Obstructive sleep apnea mediates genetic risk of Diabetes Mellitus: The Hispanic Community Health Study/Study of Latinos

Abstract

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; Hispanic or Latino; Obstructive sleep apnea; Polygenic risk score; Type 2 diabetes.

Figure 1:. T2D-PRSs associations with DM.

Panel a) Proportion of individuals by DM status over time (between clinic’s visit 1 and 2) stratified by T2D-PRS quartiles. Note: “Persistent” refers to having the same DM status in both visit 1 and visit 2; “Worsen” refers to change in DM status from normoglycemic at visit 1 to hyperglycemic at visit 2 or from hyperglycemic in visit 1 to diabetic at visit 2; “Improve” refers to change in DM status from hyperglycemic at visit 1 to normoglycemic at visit 2 or from diabetic in visit 1 to hyperglycemic or normoglycemic at visit 2. b) Estimated OR of the T2D-PRSs in association with DM at baseline in HCHS/SOL individuals with DM status at baseline c) Estimated IRR of the T2D-PRS in association with incident DM in individuals free of DM at baseline. d) Association of T2D-PRSs with DM and incident DM in HCHS/SOL individuals stratified by OSA severity levels and overall dataset. OSA severity levels were defined based on the respiratory even index (REI): mild OSA was defined as 15⩾REI⩾5, moderate-to-severe OSA was defined as REI⩾15, and REI<5 was considered no OSA. All models were adjusted for age, sex, BMI, study center and 5 genetic PCs. OR: odds ratios; IRR: incidence rate ratios; AUC: Area Under the ROC (receiver operating characteristic) Curve; T2D: type 2 diabetes; PRSs: polygenic risk scores; DM: diabetes mellitus; HCHS/SOL: Hispanic Community Health Study/Study of Latinos; EDS: excessive daytime sleepiness; OSA: obstructive sleep apnea.

Figure 2:. Associations of T2D-PRSs with poor sleep phenotypes, estimated mediation effect by OSA, causal effects of T2D on OSA and OSA on T2D.

Panel a) Estimated OR of mgbPRSsum in association with poor sleep health at baseline in HCHS/SOL individuals with DM status at baseline. Results are stratified by poor sleep health categories. b) left: Distribution of mgbPRSsum at visit 2 (horizontal dashed lines denote quantiles of the PRS values Q₀ – Q₄) right: Estimated proportion of mediation by mild to severe OSA in the association between T2D-PRS and incident DM in individuals who participated at the second visit to a clinic (N = 6,291). Significance codes: 0 >= ‘***’ < 0.001 >= ‘**’ < 0.01 >= ‘*’ < 0.05 ‘ ’ < 0.1 c) Estimated causal effect of T2D on OSA based on SNPs selected using p-value threshold < 5*10⁻⁸ in BMI-adjusted and BMI-unadjusted T2D GWASs. d) Estimated causal effect of OSA on T2D based on SNPs selected using p-value threshold < 5*10⁻⁸ in BMI-adjusted and BMI-unadjusted OSA GWASs. All models were adjusted for age, sex, BMI, study center and 5 genetic PCs. T2D: type 2 diabetes; OSA: obstructive sleep apnea; IVW: inverse variance weighted; BMI: body mass index; AUC: Area Under the ROC (receiver operating characteristic) Curve; SNPs: Single-nucleotide polymorphism; GWAS: genome wide association study