Age at Menarche Mediating Visceral Adipose Tissue's Influence on Pre-eclampsia: A Mendelian Randomization Study

Context The association between visceral adipose tissue (VAT) and pre-eclampsia (PE) shows inconsistent results and the underlying mediator remains unknown. Objective We aimed to explore the causal effect of VAT on PE risks and the mediation role of age at menarche (AAM) in explaining this relationship. Methods Summary data for PE were obtained from the FinnGen genome-wide association study (3556 cases and 114 735 controls). For exposure data, 70 genetic variants associated with the predicted VAT in 161 149 European women from UK Biobank were used as instrumental variables. Inverse variance weighted and multiple sensitivity analyses were applied. We also conducted multivariable Mendelian randomization (MR) analyses to test the association between VAT-associated single-nucleotide variations and PE. Next, mediation analyses were performed to study whether the association between VAT and PE was mediated via AAM. Results In univariable MR analysis, higher volume of VAT was associated with the advancement of AAM and increased PE risk (beta = -0.33; 95% CI, -0.49 to -0.16 for AAM; odds ratio 1.65, 95% CI, 1.23 to 2.20 for PE). After adjusting for waist circumference, waist to hip ratio, and hip circumference, the multivariable MR results presented the consistent positive causality of VAT on PE. Two-step MR analysis proved an estimated 14.3% of the positive effect of VAT on PE was mediated by AAM. Conclusion Our findings provided evidence of the causal relationship between VAT and PE and proved VAT could accelerate AAM and then contribute to the risk of incident PE.