Abstract Body: Background: OSA is a heterogeneous disease, with obesity a significant risk factor in many but not all cases of OSA, via increased airway collapsibility, reduced lung volumes, and possibly body fat distribution.

Research question: We sought to develop PRSs that summarize the genetic liability to OSA that include and exclude obesity related pathways, and to study the associations of these PRSs with OSA comorbid cardiometabolic and CVD outcomes.

Approach: Using 1.2 million 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 PRSs for OSA, relying on genome wide association studies both adjusted and unadjusted for BMI: BMIadjOSA and BMIunadjOSA PRS. We tested their associations with cardiometabolic and CVD outcomes in AoU.

Results: In association with OSA, adjusted odds ratios (ORs) per 1 standard deviation of the PRSs ranged from 1.38 to 2.75, all statistically significant (Figure). The associations of BMIadjOSA and BMIunadjOSA PRSs with CVD outcomes in AoU shared both common and distinct patterns. For example, BMIunadjOSA PRS was associated with type 2 diabetes, heart failure, and coronary artery disease, but the associations of BMIadjOSA PRS with these outcomes were statistically insignificant with estimated OR close to 1. In contrast, both BMIadjOSA and BMIunadjOSA PRSs were associated with hypertension and stroke. Sex stratified analyses revealed that BMIadjOSA PRS association with hypertension was driven by data from females: females had OR=1.1, p-value=0.002, but males OR=1.01 and statistically insignificant.

OSA PRSs were also associated with dual-energy X-ray absorptiometry (DXA) body fat measures. In BMI adjusted analysis, BMIadjOSA PRS was associated with higher visceral adipose tissue (VAT) proportion of total body fat mass (TFM), with lower proportion of gynoid fat mass out of TFM, higher proportion of android fat mass out of TFM, and lower gynoid to android fat mass. In females only, the PRS was associated with higher VAT to SAT ratio (Figure).

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 risk and associations with cardiometabolic and CVD morbidities between sex groups.