BACKGROUND Although observational studies have frequently reported an association between obstructive sleep apnea (OSA) and myocardial infarction (MI), whether this relationship is causal or primarily attributable to shared risk factors remains uncertain.

METHODS AND RESULTS We conducted a 2-sample Mendelian randomization (MR) study to evaluate the causal effect of OSA on MI. Summary statistics for OSA were obtained from FinnGen (8,998 cases and 356,128 controls),and summary statistics for MI were obtained from the UK Biobank (14,394 cases and 361,194 controls),with validation performed using data from the CARDIoGRAMplusC4D consortium. Mediation MR was further performed to assess 13 potential mediators, including obesity, glycemic traits, blood pressure, and lipid-related traits. In addition, a 6-step multivariable MR (MVMR) framework was used to estimate the direct effect of OSA after adjustment for different sets of potential confounders. Reverse MR analysis was also conducted to assess possible reverse causality. The MR analysis showed that genetically predicted OSA liability was significantly associated with an increased risk of MI (odds ratio [OR] per log-OR increase, 1.0024 [95% CI, 1.0010–1.0039]; P=0.001). Mediation analysis identified body mass index (BMI) as the most prominent mediator, with an explained proportion of 35.94% P=0.030, whereas systolic blood pressure (SBP) showed only minimal mediation 0.28%; P=0.678. In the stepwise MVMR analysis, the association between OSA and MI was markedly attenuated after simultaneous adjustment for BMI and SBP P=0.156, suggesting that the observed effect may partly reflect a shared clinical baseline. Notably, in a head-to-head model adjusting for SBP and atrial fibrillation (AF), AF remained a robust independent risk factor P=0.004, whereas OSA retained only a marginal direct effect P=0.050, indicating that the OSA–AF axis may operate independently of chronic pressure load. Reverse MR analysis found no evidence that genetic liability to MI influenced the risk of OSA.

CONCLUSIONS Our study provides genetic evidence supporting a causal association between OSA and MI and suggests that this relationship may be mediated, in part, through obesity-related and arrhythmia-related pathways. In particular, AF may represent an important intermediate node linking OSA to MI, independent of traditional hemodynamic factors such as SBP, which may have implications for the clinical management of OSA.

The authors have declared no competing interest.

Not applicable. This study is a Mendelian randomization analysis based on publicly available GWAS summary statistics and is not a clinical trial or prospective interventional study.

The authors received no funding for this study.

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:

This study was based exclusively on publicly available, de-identified summary-level data from published genome-wide association studies. No new individual-level data were collected, and no direct contact with human participants occurred. Therefore, additional institutional review board approval and informed consent were not required for this secondary analysis. Ethical approval and participant consent had been obtained in the original studies by the respective investigators.

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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).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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The summary-level data used in this study were obtained from publicly available genome-wide association study datasets, including FinnGen, UK Biobank, CARDIoGRAM, GIANT, DIAGRAM, MAGIC, GLGC, CKDGen, GUGC, and GSCAN. Detailed information on all data sources and GWAS IDs is provided in Supplementary Table 1. These datasets are available from the corresponding consortia or through publicly accessible resources such as the IEU OpenGWAS platform.

https://www.diagram-consortium.org/

https://giant-consortium.web.broadinstitute.org/

https://cardiogramplusc4d.org/

https://www.ukbiobank.ac.uk/

https://www.finngen.fi/en/access_results