Causal association of childhood body mass index (BMI) with the risk of endometrioid endometrial cancer: A two-sample Mendelian randomization study

Objective: This study aimed to investigate if childhood body mass index (BMI) causally contributed to the risk of endometrial cancer (EC), which had not been well answered. Methods: Genetic instruments were selected using single-nucleotide polymorphisms (SNPs) associated with childhood BMI in European population from a large-scale genome-wide association studies (GWAS, n= 39,620). A two-sample Mendelian randomization (MR) study was performed to evaluate the effect of higher childhood BMI on risk of EC. The data for endometrioid EC was obtained from a GWAS dataset comprising 54,884 individuals (8,758 cases and 46,126 controls). Inverse variance weighting (IVW), weighted median, weighted mode, and MR-Egger regression approaches were applied. Results: We selected 16 SNPs with genome-wide significance in childhood BMI for the analysis. The IVW analysis provided a causal link between childhood BMI and EC (beta = 0.408, standard error [SE] = 0.088, P  < 0.001). Similarly, the weighted median method also provided robust evidence for the causal correlation (beta = 0.390, SE = 0.119, P  < 0.001). Although the MR-Egger regression did not achieve the same significance (beta = 0.071, SE = 0.362, P  = 0.848), it showed a minimal intercept value indicating small bias for directionality of pleiotropic effects (intercept = 0.024; P  = 0.354). Through Cochran's Q test and visual inspection via funnel plot, the assessment of heterogeneity found no evidence of heterogeneity or asymmetry in our findings, further supporting the absence of directional pleiotropy. Conclusions: Childhood BMI and risk of EC might be causally related, and early-life intervention on weight control might be considered for children to reduce the life-span risk of EC.