The Role of Morning Plasma Cortisol in Obesity: A Bi-directional Mendelian Randomization Study

Abstract Context Cortisol, an important hormone regulated by the hypothalamic-pituitary-adrenal (HPA) axis, is associated with obesity. However, it is unclear whether the relationship between cortisol and obesity is causal or could be explained by reverse causality. Objective This work aims to assess the role of morning plasma cortisol in clinical classes of obesity. Methods In this bi-directional two-sample Mendelian Randomization (MR) study, cortisol-associated genetic variants were obtained from the CORtisol NETwork consortium (n = 12,597). The primary outcomes were obesity class I (BMI ≥ 30 kg/m 2), class II (BMI ≥ 35 kg/m 2), and class III (BMI ≥ 40kg/m 2). Inverse variance weighting (IVW) method was used as the main analysis, with weighted median, MR-Egger, and MR-PRESSO as sensitivity analyses. Conversely, genetic variants predicting clinical classes of obesity were applied to the cortisol GWAS. Results Genetically predicted cortisol was associated with reduced risk of obesity class I (OR = 0.905; 95% CI, 0.865-0.946; p < 0.001). Evidence from bi-directional MR showed that obesity class II and class III were associated with lower cortisol levels ((class II-cortisol OR = 0.953; 95% CI, 0.923-0.983; p = 0.002); (class III-cortisol OR = 0.955; 95% CI, 0.942-0.967; p < 0.001)), indicating reverse causality between cortisol and obesity. Conclusions This study demonstrates that cortisol is negatively associated with obesity and vice versa. Together, these findings suggest that blunted morning plasma cortisol secretion may be responsible for severe obesity. Regulating morning plasma secretion might be a prevention measure for obese people.