Abstract
BackgroundMany genes and molecular pathways are associated with obesity, but the mechanisms from genes to obesity are less well known. Eating behaviors represent a plausible pathway, but because the relationships of eating behaviors and obesity may be bi-directional, it remains challenging to resolve the underlying pathways. A longitudinal approach is needed to assess the contribution of genetic risk during the development of obesity in childhood. In this study we aim to examine the relationships between the polygenic risk score for body mass index (PRS-BMI), parental concern of overeating and obesity indices during childhood.MethodsThe IDEFICS/I.Family study is a school-based multicenter pan-European cohort of children observed for 6 years (mean ± SD follow-up 5.8 ± 0.4). Children examined in 2007/2008 (wave 1) (mean ± SD age: 4.4 ± 1.1, range: 2–9 years), in 2009/2010 (wave 2) and in 2013/2014 (wave 3) were included. A total of 5112 children (49% girls) participated at waves 1, 2 and 3. For 2656 children with genome-wide data we constructed a PRS based on 2.1 million single nucleotide polymorphisms. Z-score BMI and z-score waist circumference (WC) were assessed and eating behaviors and relevant confounders were reported by parents via questionnaires. Parental concern of overeating was derived from principal component analyses from an eating behavior questionnaire.ResultsIn cross-lagged models, the prospective associations between z-score obesity indices and parental concern of overeating were bi-directional. In mediation models, the association between the PRS-BMI and parental concern of overeating at wave 3 was mediated by baseline z-BMI (β = 0.16, 95% CI: 0.10, 0.21) and baseline z-WC (β = 0.17, 95% CI: 0.11, 0.23). To a lesser extent, baseline parental concern of overeating also mediated the association between the PRS-BMI and z-BMI at wave 3 (β = 0.10, 95% CI: 0.07, 0.13) and z-WC at wave 3 (β = 0.09, 95% CI: 0.07, 0.12).ConclusionsThe findings suggest that the prospective associations between obesity indices and parental concern of overeating are likely bi-directional, but obesity indices have a stronger association with future parental concern of overeating than vice versa. The findings suggest parental concern of overeating as a possible mediator in the genetic susceptibility to obesity and further highlight that other pathways are also involved. A better understanding of the genetic pathways that lead to childhood obesity can help to prevent weight gain.Trial registrationRegistry number: ISRCTN62310987 Retrospectively registered 17 September 2018.
Highlights
Obesity is a heritable and highly polygenic chronic disease [1,2,3,4]
The models had a reasonable fit to the data (RMSEA = 0.055, Comparative Fit Index (CFI) = 0.996, Tucker-Lewis Index (TLI) = 0.987 for z-body mass index (BMI); and Root Mean Square Error of Approximation (RMSEA) = 0.078, CFI = 0.991, TLI = 0.967 for z-waist circumference (WC))
Results from the causal mediation analyses The results obtained from the causal mediation analyses (Fig. 3) showed that Body Mass Index z-score (z-BMI) and Waist Circumference z-score (z-WC) at wave 1 mediated the association between the polygenic risk score (PRS)-BMI and parental concern of overeating at wave 3 (Fig. 3, Model 1)
Summary
Genetic factors explain between 40 to 60% of the proportion of the variability in body mass index (BMI) during childhood [5]. When rare variants are assessed by whole genome sequencing, the proportion of variance in BMI explained by measured genetic variants rises to 40% [6], which is close to the heritability estimates from twin and family studies. Using information from 2.1 million measured and imputed common variants irrespective of genome-wide significance [7], the newest polygenic risk score (PRS) is a single measure that quantifies the inherited susceptibility to a disease [8]. In this study we aim to examine the relationships between the polygenic risk score for body mass index (PRS-BMI), parental concern of overeating and obesity indices during childhood
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