Childhood sleep duration modifies the polygenic risk for obesity in youth through leptin pathway: the Beijing Child and Adolescent Metabolic Syndrome cohort study

Junling Fu, Yonghui Wang, Ge Li, Lanwen Han, Yu Li, Lujiao Li, Dan Feng, Yunpeng Wu, Xinhua Xiao, Mingyao Li, Struan F A Grant, Ming Li, Shan Gao, Junling Fu, Yonghui Wang, Ge Li, Lanwen Han, Yu Li, Lujiao Li, Dan Feng, Yunpeng Wu, Xinhua Xiao, Mingyao Li, Struan F A Grant, Ming Li, Shan Gao

Abstract

Background/objectives: Short sleep is an obesity risk factor, however, little is known about its interplay with genetic predisposition and pathways involved in obesity pathogenesis, especially in the longitudinal setting. We aimed to investigate a possible sleep-gene interaction for childhood obesity risk, and whether the interaction in childhood longitudinally contributes to obesity risk at a 10-year follow-up and further to test if there is any mediation through the leptin pathway.

Subjects/methods: A total of 3211 children from China (6-18 years) at baseline and 848 participants at 10-year follow-up from the Beijing Child and Adolescent Metabolic Syndrome (BCAMS) cohort study were analyzed. Baseline leptin concentrations and 12 established adult body mass index (BMI) loci were examined for the associations with habitual sleep duration.

Results: After adjusting for covariates, including pubertal stages and behavioral factors, short sleep duration at baseline was significantly associated with increased overweight/obesity risk at both baseline and follow-up. Genetic predisposition scores (GPS), particularly consisting of leptin-related SNPs (GPSleptin), were robustly associated with baseline overweight/obesity in children who slept ≤8 h/day (P < 0.001), whereas the association was ablated in those who slept ≥10 h/day (P > 0.05). Comparable observations were made at follow-up. Mediation analysis revealed a modest direct effect of the GPSleptin-sleep interaction on BMI at baseline, while a significant indirect effect of this interaction was found to be mediated principally through elevated leptin (proportion: 52.6%); moreover, the mediation effect via leptin remained stable over 10 years.

Conclusions: This study suggests that shorter sleep duration in children from China (< 8h/day), compared to longer sleep duration (≥10 h/day), has a long-term impact on the association of polygenic risk for obesity from childhood to young adulthood and leptin pathway explains a key mechanism via a modification effect. Therefore, adequate sleep duration during childhood is important for the early prevention of obesity, especially if there is a genetic predisposition to this trait.

Trial registration: ClinicalTrials.gov NCT03421444.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
A visual schematic of the path model used to test the mediation effect of leptin on the association of GPSleptin with baseline and follow-up BMI. Flow diagram showing that the mediation effect using Ln-leptin was 63.7% for baseline BMI and 70.6% for follow-up BMI. β for linear regression in the mediation models was adjusting for age, sex, residence, pubertal stages, diet score, and activity. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. BMI body mass index, GPS genetic predisposition scores
Fig. 2
Fig. 2
A visual schematic of the path model used to test the moderation effect of sleep duration and the mediation effect of leptin on the association of GPSleptin with baseline and follow-up BMI. The proposed moderator variable was baseline sleep duration, the model was used to test for an effect of the GPS-sleep interaction on baseline and follow-up BMI; the proposed mediator variable was baseline leptin levels, where this model was used to test the paths from GPS, sleep duration, and GPS-sleep interaction respectively to Ln-leptin, and from the Ln-leptin to change in BMI at both baseline and follow-up. β for linear regression in the mediation models was adjusting for age, sex, residence, pubertal stages, diet score, and activity. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. BMI body mass index, GPS genetic predisposition scores

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