Comprehensive Evidence for Mortality and Underlying Morbidity Related to Visceral Fat Distribution

ABSTRACT Linking obesity to mortality is an intriguing and controversial topic. This study tried to comprehensively assess 8 adiposity surrogates and mortality association among middle‐to‐old‐aged adults to identify a superior one, and explore explanatory disorders. Data sources included the National Health and Nutrition Examination Survey (NHANES), UK Biobank (UKB), and FinnGen R11. Cox proportional hazard model, restricted cubic spline, and Mendelian randomization (MR) were used to investigate adiposity surrogates and mortality associations. Observational and MR‐based phenome‐wide association studies (PheWASs) were performed to investigate explanatory disorders. Progressions of disease free‐disease‐death transition were assessed using multi‐state Markov (MSM) models. The NHANES and UKB analyses involved 11,706 and 352,980 participants, respectively. A body shape index (ABSI) showed consistent, stronger, and monotonically‐increasing associations with mortalities in both cohorts. MR analyses demonstrated a monotonically‐increasing causal effect of ABSI on all‐cause mortality (odds ratios [OR] = 1.370, 95% confidence interval [CI]: 1.119–1.676; P nonlinear = 0.269), which was greater than body mass index (OR = 1.279, 95% CI: 1.163–1.408; P nonlinear = 0.433). Two PheWASs identified 668 ABSI‐associated disorders, notably atherosclerosis, non‐alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), and hypercholesterolemia. Markov models revealed ABSI's role in driving transitions from disease‐free to morbidity of the 4 diseases and death. ABSI, a visceral fat indicator, showed comparative competence in mortality evaluation. The adiposity‐mortality etiology involved diverse diseases across multiple systems, notably atherosclerosis, NAFLD, T2D, and hypercholesterolemia. These findings provide more evidence facilitating development and implementation of clinical guidelines for obesity assessment.