Obstructive sleep apnea (OSA) is a prevalent disease characterised by disordered breathing during sleep. Specifically, in OSA, temporary upper airway stricture during sleep causes sleep deficiency, intermittent hypoxia and autonomic fluctuation (Patel, 2019). Epidemiological studies have estimated that approximately 22% of men and 17% of women have OSA (Franklin and Lindberg., 2015). Because of its troublesome symptoms and chronic course, OSA significantly reduces a patient’s health-related quality of life (Gottlieb and Punjabi., 2020). Gastroesophageal reflux disease (GERD) is a functional gastrointestinal disorder characterized by heartburn and regurgitation (Katz et al., 2022). According to current epidemiological research, the prevalence of GERD has increased by more than 77% over the past 10 years (Zhang D. et al., 2022). The increasing prevalence of GERD has resulted in increasingly high healthcare expenditure (Howden et al., 2021). Previous studies have identified a bidirectional relationship between OSA and GERD, where GERD appears to increase the risk of OSA and, on the other hand, OSA contributes to the development of GERD (Shibli et al., 2020).

A nationwide study reported that 12.21% of GERD patients have a concurrent diagnosis of OSA, with the prevalence being approximately triple that observed in the general population (Mahfouz et al., 2022). Similarly, compared to people without OSA, nocturnal gastroesophageal reflux is more common in OSA patients (Fass et al., 2005). In addition, continuous positive airway pressure treatment can reduce gastroesophageal reflux alongside improvements in OSA symptoms (Wang et al., 2020). A cross-sectional study observed a positive correlation between GERD and OSA, and this relationship was unlikely to be affected by potential confounders and different diagnostic criteria (Gilani et al., 2016). However, several studies have produced conflicting results. From example, Shepherd et al. found that obesity, rather than OSA per se, is the cause of GERD in OSA patients (Shepherd and Orr., 2016). Another study reported that the occurrence of GERD had no relation to the severity of OSA (Kuribayashi et al., 2010). Thus, the association between OSA and GERD remains controversial.

Mendelian randomization (MR) is a data analysis method that uses genotypes as instrumental variables (IVs) to infer causal relationships between features of interest (Xu et al., 2022). Mendel’s second law states that genotypes are allocated randomly at conception and are unlikely to be affected by environmental confounders. In addition, DNA sequences are invariant, and the flow of biological information is unidirectional. Therefore, MR can minimize reverse causation and avoid confusion (Swerdlow et al., 2016). Two-sample MR is an extension of the basic MR design. This MR analysis is conducted using the exposure and outcome data obtained from different or partially overlapping samples (Hartwig et al., 2016). It is widely applicable and can avoid pseudo-positive results. Therefore, this study implemented a two-sample MR analysis to reveal the causal relationship between OSA and GERD. The data for this analysis were obtained from published genome-wide association studies (GWAS).

To the best of our knowledge, this is the first two-sample MR study to explore the causal association between OSA and GERD. According to our findings, OSA is causally related to GERD in individuals of European descent. Moreover, GERD also causally increases the risk of OSA. In view of the increasing health burden caused by OSA and GERD, this study provides new insight into the diagnosis and treatment of these two diseases.

Several case-control studies have failed to reveal a causal relationship between OSA and GERD due to the potential influence of confounders such as gender, age, obesity, physical activity, and alcohol use (Shibli et al., 2020). MR analysis can effectively avoid confounders and reverse causation bias in observational studies. It can also overcome the high cost and low practicability of randomized controlled trials. Thus, MR analysis is a powerful tool that can provide strong evidence that OSA is causally associated with GERD and that GERD is causally associated with OSA.

Results from a meta-analysis indicated that OSA and GERD are closely related, with a pooled OR of 1.75 (Wu et al., 2019). It is generally believed that OSA results in sleep fragmentation and sleep deprivation from awakenings (Yeghiazarians et al., 2021). A randomized controlled trial reported that sleep deficiency can increase oesophageal acid exposure, and even in healthy subjects, a lack of sleep can contribute to abnormal pH testing (Yamasaki et al., 2019). This might be the reason why OSA increases the incidence of GERD. An alternative hypothesis is that OSA can increase the respiratory workload and raise the abdominal-gastric pressure, which leads to lower oesophageal sphincter relaxations, and then reflux occurring (Tamanna et al., 2016; Ozcelik et al., 2017; Gleeson and McNicholas., 2022).

Previous cohort studies have revealed that more severe OSA symptoms are frequently encountered in patients with GERD, as compared to the healthy population (Emilsson et al., 2013; Kim et al., 2018). In addition, oesophagogastroduodenoscopy findings have demonstrated that GERD can cause OSA (Kim et al., 2018). These results illustrated that GERD might be associated with a higher risk of OSA, which is consistent with the current MR estimates. Thus, GERD may be a novel predictor of OSA diagnosis. The possible mechanism involves activation of the oesophageal-bronchial neuronal pathway due to reflux of the stomach contents, leading to bronchoconstriction (Houghton et al., 2016). However, the complex pathophysiology underlying the causal relationship between GERD and OSA is not completely understood. More research is required to further clarify this mechanism.

In the current MR analysis, the exposure and outcome genetic data were obtained from different European countries, which minimizes population stratification and sample overlap. Further, the GWAS summary data were obtained from large case-control samples (307,927 for OSA; 602,604 for GERD). Hence, this MR analysis is powered to detect genetic effects on outcome risks. Although a more liberal threshold (p < 5E-07) was used to select OSA-related IVs, the included genetic IVs were all strong IVs, with a minimum F statistic of 207. Non-etheless, this study has several limitations that should be acknowledged. First, the results of this study are based on data from individuals of European ancestry; thus, the findings may not apply to other ethnicities. Second, the p values for the Cochran Q test were less than 0.05, suggesting the presence of some heterogeneity in the effect estimates. However, this did not invalidate the random-effects IVW estimates, and the MR-Egger intercept analysis did not detect any directional pleiotropy, which provides validation of the robustness of the MR results.

Even though the mechanism underlying the association between OSA and GERD is not fully clear, the current MR analysis results suggest that OSA plays an important role in the pathogenesis of GERD, and vice versa. These findings have implications for reducing the risks of OSA and GERD. When managing and treating OSA patients, we must pay attention to their gastrointestinal symptoms. If we suspect that a patient has GERD symptoms (such as chest pain, chronic cough, laryngitis) (Gyawali et al., 2018), 24-h pH monitoring or upper gastrointestinal endoscopy is recommended. Non-pharmacologic and behavioural interventions for GERD patients (such as dietary control, weight reduction, and cutting alcohol consumption) may also be effective for OSA patients. In addition, patients with GERD can have latent OSA, so including questions about GERD when taking the patient’s clinical history may be significant in the screening and prevention of OSA.