Effect of gastroesophageal reflux disease on sleep disorders: a Mendelian randomization study

Background Recently observational studies have consistently shown an association between gastroesophageal reflux disease (GERD) and sleep disorders. In this study, Mendelian randomization (MR) analysis was performed to determine the genetic causal relationship between GERD and the risk of sleep disorders. Methods The summary statistics of GERD and sleep disorders were obtained through large-scale genome-wide association studies (GWAS). In addition to exploring sleep disorders, a deeper analysis was conducted on some major categories of sleep disorders such as sleep apnoea and insomnia. Various MR analysis methods including inverse-variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode were performed, and the results of IVW were taken as the primary results. In addition, sensitivity analyses including heterogeneity test and pleiotropy test were also performed to test the robustness of the MR results. Results After removing the ineligible SNPs and the palindromic SNPs, IVW detected a significant effect of GERD on sleep disorders (OR = 1.436, 95% CI: 1.309-1.576, p = 2.099E-14) and sleep apnoea (OR = 1.486, 95% CI: 1.341-1.647, p = 4.409E-14). However, there was no genetic causality in the effect of GERD on insomnia (IVW OR = 1.146, 95% CI: 0.877-1.498, p = 0.319). Furthermore, the heterogeneity test and pleiotropy test found no evidence of bias, which indicated the results were robust. Conclusions Our study found that the presence of GERD increased the risk of sleep disorders and sleep apnoea, but not the risk of insomnia. Further research is needed to identify the specific mechanisms of causal relationships. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by a grant from the Science and Technology Program of Guangzhou, China (202206010103); and the Natural Science Foundation of Guangdong Province (2022A1515012469). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The present study only used summary data from relevant GWASs. The summary statistics on sleep disorders, sleep apnoea, and insomnia were obtained from FinnGen consortium. The summary statistics on gastroesophageal reflux disease were obtained from GWAS conducted by Jue-Sheng Ong et al., which had been deposited at the GWAS catalog (). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript/supplemental material. * GERD : Gastroesophageal reflux disease OAS : Obstructive sleep apnoea RCTs : Randomized controlled trials MR : Mendelian randomization SNPs : Single nucleotide polymorphisms IVs : instrumental variables GWAS : Genome-wide association study LD : linkage disequilibrium IVW : Inverse variance weighted MR-PRESSO : MR Pleiotropy RESidual Sum and Outlier CI : Confidence intervals OR : Odds ratio