Steroid Hormone Biosynthesis and Dietary Related Metabolites associated with Excessive Daytime Sleepiness

BackgroundExcessive daytime sleepiness (EDS) is a complex sleep problem that affects approximately 33% of the United States population. Although EDS usually occurs in conjunction with insufficient sleep, and other sleep and circadian disorders, recent studies have shown unique genetic markers and metabolic pathways underlying EDS. Here, we aimed to further elucidate the biological profile of EDS using large scale single- and pathway-level metabolomics analyses. MethodsMetabolomics data were available for 877 metabolites in 6,071 individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and EDS was assessed using the Epworth Sleepiness Scale (ESS) questionnaire. We performed linear regression for each metabolite on continuous ESS, adjusting for demographic, lifestyle, and physiological confounders, and in sex specific groups. Subsequently, gaussian graphical modelling was performed coupled with pathway and enrichment analyses to generate a holistic interactive network of the metabolomic profile of EDS associations. FindingsWe identified seven metabolites belonging to steroids, sphingomyelin, and long chain fatty acids sub-pathways in the primary model associated with EDS, and an additional three metabolites in the male-specific analysis. The identified metabolites particularly played a role in steroid hormone biosynthesis. InterpretationOur findings indicate that an EDS metabolomic profile is characterized by endogenous and dietary metabolites within the steroid hormone biosynthesis pathway, with some pathways that differ by sex. Our findings identify potential pathways to target for addressing the causes or consequences of EDS and related sleep disorders. FundingDetails regarding funding supporting this work and all studies involved are provided in the acknowledgments section. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThere is a growing recognition of the paramount importance of sleep on health and cardiometabolic disease. Excessive daytime sleepiness (EDS), one of the key common sleep treatment targets, has been linked to increased risk of mortality, hypertension, cardiovascular disease, car accidents as well as decrease in life quality, and productivity. Despite its impact on health, much remains unknown about the biological mechanisms of EDS and if those mechanisms are independent from other sleep disorders. Recent genetic evidence that shows that EDS is associated with specific genetic biomarkers supports the need to further study the underlying biology of EDS. Added value of this studyHere, we used measurements of metabolites, the products and by-products of metabolism to identify the metabolomic profile of EDS. Metabolites are produced by the biological reactions within the body via proteins--themselves products of genes--and by the breakdown of external sources such as nutritional intake and breathing air pollutants. Therefore, metabolomics enables study of the effects of nutrition, environmental exposures, and genetics. In this study we aimed to identify the metabolites that were associated with excessive daytime sleepiness. Additionally, we mapped these metabolites into a publicly available online biological network of human metabolism pathways to obtain an understanding of our findings on a larger scale. Implications of all the available evidenceIdentifying the metabolites and pathways related to daytime sleepiness provides insights into the biological mechanisms of EDS and suggests future research opportunities to identify targets for prevention, prediction, and treatments for EDS and potentially other sleep disorders coupled with sleepiness. In this study we found 7 such metabolites--some endogenously synthesised and some obtained from dietary sources--associated with EDS. The network analysis implicated the steroid hormone biosynthesis pathway as a shared pathway underlying those metabolites, and identified linkages to key metabolites related to sleep: melatonin and cortisol metabolism.