Objective: We sought to evaluate whether obstructive sleep apnea (OSA), and other sleep disorders, increase genetic risk of developing diabetes mellitus (DM). Research Design and Methods: Using GWAS summary statistics from the DIAGRAM consortium and Million Veteran Program, we developed multi-ancestry Type 2 Diabetes (T2D) polygenic risk scores (T2D-PRSs) useful in admixed Hispanic/Latino individuals. We estimated the association of the T2D-PRS with cross-sectional and incident DM in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We conducted a mediation analysis with T2D-PRSs as an exposure, incident DM as an outcome, and OSA as a mediator. Additionally, we performed Mendelian randomization (MR) analysis to assess the causal relationship between T2D and OSA. Results: Of 12,342 HCHS/SOL participants, at baseline, 48.4% were normoglycemic, 36.6% were hyperglycemic, and 15% had diabetes, and 50.9% identified as female. Mean age was 41.5, and mean BMI was 29.4. T2D-PRSs was strongly associated with baseline DM and with incident DM. At baseline, a 1 SD increase in the primary T2D-PRS had DM adjusted odds ratio (OR) = 2.67, 95% CI [2.40; 2.97] and a higher incident DM rate (incident rate ratio (IRR) = 2.02, 95% CI [1.75; 2.33]). In a stratified analysis based on OSA severity categories the associations were stronger in individuals with mild OSA compared to those with moderate to severe OSA. Mediation analysis suggested that OSA mediates the T2D-PRS association with DM. In two-sample MR analysis, T2D-PRS had a causal effect on OSA, OR = 1.03, 95% CI [1.01; 1.05], and OSA had a causal effect on T2D, with OR = 2.34, 95% CI [1.59; 3.44]. Conclusions: OSA likely mediates genetic effects on T2D. Keywords: Diabetes; Type 2 diabetes; Obstructive sleep apnea; Polygenic risk score; Hispanic or Latino

Dr. Redline discloses consulting relationships with Eli Lilly Inc. Additionally, Dr. Redline serves as an unpaid member of the Apnimed Scientific Advisory Board, as an unpaid board member for the Alliance for Sleep Apnoea Partners and for the National Sleep Foundation.

The work was supported by National Heart Lung and Blood Institute (NHLBI) grants R01HL161012 to T.S. and R35HL135818 to S.R., and National Institute on Aging grant R01AG080598 to T.S. The Hispanic Community Health Study/Study of Latinos is a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (HHSN268201300001I / N01-HC-65233), University of Miami (HHSN268201300004I / N01-HC-65234), Albert Einstein College of Medicine (HHSN268201300002I / N01-HC-65235), University of Illinois at Chicago (HHSN268201300003I / N01- HC-65236 Northwestern Univ), and San Diego State University (HHSN268201300005I / N01-HC-65237). The following Institutes/Centers/Offices have contributed to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, NIH Institution-Office of Dietary Supplements.

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 work was approved by the Institutional Review Board (IRB) of the Mass General Brigham Biobank, and by the Beth Israel Deaconess Medical Center Committee on Clinical Investigations. The HCHS/SOL was approved by the IRBs at each field center, where all participants gave written informed consent, and by the Non-Biomedical IRB at the University of North Carolina at Chapel Hill, to the HCHS/SOL Data Coordinating Center. All IRBs approving the HCHS/SOL study are: Non-Biomedical IRB at the University of North Carolina at Chapel Hill. Chapel Hill, NC; Einstein IRB at the Albert Einstein College of Medicine of Yeshiva University. Bronx, NY; IRB at Office for the Protection of Research Subjects (OPRS), University of Illinois at Chicago. Chicago, IL; Human Subject Research Office, University of Miami. Miami, FL; Institutional Review Board of San Diego State University, San Diego, CA. All methods and analyses of HCHS/ SOL participants' materials and data were carried out in accordance with human subject research guidelines and regulations.

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).

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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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Ancestry-specific summary statistics from GWAS of DM published in 2022 (Mahajan et al) in the DIAGRAM consortium were downloaded from https://diagram-consortium.org/downloads.html. HARE-group specific summary statistics from GWAS of DM in MVP published in 2020 (Vujkovic et al) were downloaded by dbGaP application to study accession phs001672. SNPs and weights for ancestry-specific T2D-PRSs are provided in the GitHub repository https://github.com/YanaHrytsenko/DM_PRS_OSA_mediation.

https://github.com/YanaHrytsenko/DM_PRS_OSA_mediation