies have investigated the potential association between OSA and VTE, elucidating aspects of the association from these studies is challenging due to the limitations of potential confounders and reverse causality bias. Mendelian randomization (MR) is a genetic epidemiological methodology that utilizes genetic variants, such as single-nucleotide polymorphisms (SNPs), as instrumental variables (IVs) to infer the genetic association between exposure and outcome. 16 The advantage of MR analysis lies in the random assignment of genetic variants during meiosis, which effectively circumvents the effects of potential confounders and reverse causality encountered in classical epidemiologic studies. 17

Data Source and Selection of Instrumental Variables

Summary-level data for OSA were obtained from the GWAS study conducted by Jiang et al on European individuals, which included 2,827 cases and 453,521 controls, covering 11,831,932 SNPs. 18 To ensure the robustness of the findings, additional datasets for OSA were acquired from a GWAS meta-analysis conducted by Campos and colleagues, comprising 25,008 cases of European ancestry and 337,630 controls, involving 9,031,949 SNPs for validation analysis. 19 The study conducted a meta-analysis of GWAS datasets from five cohorts in the United Kingdom, Canada, Australia, the United States, and Finland. These summary-level GWAS statistics for OSA can be accessed from the GWAS Catalog ( https://www.ebi.ac.uk/gwas/downloads ). VTE was defined as a condition comprising PE (blockage of the pulmonary artery or its branches by an embolus) and DVT (formation of a blood clot in a deep vein). The GWAS datasets for VTE (19,372 cases and 357,905 controls), PE (9,243 cases and 367,108 controls), and DVT (9,109 cases and 324,121 controls) were derived from the FinnGen consortium (Release 9, https://r9.finngen.fi/ ). Detailed information regarding the data sources is provided in Table 1 .

The selection criteria for IVs were as follows: (1) the threshold for genome-wide significant SNPs for VTE (including PE and DVT) was set at p  < 5.0 × 10 −8 , while the threshold for OSA was adjusted to p  < 1 × 10 −5 due to the inability to detect OSA-associated SNPs using a significance level of p  < 5.0 × 10 −8 . (2) SNPs with linkage disequilibrium effects ( r 2  < 0.001 within a 10,000-kb window) were excluded to ensure the independence of the selected IVs. (3) The strength of the association between IVs and exposure was measured using the F-statistic [F-statistic = (Beta/SE) 2 ]. 20 SNPs with F-statistics >10 were retained to avoid the effects of weak instrumental bias. (4) During the harmonization process, SNPs that did not match the results were removed, along with palindromic SNPs with ambiguous allele frequencies (0.42–0.58). 21 (5) Previous studies have demonstrated obesity as an established risk factor for OSA and VTE. 22 23 SNPs associated with body mass index were queried and excluded by Phenoscanner (http://www.phenoscanner.medschl.cam.ac.uk/). The flowchart of IV selection is shown in Fig. 1 .

Statistical Analysis

This study employed the multiplicative random-effects inverse variance weighted (IVW) method as the primary approach for conducting MR analysis to evaluate the genetic association between OSA and VTE. The IVW method meta-analyzes the Wald ratio estimates for each SNP on the outcome, providing precise estimates of causal effects when all selected SNPs are valid IVs. 24 However, the estimates of causal effects from the IVW method may be biased by the influence of pleiotropic IVs. To ensure the validity and robustness of the results, sensitivity analyses were implemented using three additional MR methods, namely MR–Egger, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO). The MR–Egger method is able to generate reliable causal estimates even in situations where all IVs are invalid. Additionally, MR–Egger offers an intercept test to detect horizontal pleiotropy, with a significance threshold of p <0.05 indicating the presence of horizontal pleiotropy. 25 In comparison to the IVW and MR–Egger methods, the weighted median method demonstrates greater robustness and provides consistent estimates of causal effects, even when up to 50% of the IVs are invalid instruments. 26 The MR-PRESSO method identifies outliers with potential horizontal pleiotropy and provides estimates after removing the outliers, where p <0.05 for the global test indicates the presence of outliers with horizontal pleiotropy. 27 Furthermore, the Cochran Q test was utilized to examine heterogeneity, with a significance threshold of p <0.05 indicating significant heterogeneity.

