Birthweight, time-varying adiposity growth and early menarche in girls: A Mendelian randomisation and mediation analysis

Abstract

To explore the causal effect of time-varying z-BMI growth on early menarche using Mendelian randomisation (MR); to identify critical adiposity predictors of early menarche; to compare the effects of birthweight and time-varying z-BMI growth as mediators of the path from genes to early menarche using mediation analysis. We used data from the Taiwan Children Health Study with 21 obesity-related single-nucleotide polymorphisms (SNPs) to yield genetic (instrumental variable)IVs for adiposity. Children with available data on genotyping, birthweight, adiposity, and menarcheal age were included. In MR analyses, results based on the time-varying z-BMI growth show more statistical power and capture more information of adiposity growth (p=0.01) than those based on single point z-BMI (p=0.02). Among adiposity measures, critical predictors of early menarche are fat free mass (RR=1.33, 95% CI 1.07-1.65) and waist/height ratio (RR=1.27, 95% CI 1.03-1.56). Other potential predictors of early menarche are sum of skinfold (RR=1.24, 95% CI 1.03-1.48) and total body fat (RR=1.20, 95% CI 1.05-1.38). In both one-mediation and multi-mediation analyses, time-varying z-BMI growth in the prepubertal years plays a crucial mediator in the pathway from the genes to early menarche. This study discovered that greater prepubertal adiposity growth is a crucial mediator in the path from genes to early menarche. For girls with genes positively associated with obesity; and/or of lower birthweight, a strategy to prevent childhood adiposity should be implemented in order to avoid early menarche development.