Background Obstructive sleep apnea (OSA) is associated with a wide range of comorbidities, but large-scale phenome-wide analyses in clinical biobanks remain under-reported. In this study, we identified common comorbidities enriched in patients with OSA, tested the temporality of these associations, and analyzed relevant associations with summary sleep recording data.

Methods 48,251 participants with OSA in the Mass General Brigham healthcare system were identified using a natural language processing phenotyping algorithm and/or evidence of an elevated apnea-hypopnea index (AHI). Controls were matched (2:1) on demographics, body mass index (BMI), and healthcare utilization. Associations with 358 incident and 563 cross-sectional diseases were tested using Modified Poisson regression, adjusting for covariates. Sensitivity analyses examined timing by binning data in years relative to the first OSA diagnosis. Selected laboratory results were obtained based on associated diseases. Associated diseases were tested with sleep recording statistics (n ≤18,348).

Findings 179 incident and 421 cross-sectional diseases were associated with OSA at Bonferroni significance. 37 diseases had Bonferroni-significant sex interactions. Several associations were significant years before the first recorded OSA diagnosis. Four red blood cell laboratory measures were significant ten years prior to the first diagnosis. One incident and 47 cross-sectional diseases were associated with the AHI and/or chronic hypoxemia.

Interpretation Obstructive sleep apnea is associated with enrichment of hundreds of diseases, several of which are supported by orthogonal polysomnographic evidence. Leveraging early signs of OSA in clinical data may help to identify at-risk patients.

Funding National Institutes of Health and the American Academy of Sleep Medicine Foundation.

BEC is supported by NIH/NHLBI R01HL153805 and American Academy of Sleep Medicine Foundation 338-SR-24 and has consulted for Apnimed using an unrelated dataset. He has received an honoraria from the American Academy of Sleep Medicine and the Sleep Research Society. LL, MD, CY, SMH, XY, MOG, RMA, FRN, AR, HW, HLK, and NAS have no conflict of interest to disclose. AA received grant support from Somnifix, has served as a consultant for Apnimed, Eli Lilly, Amgen, Cerebra, Zoll Respicardia, and Inspire Medical Systems, and has received an honoraria from ProSomnus. Apnimed is developing pharmacological treatments for Obstructive Sleep Apnea. AA's interests were reviewed by Brigham and Women's Hospital and Mass General Brigham in accordance with their institutional policies. AA is also a co-inventor of intellectual property (IP) via his Institution pertaining to wearable sleep apnea phenotyping (patented). SBA has consulted for D.E. Shaw and has received an honoraria from Harvard University. SAS received grant support from Apnimed, Inspire Medical Systems, Prosomnus, SleepRes, and Dynaflex, and has served as a consultant for Apnimed, Nox Medical, Inspire Medical Systems, Eli Lilly, Merck, Forepont, Respicardia, and LinguaFlex. He has received an honoraria from Tufts University. He is co-inventor of intellectual property via his Institution pertaining to combination pharmacotherapy for sleep apnea (patented, licensed, royalties), and to wearable sleep apnea phenotyping (patented). He has equity in Achaemenid, a company commercializing oral appliance biosensor technology. His industry interactions are actively managed by his Institution. LJE has received consulting fees from the American Academy of Sleep Medicine, eviCore, and Carelon. MKP has received grants from Jazz and Biomobie, consulting fees from Jazz, and an honoraria from Oakstone. She has received travel support from World Sleep and the Taiwan Neurological Society. SR received personal fees from Eli Lilly and is an unpaid consultant to Apnimed and board member of the National Sleep Foundation and Alliance of Sleep Apnea Partners; and is Editor-in-Chief of Sleep Health.

This study was funded by NIH/NHLBI R01HL153805 and American Academy of Sleep Medicine Foundation 338-SR-24.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee/IRB of Mass General Brigham gave ethical approval for this work (protocols 2024P002360, 2021P003546, and 2010P001765).

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The primary data contain protected health information and cannot be shared. All supporting summary analysis results are included in the appendix.