Instrumental Variable Selection

As previously outlined, a total of 13 and 28 SNPs were identified through a rigorous screening process to evaluate the effects of OSA on VTE, PE, and DVT. In the reverse MR analysis, 23, 14, 18, 19, 11, and 13 SNPs were identified to assess the implications of reverse association, respectively. Additional details regarding these genetic variants utilized for MR analysis are provided in Tables 2 and 3 .

Effects of OSA on VTE

Fig. 2 shows the estimates of the effects for OSA on VTE, PE, and DVT. In the initial MR analysis using the OSA (Jiang et al) dataset, the random-effects IVW method revealed no significant association between OSA and the risk of VTE (odds ratio [OR]: 0.964, 95% confidence interval [CI]: 0.914-1.016, p  = 0.172), PE (OR: 0.929, 95% CI: 0.857–1.006, p  = 0.069), PE (OR: 0.929, 95% CI: 0.857–1.006, p  = 0.069), and DVT (OR: 1.001, 95% CI: 0.936–1.071, p  = 0.973). No heterogeneity was observed using the Cochran Q test (all p * > 0.05). The MR–Egger intercept test (all p ** > 0.05) and the MR-PRESSO global test (all p *** > 0.05) failed to detect any evidence of pleiotropy.

The validation analysis using genetic variants of OSA (Campos et al) yielded similar results. Notably, heterogeneity was observed in the sensitivity analysis for OSA (Campos et al) and VTE ( p * = 0.018). However, considering the random-effects IVW model employed, the level of heterogeneity was deemed acceptable. 28 Despite the presence of outliers suggested by the MR-PRESSO global test ( p  = 0.015), no significant association between OSA and VTE (OR: 1.071, 95% CI: 0.917–1.251, p  = 0.396) was found after excluding an outlier (rs7106583). In addition, none of the three complementary MR methods supported a genetic association between OSA and VTE.

Effects of VTE on OSA

We conducted reverse MR analysis to further evaluate the effects of VTE (including PE and DVT) on OSA. Both MR analyses yielded consistent results, indicating no significant effects of VTE, PE, and DVT on OSA (see Fig. 3 ). Moreover, the Cochran Q test revealed no heterogeneity (all p * > 0.05), and both the MR–Egger intercept test and the MR-PRESSO global test found no evidence of pleiotropy (all p ** > 0.05 and p *** > 0.05, respectively) (see Fig. 3 ). In summary, a range of sensitivities confirmed the reliability of the MR results.

Discussion

Our findings contradict some previous observational studies suggesting a link between susceptibility to OSA and an increased risk of VTE. 29 30 31 32

However, these studies were hindered by inadequate consideration of confounding factors, particularly obesity, along with methodological flaws and small sample sizes. Obesity is widely recognized as a significant risk factor for both OSA 33 and VTE. 34 Therefore, it is crucial not to overlook the impact of obesity in striving for a deeper understanding of the potential association between OSA and VTE. Notably, a cohort study involving 31,309 subjects indicated a higher likelihood of VTE development among patients with more severe OSA. Yet, this association disappeared upon adjusting for confounders, notably obesity levels. 35 Thus, it is plausible that the observed association between OSA and VTE could be attributed to obesity confounding. Additionally, Aman and his colleagues' report yielded consistent results, suggesting that OSA does not elevate the risk of VTE after adjusting for obesity confounding. 36

While our MR study did not find evidence supporting a genetic association between OSA and VTE, it remains possible that OSA could influence the onset or progression of VTE. Virchow's triad depicts three major factors inducing VTE: endothelial injury, venous stasis, and hypercoagulability. 37 The pathophysiologic mechanism linking OSA and VTE remains unknown but may be associated with OSA's capacity to affect the three classical mechanistic pathways of Virchow's triad. 38 Intermittent hypoxia, a signature feature of OSA, can induce oxidative stress and activate inflammatory markers, further damaging the vascular endothelium. 39 40 OSA-associated hemodynamic alterations and reduced physical activities may result in venous stasis. 41 A growing number of studies have demonstrated a strong correlation between OSA and hypercoagulability. A retrospective cohort study aimed at assessing coagulation in patients with OSA suggested that patients with moderate to severe OSA experienced elevated markers of blood coagulability, primarily evidenced by shortened prothrombin time, compared to healthy individuals. 42 Two additional studies of thrombotic parameters found that patients with OSA possessed higher levels of the thrombin–antithrombin complex. 43 44 Furthermore, several coagulation factors, such as fibrinogen, coagulation factor VII, coagulation factor XII, and vascular hemophilic factor, which play a crucial role in the coagulation process, are elevated in patients with OSA. 45 Collectively, this evidence supports that patients with OSA are in a state of hypercoagulability, facilitating our understanding of the underlying pathophysiologic mechanisms between OSA and VTE. Considering these potential mechanisms, future large-scale studies are necessary to thoroughly explore the potential association between OSA and VTE, delving into greater depth.

