Casual Associations and Shape Between Prepuberty Body Mass Index and Early Onset of Puberty: A Mendelian Randomization and Dose–Response Relationship Analysis

BACKGROUND: There is an ongoing controversial issue regarding whether onset of puberty is related to childhood BMI. OBJECTIVES: This study aims at investigating the causal association and its shape between prepuberty BMI and early puberty onset. METHODS: Breast development and testicular volume were assessed annually from a population-based prospective cohort of 997 children for consecutive years by professional endocrinologists. Seventeen puberty- and BMI-related SNPs were selected to calculate the polygenic risk score. The two-stage least square method was used to assess and confirm causal effects. A dose–response association between prepuberty BMI and early puberty onset was conducted by using restricted cubic spline Cox regression. RESULTS: After adjusting for covariates, prepuberty BMI was positively associated with early thelarche among girls (coefficients = 0.18, 95% CI: 0.01, 0.29). A non-linear model suggested an inverted U-shaped relationship between prepuberty BMI and risk for early thelarche (χ(2) = 276.3, p < 0.001). The risk for early thelarche increased rapidly from prepuberty BMI at 15.70 kg/m(2) (P(25)) to 20.75 kg/m(2) (P(85)) and gradually decreased afterward. Compared with the P(25) of prepuberty BMI, the HRs (95% CI) for early thelarche were 5.08 (1.15, 8.55), 4.48 (1.02, 7.74), 10.15 (3.93, 17.50), and 8.43 (1.91, 13.71) for percentiles P(25)–P(50), P(50)–P(75), P(75)–P(85), and ≥P(85) of BMI categories, respectively. In boys, compared with the P(25) of prepuberty BMI, boys with BMI between P(25) and P(50) showed an increased risk of early puberty (HR: 3.94, 95% CI: 1.44, 6.80). CONCLUSIONS: Prepuberty BMI may serve the purpose of identifying the girls at higher risk of early thelarche, which could assist in the adaptation of prevention and intervention strategies targeting childhood obesity. The findings emphasize a non-linear correlation between prepuberty BMI and early puberty onset.