Abstract
BACKGROUND: Observational studies suggest an association between elevated body mass index (BMI) and perianal abscess risk, but residual confounding and reverse causality limit causal inference. Mendelian randomization (MR) offers a robust approach to assess causality by leveraging genetic variants as instrumental variables. This study aimed to evaluate the causal relationship between BMI and perianal abscess using a MR framework. METHODS: We analyzed European-ancestry genome-wide association study (GWAS) data for BMI (n = 359,983) and perianal abscess (1,287 cases/182,423 controls). A total of 364 independent SNPs associated with BMI at genome-wide significance (P < 5 × 10⁻⁸) were selected as instrumental variables, with stringent linkage disequilibrium clumping (r² < 0.01, clumping distance > 10,000 kb). Causal estimates were derived using inverse-variance weighted (IVW), MR-Egger, weighted median, and MR-PRESSO methods. Multivariable MR (MVMR) adjusted for lipid metabolism disorders and insulin resistance. Sensitivity analyses assessed pleiotropy, heterogeneity, and instrument strength. RESULTS: Genetically predicted higher BMI was causally associated with an increased risk of perianal abscess (IVW: OR = 1.94, 95%CI: 1.46-2.68, P = 3.8 × 10⁻⁶). Consistency across methods (MR-Egger: OR = 2.80; weighted median: OR = 2.30) and MVMR adjustment (OR = 1.47, 95%CI: 1.12-1.93) supported robustness. No evidence of directional pleiotropy (MR-Egger intercept P = 0.30) or heterogeneity (I² = 7.6%; MR-PRESSO global test P = 0.148) was observed. Instrument strength was sufficient (mean F-statistic = 37.75), mitigating weak instrument bias. CONCLUSION: This MR study provides robust genetic evidence supporting BMI as a causal risk factor for perianal abscess. The findings highlight obesity management as a potential preventive strategy, though multifactorial mechanisms warrant further investigation.