Tables

Table 1 Information on data sources

Trait Sample size Case Control No. of SNPs Participates PMID/Link
OSA (Jiang et al) 456,348 2,827 453,521 11,831,932 European ancestry 34737426
OSA (Campos et al) 362,638 25,008 337,630 9,031,949 European ancestry 36525587
VTE 377,277 19,372 357,905 20,170,236 European ancestry FinnGen consortium ( https://www.finngen.fi/fi )
PE 376,351 9,243 367,108 20,170,202 European ancestry FinnGen consortium ( https://www.finngen.fi/fi )
DVT 333,230 9,109 324,121 20,169,198 European ancestry FinnGen consortium ( https://www.finngen.fi/fi )

Table 2 Genetic variants used in the MR analysis

Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Jiang et al) and their associations with VTE, PE, and DVT
Exposure: OSA (Jiang et al) Exposure: OSA (Jiang et al) Exposure: OSA (Jiang et al) Exposure: OSA (Jiang et al) Outcome: VTE Outcome: VTE Outcome: VTE Outcome: PE Outcome: PE Outcome: PE Outcome: DVT Outcome: DVT Outcome: DVT
SNP EA OA Beta SE p -Value F-statistic Beta SE p -Value Beta SE p -Value Beta SE p -Value
1 rs114417992 C G 0.48798 0.10793 6.15E-06 20.4409 0.00702 0.04378 0.87253 −0.0542 0.06211 0.3832 −0.0052 0.06334 0.93511
2 rs115071002 T C −0.3775 0.0807 2.90E-06 21.8836 −0.0521 0.05045 0.30146 0.0359 0.07185 0.61729 −0.0633 0.07247 0.38241
3 rs117025138 C G 0.42795 0.09571 7.78E-06 19.9915 −0.0149 0.05477 0.78611 0.0087 0.07809 0.91129 −0.0338 0.07836 0.66637
4 rs117474005 T C 0.64176 0.14138 5.64E-06 20.6051 −0.0095 0.04108 0.81724 −0.0009 0.05862 0.98772 −0.0301 0.05891 0.60971
5 rs139183760 C G 0.82973 0.16928 9.50E-07 24.0262 0.06514 0.07681 0.39643 0.04441 0.10929 0.68448 0.04761 0.11024 0.66585
6 rs148047757 A G 0.47481 0.10699 9.08E-06 19.6952 −0.0522 0.0352 0.13769 −0.044 0.04999 0.37895 −0.0294 0.05078 0.562
7 rs150798389 C A 0.7875 0.17391 5.95E-06 20.505 −0.2884 0.1435 0.04447 −0.2436 0.20053 0.22438 −0.1329 0.20679 0.52056
8 rs16850412 A G 0.19514 0.04353 7.36E-06 20.0977 0.02674 0.01584 0.09145 0.04785 0.02253 0.03368 0.0173 0.02277 0.44739
9 rs1911999 C T −0.1312 0.02965 9.59E-06 19.5917 0.01759 0.01111 0.11349 0.0376 0.01577 0.01714 0.00223 0.01596 0.88889
10 rs2302012 A G 0.12829 0.02871 7.88E-06 19.9669 −0.0104 0.01076 0.33549 −0.0272 0.0153 0.07541 0.00767 0.01545 0.61949
11 rs35963104 T C 0.16572 0.03452 1.59E-06 23.0393 −0.0076 0.01354 0.57685 −0.02 0.01924 0.29896 −0.007 0.01942 0.71778
12 rs60445800 T C 0.29191 0.06499 7.06E-06 20.1758 −0.0268 0.02361 0.25672 −0.0649 0.03349 0.05277 0.0112 0.03388 0.74095
13 rs9587442 T C 0.44308 0.09584 3.78E-06 21.3735 −0.0385 0.03346 0.24969 −0.0101 0.04781 0.83322 0.00182 0.04783 0.96962
Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT Genetic instruments for OSA (Campos et al) and their associations with VTE, PE, and DVT
Exposure: OSA (Campos et al) Exposure: OSA (Campos et al) Exposure: OSA (Campos et al) Exposure: OSA (Campos et al) Outcome: VTE Outcome: VTE Outcome: VTE Outcome: PE Outcome: PE Outcome: PE Outcome: DVT Outcome: DVT Outcome: DVT
SNP EA OA Beta SE p -Value F-statistic Beta SE p -Value Beta SE p -Value Beta SE p -Value
1 rs10777826 T C −0.0319 0.00664 1.58E-06 23.0496 0.00684 0.01097 0.53296 0.01049 0.01557 0.50053 0.01763 0.01576 0.26318
