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

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.