ABSTRACT Obstructive sleep apnea (OSA) is a common chronic sleep disorder in adults with a serious impact on health. In addition to age and sex, obesity has been identified as the strongest risk factor for OSA. However, the underlying mechanisms linking obesity with OSA pathogenesis are not fully understood. Although accumulating evidence (based predominantly on cross-sectional studies) suggests that inflammation and metabolic dysfunction may represent two potential modifiable etiologic pathways for OSA, few population- based, prospective studies have been conducted to evaluate their roles in OSA development. In this highly translational project, I will leverage the wealth of data from 4 large prospective US cohorts: the Nurses' Health Study (NHS), NHSII, the Health Professional Follow-up Study (HPFS) and the Multi-Ethnic Study of Atherosclerosis (MESA). I will use genetic and biomarker-based approaches to elucidate the importance of inflammatory and metabolic pathways in OSA etiology. In Aim 1, I will use Mendelian randomization to examine whether genetic susceptibility to obesity, inflammation and metabolic dysfunction is associated with higher risk of developing OSA. Results from Mendelian randomization will help distinguish causal from non- causal associations that arise from non-genetic, cross-sectional, observational studies due to confounding or reverse causation. I will further examine gene-lifestyle interactions and sex differences in these genetic associations. In Aim 2, I will evaluate whether inflammatory (e.g., CRP, IL-6, TNF-?) and metabolic (e.g., metabolomics, insulin, leptin, cholesterol) biomarkers that have been measured from archived blood samples predict sleep-disordered breathing. These biomarkers will provide further insights into the mechanistic pathways that may serve as potential therapeutic and pharmaceutical targets for intervention. Lastly, I will measure sleep-disordered breathing in 200 NHS/NHSII/HPFS participants using an FDA-approved device designed for at-home OSA diagnosis, and replicate the biomarker associations in Aim 2 with the objective measures. I will acquire additional expertise in sleep epidemiology, OSA physiology, genetic analysis, and primary sleep data collection/management. My training and research will be guided by a world-class mentoring/consulting team, each with substantial expertise in the core areas: Drs. Susan Redline (OSA), Frank Hu (lifestyles), Shelley Tworoger (biomarkers), Richa Saxena (genetics), Clary Clish (metabolomics) and Eric Tchetgen Tchetgen (biostatistics). In sum, this innovative project will advance our understanding of the inflammatory and metabolic pathways in OSA development from multiple dimensions, and help me emerge as an independent investigator with unique interdisciplinary skills in sleep/OSA epidemiology research.