2 rs10878269 T C 0.03308 0.0069 1.61E-06 23.0112 −0.0208 0.01191 0.08097 −0.0262 0.01693 0.12108 −0.015 0.01711 0.37964
3 rs111909157 T C −0.1355 0.02658 3.40E-07 26.01 0.02664 0.04222 0.52808 0.03995 0.05999 0.5054 0.0364 0.06089 0.55
4 rs116114601 A G −0.0873 0.01969 9.20E-06 19.6692 −0.0401 0.04098 0.32779 −0.0676 0.05814 0.24516 −0.0182 0.05873 0.75679
5 rs11989172 C G −0.0378 0.00839 6.73E-06 20.268 −0.0217 0.01283 0.09 −0.039 0.01823 0.03222 0.01058 0.01842 0.56561
6 rs12265404 A G 0.04931 0.01041 2.17E-06 22.4392 0.05233 0.0166 0.00162 0.05687 0.0233 0.01467 0.04278 0.02358 0.06956
7 rs12306339 A C −0.0488 0.01083 6.64E-06 20.295 −0.0051 0.01804 0.77914 −0.023 0.02561 0.37006 0.01462 0.02593 0.57292
8 rs13098300 T C 0.03715 0.00712 1.84E-07 27.1962 0.00251 0.01202 0.83434 0.0101 0.01708 0.55432 5.55E-05 0.01727 0.99744
9 rs140548601 C G −0.1158 0.02428 1.85E-06 22.7529 0.05503 0.04711 0.24277 0.09206 0.06692 0.16895 0.04613 0.06762 0.49515
10 rs143417867 A G −0.3666 0.07088 2.30E-07 26.7599 −0.1487 0.2216 0.5021 0.15664 0.31582 0.61991 −0.0868 0.31594 0.78353
11 rs1942263 A G 0.04569 0.01016 6.93E-06 20.214 −0.0156 0.01713 0.36361 −0.0136 0.02436 0.57584 −0.0318 0.02468 0.19751
12 rs2876633 A T −0.0355 0.00695 3.43E-07 25.9896 −0.0104 0.01158 0.36765 −0.0104 0.01645 0.52845 0.0032 0.01664 0.84772
13 rs35847366 A G 0.0545 0.01172 3.31E-06 21.6318 −0.0365 0.01831 0.04596 −0.0383 0.02603 0.14125 −0.0511 0.02629 0.0517
14 rs36051007 T C 0.03481 0.00716 1.14E-06 23.6682 −0.0037 0.01095 0.73452 −0.0145 0.01557 0.35199 0.00723 0.01573 0.64597
15 rs3774800 A G −0.0309 0.0069 7.79E-06 19.9898 0.00395 0.01151 0.73124 −0.0107 0.01634 0.51218 0.0093 0.01654 0.57396
16 rs4542364 A G 0.03028 0.00673 6.69E-06 20.277 −0.0053 0.01084 0.6236 −0.0199 0.01541 0.19737 0.00163 0.01559 0.91663
17 rs4675933 T C −0.0329 0.00709 3.44E-06 21.5482 0.00822 0.01093 0.45187 0.00396 0.01554 0.79863 0.01593 0.01568 0.30957
18 rs533143 T C 0.03237 0.00732 9.73E-06 19.5629 0.02892 0.01429 0.04304 0.02757 0.02031 0.1747 0.0111 0.02054 0.58881
19 rs60653979 A G 0.03384 0.0068 6.43E-07 24.7805 0.01098 0.01083 0.31063 −0.0154 0.01539 0.31844 0.02887 0.01557 0.06364
20 rs62559379 C G 0.0706 0.01455 1.22E-06 23.5419 −0.0163 0.02726 0.54934 −0.028 0.03871 0.46867 −0.0113 0.03915 0.77255
21 rs7106583 T C 0.03868 0.00839 4.09E-06 21.2244 −0.0434 0.014 0.00194 −0.0205 0.02006 0.30655 −0.0414 0.0203 0.04114
22 rs72904209 T C −0.0446 0.00983 5.67E-06 20.5934 −0.0153 0.01617 0.34449 −0.0355 0.02292 0.1215 −0.0066 0.02327 0.77599
23 rs73141516 T C 0.06496 0.01415 4.40E-06 21.0865 0.0084 0.02184 0.70062 −0.0241 0.03105 0.43797 0.03405 0.03133 0.27717
24 rs73164714 T C −0.0695 0.01285 6.43E-08 29.2248 −0.028 0.03721 0.45256 0.00562 0.05276 0.91513 −0.0139 0.05319 0.79352
25 rs7800775 A G 0.03487 0.00785 8.98E-06 19.7136 0.00351 0.01357 0.79598 0.00758 0.01929 0.69414 −0.0166 0.01948 0.39528
26 rs794999 A G 0.03421 0.00764 7.64E-06 20.0256 0.00108 0.01258 0.93171 0.0139 0.01786 0.43649 0.00374 0.01807 0.83582
27 rs9464135 A G −0.0309 0.00663 3.11E-06 21.7436 −0.0076 0.01055 0.47151 0.01164 0.015 0.43786 −0.0375 0.01516 0.01337
28 rs9567762 A T 0.03635 0.00823 9.92E-06 19.5276 0.01223 0.01084 0.25934 0.00403 0.0154 0.7934 0.01552 0.01557 0.31884

