Causal associations of body mass index and waist-to-hip ratio with acute appendicitis: a Mendelian randomization study

BackgroundAcute appendicitis (AA) is a common surgical emergency. Observational studies have reported associations between obesity-related anthropometric traits and AA, but these associations may be affected by confounding and reverse causation. We used Mendelian randomization (MR) to investigate the potential causal effects of body mass index (BMI) and waist-to-hip ratio (WHR) on AA risk. Methods and FindingsWe obtained genome-wide association study (GWAS) summary statistics for BMI (ukb-b-19953), WHR (ieu-a-73), and AA (finn-b-K11_APPENDACUT) from the IEU Open GWAS database. We conducted single-variable MR (SVMR) and multivariable MR (MVMR) analyses. The primary estimator was inverse-variance weighted (IVW) MR, complemented by MR-Egger, weighted median, weighted mode, and simple mode methods. Instrument strength was assessed using the variance explained and F-statistics. Sensitivity analyses included Cochrans Q for heterogeneity, MR-Egger intercept and MR-PRESSO global test for horizontal pleiotropy, leave-one-out analysis, and Steiger directionality testing. We mapped instrumental variants to cis-eQTL genes (eQTLGen) and performed GO and KEGG enrichment analyses. In SVMR, genetically predicted BMI (OR 1.145, P = 0.0006) and WHR (OR 1.336, P = 0.0040) were associated with higher AA risk. Instruments were strong (BMI: [Formula]; mean/min F-statistic= 64.15/29.76; WHR: [Formula]; mean/min F-statistic= 48.41/29.75). Sensitivity analyses did not show strong evidence of heterogeneity or directional pleiotropy, and Steiger tests supported the hypothesized direction (exposure -> outcome). In MVMR including both traits, WHR remained associated with AA risk (OR 1.374, P = 0.0110), whereas BMI was not (P = 0.8000). Enrichment analyses suggested WHR-mapped genes were enriched in pathways related to adipocyte differentiation, while BMI-mapped genes were enriched in terms including nuclear envelope and endocytosis-related pathways. ConclusionsThese MR analyses are consistent with a potential causal relationship between obesity-related traits and AA risk, with WHR showing an association independent of BMI in multivariable models. Further work in diverse populations and with additional sensitivity analyses is warranted to assess robustness to pleiotropy and generalizability.