ArticleMedicine2026
Unraveling the causal web of 4 adiposity indices and 92 multi-system outcomes: A body-wide Mendelian randomization study.
Article in Medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Body mass index (BMI) reflects general adiposity, waist circumference (WC) and hip circumference (HC) indicate regional fat distribution, and total fat percentage (TFP) represents overall body fat composition, while their independent disease-risk contributions remain unclear. Therefore, this study aimed to investigate the comparative and independent genetically predicted effects of 4 adiposity indices (BMI, WC, HC, and TFP) on 92 obesity-related outcomes. Two‑sample MR (TSMR) primarily employed the inverse-variance weighted (IVW) method, with MR‑Egger and maximum likelihood for supplementary analyses; multivariable MR (MVMR) applied the IVW and MR‑Egger methods. Sensitivity analyses were conducted to assess pleiotropy, heterogeneity, and outliers. All exposure datasets had sample sizes exceeding 300,000. Exposure and outcome data were obtained from large public consortia, including FinnGen and UK Biobank; most participants were of European ancestry, and there was no sample overlap between exposure and outcome datasets. TSMR using the IVW method (Bonferroni‑corrected P < .0001) demonstrated stronger positive associations between BMI and WC (18/92 and 21/92 outcomes, respectively) than HC (n = 13) and TFP (n = 9). MVMR using the IVW method revealed distinct independent causal associations between the different adiposity indices and diseases. BMI was independently and positively associated with a diverse range of health outcomes, including cardiometabolic (hypertension, and serum uric acid), respiratory (chronic obstructive pulmonary disease), gastrointestinal (gastroesophageal reflux disease [GERD]), musculoskeletal (osteoarthritis), and neuropsychiatric (sleep disorders and sleep apnea syndrome) diseases. WC was independently associated with an increased risk of multiple conditions, particularly cardiovascular and metabolic disorders (CMDs) and inflammatory conditions (e.g., atrial fibrillation, heart failure, hypertension, peripheral atherosclerosis, asthma, and cholecystitis). The independent causal effects of adiposity indices on outcomes remained robust even after separate adjustments for adipokines and inflammatory markers. However, TFP showed a positive association only with GERD among the 92 outcomes. Conversely, HC was negatively associated with the risk of multiple outcomes, notably CMDs. Results from MVMR using the IVW method and multivariable MR-Egger were consistent. Sensitivity analyses did not indicate substantial pleiotropy. The comprehensive MR analysis demonstrated the differential health effects of adiposity indices on multiple conditions. However, further studies are required to elucidate the underlying biological pathways.
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