Table 3 Genetic variants used in the reverse MR analysis

Genetic instruments for VTE/PE/DVT and their associations with OSA (Jiang et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Jiang et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Jiang et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Jiang et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Jiang et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Jiang et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Jiang et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Jiang et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Jiang et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Jiang et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Jiang et al)
Exposure: VTE Exposure: VTE Exposure: VTE Exposure: VTE Outcome: OSA (Jiang et al) Outcome: OSA (Jiang et al) Outcome: OSA (Jiang et al)
SNP EA OA Beta SE p -Value F-statistic Beta SE p -Value
1 rs10896706 A G 0.0702142 0.0121006 6.53E-09 33.669456 −0.0597845 0.029345 0.0416207
2 rs113079063 T G 0.378107 0.0507769 9.59E-14 55.449428 0.0050364 0.0876134 0.954159
3 rs114026832 A C 0.773925 0.099915 9.50E-15 59.997944 0.0578773 0.180543 0.748533
4 rs114767153 T A −0.20888 0.0348173 1.98E-09 35.991798 −0.0712189 0.0909972 0.433833
5 rs116997538 T C 0.403288 0.0383066 6.42E-26 110.83665 −0.067735 0.123897 0.584581
6 rs12054563 G A −0.126677 0.0176431 6.97E-13 51.552027 0.0602695 0.0663601 0.363763
7 rs1560711 T C 0.122379 0.0141465 5.11E-18 74.836901 0.0310044 0.0321024 0.334145
8 rs174529 C T −0.0686342 0.0107211 1.54E-10 40.982878 −0.0053417 0.0276673 0.846904
9 rs188337046 T C 0.16048 0.0250424 1.47E-10 41.066712 0.178311 0.206621 0.388145
10 rs2066865 A G 0.186112 0.0112369 1.30E-61 274.31889 0.0083154 0.0313691 0.790945
11 rs2519785 G A −0.0702991 0.0118882 3.35E-09 34.967721 0.0074319 0.0297183 0.802526
12 rs3756011 A C 0.192712 0.0105525 1.65E-74 333.50841 −0.0026386 0.0272831 0.922956
13 rs57328376 G A 0.0697584 0.0109198 1.68E-10 40.809724 −0.0101806 0.0290533 0.726031
14 rs576123 T C −0.237396 0.0104973 3.09E-113 511.43633 0.00819 0.0287779 0.775956
15 rs5896 T C 0.109291 0.0125852 3.82E-18 75.413406 0.0614773 0.0388191 0.113265
16 rs6025 T C 0.873415 0.0298388 2.42E-188 856.79828 0.0502217 0.0899796 0.576745
17 rs6060308 A G 0.101587 0.0112359 1.55E-19 81.744876 0.0521936 0.0308737 0.0909227
18 rs60681578 C A −0.118392 0.0150029 2.99E-15 62.272211 0.0169103 0.0390773 0.665204
19 rs62350309 G A −0.173509 0.0181448 1.15E-21 91.440721 −0.071956 0.0634685 0.256909
20 rs628094 A G 0.0818781 0.0114389 8.19E-13 51.235029 0.0027028 0.0302168 0.928726
21 rs72708961 C T 0.0891913 0.0159445 2.22E-08 31.291269 −0.0765307 0.0367798 0.0374539
22 rs7772305 G A −0.0726964 0.0111586 7.28E-11 42.443031 0.0585778 0.0307164 0.0565137
23 rs78807356 T G 0.541094 0.0563616 7.96E-22 92.167713 0.101617 0.0796139 0.201825
Exposure: PE Exposure: PE Exposure: PE Exposure: PE Outcome: OSA (Jiang et al) Outcome: OSA (Jiang et al) Outcome: OSA (Jiang et al)
