Polygenic scores for obstructive sleep apnea based on BMI-adjusted and -unadjusted genetic associations reveal pathways contributing to cardiovascular disease

Background Obstructive sleep apnea (OSA) is a heterogeneous disease, with obesity a significant risk factor via increased airway collapsibility, reduced lung volumes, and possibly body fat distribution. Methods Using race/ethnic diverse samples from the Million Veteran Program, FinnGen, TOPMed, All of Us (AoU), Geisinger’s MyCode, MGB Biobank, and the Human Phenotype Project (HPP), we developed, selected, and assessed polygenic scores (PGSs) for OSA, relying on genome-wide association studies both adjusted and unadjusted for BMI: BMIadjOSA- and BMIunadjOSA-PGS. We tested their associations with CVD in AoU. Results Adjusted odds ratios (ORs) for OSA per 1 standard deviation of the PGSs ranged from 1.38 to 2.75. The associations of BMIadjOSA- and BMIunadjOSA-PGSs with CVD outcomes in AoU shared both common and distinct patterns. For example, BMIunadjOSA-PGS was associated with type 2 diabetes, heart failure, and coronary artery disease, but the associations of BMIadjOSA-PGS with these outcomes were statistically insignificant with estimated OR close to 1. In contrast, both BMIadjOSA- and BMIunadjOSA-PGSs were associated with hypertension and stroke. Sex stratified analyses revealed that BMIadjOSA-PGS association with hypertension was driven by data from OR=1.1, p-value=0.002, OR=1.01 p-value=0.2 in males). OSA PGSs were also associated with dual-energy X-ray absorptiometry (DXA) body fat measures with some sex-specific associations. Conclusions Distinct components of OSA genetic risk are related to obesity and body fat distribution, and may influence clinical outcomes. These may explain differing OSA risks and associations with cardiometabolic morbidities between sex groups.