• Clare H Llewellyn, Maciej Trzaskowski, Cornelia H M van Jaarsveld, Robert Plomin, and Jane Wardle.
• Health Behaviour Research Centre, Department of Epidemiology and Public Health, University College London, London, England2Division of Health and Social Care Research, King's College London, London, England.
• JAMA Pediatr. 2014 Apr 1;168(4):338-44.

ImportanceA better understanding of the cause of obesity is a clinical priority. Obesity is highly heritable, and specific genes are being identified. Discovering the mechanisms through which obesity-related genes influence weight would help pinpoint novel targets for intervention. One potential mechanism is satiety responsiveness. Lack of satiety characterizes many monogenic obesity disorders, and lower satiety responsiveness is linked with weight gain in population samples.ObjectiveTo test the hypothesis that satiety responsiveness is an intermediate behavioral phenotype associated with genetic predisposition to obesity in children.Design, Setting, And ParticipantsCross-sectional observational study of a population-based cohort of twins born January 1, 1994, to December 31, 1996 (Twins Early Development Study). Participants included 2258 unrelated children (53.3% female; mean [SD] age, 9.9 [0.8] years), one randomly selected from each twin pair.ExposureGenetic predisposition to obesity. We created a polygenic risk score (PRS) comprising 28 common obesity-related single-nucleotide polymorphisms identified in a meta-analysis of obesity-related genome-wide association studies.Main Outcomes And MeasuresSatiety responsiveness was indexed with a standard psychometric scale (Child Eating Behavior Questionnaire). Using 1990 United Kingdom reference data, body mass index SD scores and waist SD scores were calculated from parent-reported anthropometric data for each child. Information on satiety responsiveness, anthropometrics, and genotype was available for 2258 children. We examined associations among the PRS, adiposity, and satiety responsiveness.ResultsThe PRS was negatively related to satiety responsiveness (β coefficient, -0.060; 95% CI, -0.019 to -0.101) and positively related to adiposity (β coefficient, 0.177; 95% CI, 0.136-0.218 for body mass index SD scores and β coefficient, 0.167; 95% CI, 0.126-0.208 for waist SD scores). More children in the top 25% of the PRS were overweight than in the lowest 25% (18.5% vs 7.2%; odds ratio, 2.90; 95% CI, 1.98-4.25). Associations between the PRS and adiposity were significantly mediated by satiety responsiveness (P = .006 for body mass index SD scores and P = .005 for waist SD scores).Conclusions And RelevanceThese results support the hypothesis that low satiety responsiveness is one of the mechanisms through which genetic predisposition leads to weight gain in an environment rich with food. Strategies to enhance satiety responsiveness could help prevent weight gain in genetically at-risk children.

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