SNP EA OA Beta SE p -Value F-statistic Beta SE p -Value
1 rs117210485 A G 0.150787 0.0228699 4.30E-11 43.470964 0.0214618 0.114177 0.8509
2 rs11758950 T C 0.203947 0.0367907 2.97E-08 30.729716 0.0418521 0.0821953 0.610627
3 rs143620474 A G 0.281243 0.0512263 4.01E-08 30.142375 0.546819 0.155226 0.0004271
4 rs1481808 C T −0.480929 0.0875759 3.98E-08 30.157318 −0.164933 0.105459 0.117828
5 rs1560711 T C 0.144704 0.0202073 8.01E-13 51.279584 0.0310044 0.0321024 0.334145
6 rs1894692 A G −0.547808 0.0457764 5.29E-33 143.21004 0.0002365 0.0951533 0.998017
7 rs2066865 A G 0.227484 0.0158067 5.85E-47 207.11869 0.0083154 0.0313691 0.790945
8 rs28584824 A C −0.155264 0.0279234 2.69E-08 30.917541 −0.0268756 0.0782108 0.731124
9 rs3756011 A C 0.234784 0.0149143 7.77E-56 247.81709 −0.0026386 0.0272831 0.922956
10 rs62350309 G A −0.202534 0.0260372 7.33E-15 60.507237 −0.071956 0.0634685 0.256909
11 rs635634 C T −0.239636 0.0177935 2.43E-41 181.37664 0.0064596 0.0347197 0.852404
12 rs665082 C G −0.175581 0.030484 8.42E-09 33.175015 −0.343267 0.216405 0.112688
13 rs77165492 C T 0.209269 0.0275462 3.03E-14 57.714695 −0.0445618 0.0457769 0.330327
14 rs78807356 T G 0.515784 0.0795096 8.75E-11 42.082022 0.101617 0.0796139 0.201825
Exposure: DVT Exposure: DVT Exposure: DVT Exposure: DVT Outcome: OSA (Jiang et al) Outcome: OSA (Jiang et al) Outcome: OSA (Jiang et al)
SNP EA OA Beta SE p -Value F-statistic Beta SE p -Value
1 rs113079063 T G 0.436284 0.0717563 1.20E-09 36.967365 0.0050364 0.0876134 0.954159
2 rs116997538 T C 0.466245 0.0534583 2.74E-18 76.067315 −0.067735 0.123897 0.584581
3 rs13377102 A T −0.233255 0.0255094 6.02E-20 83.610619 −0.0250186 0.0389518 0.520681
4 rs2066865 A G 0.184507 0.0161145 2.36E-30 131.09678 0.0083154 0.0313691 0.790945
5 rs2289252 T C 0.197972 0.015135 4.26E-39 171.09712 −0.0018411 0.0272571 0.946148
6 rs2519785 G A −0.0982467 0.0169973 7.46E-09 33.409968 0.0074319 0.0297183 0.802526
7 rs576123 T C −0.297682 0.014983 7.70E-88 394.73678 0.00819 0.0287779 0.775956
8 rs5896 T C 0.141024 0.017945 3.88E-15 61.75884 0.0614773 0.0388191 0.113265
9 rs6025 T C 1.10439 0.0393903 5.71E-173 786.07929 0.0502217 0.0899796 0.576745
10 rs6060237 G A 0.168453 0.0198214 1.92E-17 72.225216 0.0318432 0.0414073 0.441879
11 rs60681578 C A −0.137615 0.021627 1.98E-10 40.489181 0.0169103 0.0390773 0.665204
12 rs62350309 G A −0.162704 0.0259998 3.90E-10 39.161241 −0.071956 0.0634685 0.256909
13 rs666870 A G 0.0924832 0.0159069 6.10E-09 33.802949 0.0127968 0.0271558 0.637472
14 rs7308002 A G 0.0978174 0.01576 5.41E-10 38.522974 −0.0027934 0.0275746 0.919309
15 rs76151810 A C 0.153073 0.0273112 2.09E-08 31.413449 −0.0018493 0.0507256 0.970918
16 rs7772305 G A −0.100251 0.016057 4.28E-10 38.980608 0.0585778 0.0307164 0.0565137
17 rs78807356 T G 0.621447 0.0792414 4.42E-15 61.504078 0.101617 0.0796139 0.201825
18 rs9865118 T C 0.0863804 0.0151814 1.27E-08 32.374776 0.0363583 0.0268338 0.175436
Genetic instruments for VTE/PE/DVT and their associations with OSA (Campos et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Campos et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Campos et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Campos et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Campos et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Campos et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Campos et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Campos et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Campos et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Campos et al) Genetic instruments for VTE/PE/DVT and their associations with OSA (Campos et al)
Exposure: VTE Exposure: VTE Exposure: VTE Exposure: VTE Outcome: OSA (Campos et al) Outcome: OSA (Campos et al) Outcome: OSA (Campos et al)
SNP EA OA Beta SE p -Value F-statistic Beta SE p -Value
1 rs10896706 A G 0.0702142 0.0121006 6.53E-09 33.669456 0.0073376 0.0072794 0.3136
2 rs114767153 T A −0.20888 0.0348173 1.98E-09 35.991798 −0.0240477 0.0220217 0.2749
3 rs116997538 T C 0.403288 0.0383066 6.42E-26 110.83665 −0.0202903 0.0346251 0.558
4 rs12054563 G A −0.126677 0.0176431 6.97E-13 51.552027 −0.0164525 0.0159578 0.3025
5 rs1560711 T C 0.122379 0.0141465 5.11E-18 74.836901 −0.0033405 0.0090041 0.7104
6 rs174529 C T −0.0686342 0.0107211 1.54E-10 40.982878 −0.0016235 0.0068503 0.8124
7 rs2066865 A G 0.186112 0.0112369 1.30E-61 274.31889 −0.0033999 0.0077623 0.6612
8 rs3756011 A C 0.192712 0.0105525 1.65E-74 333.50841 0.000575 0.0067645 0.9326
9 rs57328376 G A 0.0697584 0.0109198 1.68E-10 40.809724 −0.0010062 0.0071873 0.8885
10 rs576123 T C −0.237396 0.0104973 3.09E-113 511.43633 0.0183551 0.0086786 0.03441
11 rs5896 T C 0.109291 0.0125852 3.82E-18 75.413406 0.020985 0.0096527 0.02974
12 rs6025 T C 0.873415 0.0298388 2.42E-188 856.79828 0.0380118 0.0218836 0.08241
13 rs6060308 A G 0.101587 0.0112359 1.55E-19 81.744876 −0.0009288 0.0074901 0.9013
14 rs60681578 C A −0.118392 0.0150029 2.99E-15 62.272211 0.0085067 0.0117172 0.4678
15 rs62350309 G A −0.173509 0.0181448 1.15E-21 91.440721 0.0075114 0.0152982 0.6233
16 rs628094 A G 0.0818781 0.0114389 8.19E-13 51.235029 −0.0022354 0.0074021 0.7627
17 rs72708961 C T 0.0891913 0.0159445 2.22E-08 31.291269 −0.0170636 0.0090957 0.06059
18 rs7772305 G A −0.0726964 0.0111586 7.28E-11 42.443031 0.016709 0.0086396 0.05311
19 rs80137017 T C −0.208902 0.0177996 8.30E-32 137.74147 0.0152022 0.0099426 0.1262
Exposure: PE Exposure: PE Exposure: PE Exposure: PE Outcome: OSA (Campos et al) Outcome: OSA (Campos et al) Outcome: OSA (Campos et al)
SNP EA OA Beta SE p -Value F-statistic Beta SE p -Value
1 rs117210485 A G 0.150787 0.0228699 4.30E-11 43.470964 −0.0346523 0.0239146 0.1473
2 rs143620474 A G 0.281243 0.0512263 4.01E-08 30.142375 0.0124988 0.0892769 0.8889
3 rs1481808 C T −0.480929 0.0875759 3.98E-08 30.157318 −0.0281243 0.0269648 0.297
4 rs1560711 T C 0.144704 0.0202073 8.01E-13 51.279584 −0.0033405 0.0090041 0.7104
5 rs2066865 A G 0.227484 0.0158067 5.85E-47 207.11869 −0.0033999 0.0077623 0.6612
6 rs28584824 A C −0.155264 0.0279234 2.69E-08 30.917541 0.0324135 0.0191569 0.09056
7 rs3756011 A C 0.234784 0.0149143 7.77E-56 247.81709 0.000575 0.0067645 0.9326
8 rs62350309 G A −0.202534 0.0260372 7.33E-15 60.507237 0.0075114 0.0152982 0.6233
9 rs635634 C T −0.239636 0.0177935 2.43E-41 181.37664 0.0139975 0.0096935 0.1488
10 rs77165492 C T 0.209269 0.0275462 3.03E-14 57.714695 0.0013946 0.0114311 0.9026
11 rs80137017 T C −0.230014 0.02543 1.50E-19 81.811776 0.0152022 0.0099426 0.1262
Exposure: DVT Exposure: DVT Exposure: DVT Exposure: DVT Outcome: OSA (Campos et al) Outcome: OSA (Campos et al) Outcome: OSA (Campos et al)
SNP EA OA Beta SE p -Value F-statistic Beta SE p -Value
1 rs116997538 T C 0.466245 0.0534583 2.74E-18 76.067315 −0.0202903 0.0346251 0.558
2 rs13377102 A T −0.233255 0.0255094 6.02E-20 83.610619 0.0085579 0.0096591 0.3759
3 rs2066865 A G 0.184507 0.0161145 2.36E-30 131.09678 −0.0033999 0.0077623 0.6612
4 rs576123 T C −0.297682 0.014983 7.70E-88 394.73678 0.0183551 0.0086786 0.03441
5 rs5896 T C 0.141024 0.017945 3.88E-15 61.75884 0.020985 0.0096527 0.02974
6 rs6025 T C 1.10439 0.0393903 5.71E-173 786.07929 0.0380118 0.0218836 0.08241
7 rs6060237 G A 0.168453 0.0198214 1.92E-17 72.225216 0.0060526 0.0101724 0.5518
8 rs60681578 C A −0.137615 0.021627 1.98E-10 40.489181 0.0085067 0.0117172 0.4678
9 rs62350309 G A −0.162704 0.0259998 3.90E-10 39.161241 0.0075114 0.0152982 0.6233
10 rs666870 A G 0.0924832 0.0159069 6.10E-09 33.802949 0.0074616 0.0067221 0.2669
11 rs7308002 A G 0.0978174 0.01576 5.41E-10 38.522974 −0.0023644 0.0068533 0.7298
12 rs7772305 G A −0.100251 0.016057 4.28E-10 38.980608 0.016709 0.0086396 0.05311
13 rs9865118 T C 0.0863804 0.0151814 1.27E-08 32.374776 −0.0005648 0.0066442 0.9323

Figures

Fig. 1 The flowchart of instrumental variables selection. LD, linkage disequilibrium; SNPs, single-nucleotide polymorphisms; BMI, body mass index; VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; OSA, obstructive sleep apnea; ①, represents OSA (Jiang et al) as the outcome; ②, represents OSA (Campos et al) as the outcome.

Fig. 2 The genetic association of OSA with VTE/PE/DVT. OSA, obstructive sleep apnea; VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; MR, mendelian randomization; IVW, inverse variance weighted; PRESSO, pleiotropy residual sum and outlier; P*, represents P for heterogeneity test; P**, represents P for MR-Egger intercept; P***, represents P for MR-PRESSO global test.

Fig. 3 The genetic association of VTE/PE/DVT with OSA. OSA, obstructive sleep apnea; VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; MR, mendelian randomization; IVW, inverse variance weighted; PRESSO, pleiotropy residual sum and outlier; P*, represents P for heterogeneity test; P**, represents P for MR-Egger intercept; P***, represents P for MR-PRESSO global test.

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