Clare H. Llewellyn

The FTO gene and measured food intake in children

Objective:Polymorphisms in the obesity-associated gene, FTO, have been linked with sensitivity to satiety in children, indicating FTO may be influencing one of the regulatory drivers underlying food intake. In this study, we tested the hypothesis that food intake in a standard eating behaviour paradigm in which palatable food is offered under conditions of satiety would be associated with FTO genotype status, after controlling for differences in body mass index (BMI).Methods:Participants were 131 children aged 4–5 years, taking part in a behavioural study of food intake for whom DNA was available for genotyping. The phenotypic indicator of intake was the childs consumption of palatable food presented after having eaten a meal. We also assessed physical activity using parental reports of the childs enjoyment of active games, their level of activity relative to other children and a standard measure of fidgetiness. Associations between polymorphisms of the intronic FTO single nucleotide polymorphism (rs9939609) and behaviour (food intake and activity) were assessed by analysis of variance controlling for sex, age and BMI s.d. scores.Results:The distribution of AA (homogenous for A allele), AT (heterogeneous T and A alleles) and TT (homogenous for T allele) genotypes was 18, 50 and 32%, respectively. As predicted, TT homozygotes ate significantly less than heterozygotes (P=0.03) or AA homozygotes (P=0.02). The effect was not diminished by controlling for BMI s.d. scores. There were no significant associations between FTO genotype and any marker of physical activity.Conclusions:We showed that children with two copies of the lower-risk FTO alleles ate less than those with one or two higher-risk alleles. We conclude that the T allele is protective against overeating by promoting responsiveness to internal signals of satiety.

Eating rate is a heritable phenotype related to weight in children

BACKGROUND There is growing interest in the heritability of behavioral phenotypes related to adiposity. One potential candidate is the speed of eating, although existing evidence for an association with weight is mixed. OBJECTIVE We aimed to assess the speed of eating in a sample of 10-12-y-old children to test the hypotheses that higher eating rate is related to greater adiposity and that eating rate is a heritable characteristic. DESIGN Video data of 254 twin children eating a standard meal at home were used to record eating rate (bites/min) and changes in eating rate across the 4 quarters of the meal. Adiposity was indexed with body mass index SD scores relative to British 1990 norms; for some analyses, children were categorized into groups of overweight or obese and into 2 subgroups of normal-weight (lower normal-weight or higher normal-weight) for comparison of the eating rate within the normal range as well as between clinical and nonclinical groups. All analyses controlled for clustering in twin pairs. Heritability of eating rate was modeled by using standard twin methods. RESULTS There was a significant linear association across the 3 weight groups for eating rate (P = 0.010), and regression analyses showed that eating rate increased by 0.18 bites/min for each 1-unit increase in body mass index SD score (P = 0.005). The heritability of eating rate was high (0.62; 95% CI: 0.45, 0.74). There was no association between weight group and a change (ie, deceleration) in eating rate over the mealtime. CONCLUSION Faster eating appears to be a heritable behavioral phenotype related to higher weight.

Adiposity and 'eating in the absence of hunger' in children.

Objective:To examine the association between eating in the absence of hunger (EAH) and adiposity in children.Design:Two cross-sectional studies in community settings.Subjects:For study 1, 348 children (178 girls and 170 boys) aged 7–9 years were recruited as part of the Physical Exercise and Appetite in Children Study. In study 2, participants were a subsample of children aged 9–12 years (N=316; 192 girls and 124 boys) from the Twins Early Development Study.Measurements:EAH was operationalized as intake of highly palatable sweet snacks after a mixed meal at school (study 1) or home (study 2). Weight (kg) and height (m) measurements were used to calculate the body mass index (BMI) s.d. scores. Children were grouped using the standard criteria for underweight, healthy weight, overweight and obesity. The healthy weight range was further subdivided into lower healthy weight (⩽50th centile) and higher healthy weight (>50th centile) to examine the distribution of EAH across the adiposity continuum.Results:In both studies, EAH showed a significant positive association with adiposity in boys after adjusting for covariates (P<0.001), with a linear increase in the intake across underweight, healthy weight and overweight groups. The association between EAH and adiposity was not significant in girls in either study, although in study 1, results showed a quadratic trend, with EAH increasing through the underweight and healthy weight ranges and decreasing in overweight and obese groups.Conclusion:EAH is a behavioural phenotype that is not specific to overweight children but instead shows a graded association with adiposity across the weight continuum, particularly in boys. In this study, the effect was less pronounced in girls, which may reflect social desirability pressures constraining food intake among heavier girls.

Satiety Mechanisms in Genetic Risk of Obesity

IMPORTANCE A 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. OBJECTIVE To test the hypothesis that satiety responsiveness is an intermediate behavioral phenotype associated with genetic predisposition to obesity in children. DESIGN, SETTING, AND PARTICIPANTS Cross-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. EXPOSURE Genetic 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 MEASURES Satiety 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. RESULTS The 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 RELEVANCE These 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.

Finding the missing heritability in pediatric obesity: the contribution of genome-wide complex trait analysis

Known single-nucleotide polymorphisms (SNPs) explain <2% of the variation in body mass index (BMI) despite the evidence of >50% heritability from twin and family studies, a phenomenon termed ‘missing heritability’. Using DNA alone for unrelated individuals, a novel method (in a software package called Genome-wide Complex Trait Analysis, GCTA) estimates the total additive genetic influence due to common SNPs on whole-genome arrays. GCTA has made major inroads into explaining the ‘missing heritability’ of BMI in adults. This study provides the first GCTA estimate of genetic influence on adiposity in children. Participants were from the Twins Early Development Study (TEDS), a British twin birth cohort. BMI s.d. scores (BMI-SDS) were obtained from validated parent-reported anthropometric measures when children were about 10 years old (mean=9.9; s.d.=0.84). Selecting one child per family (n=2269), GCTA results from 1.7 million DNA markers were used to quantify the additive genetic influence of common SNPs. For direct comparison, a standard twin analysis in the same families estimated the additive genetic influence as 82% (95% CI: 0.74–0.88, P<0.001). GCTA explained 30% of the variance in BMI-SDS (95% CI: 0.02–0.59; P=0.02). These results indicate that 37% of the twin-estimated heritability (30/82%) can be explained by additive effects of multiple common SNPs, and provide compelling evidence for strong genetic influence on adiposity in childhood.

Prospective associations between appetitive traits and weight gain in infancy

BACKGROUND Differences in appetitive traits such as food-cue or satiety responsiveness have been hypothesized to contribute to variability in weight gain. However, existing data were largely cross-sectional and could not exclude the possibility that differences in appetitive traits were consequences of differences in weight. OBJECTIVE We tested whether prospective associations between appetitive traits and subsequent weight were stronger than associations between weight and subsequent appetitive traits. DESIGN Data were from Gemini, which is a population-based cohort of 2402 families with twins. Parents completed a Baby Eating Behavior Questionnaire to assess 4 appetitive traits for each twin at ages 3 and 15 mo. We obtained infant weights at 3, 9, and 15 mo from records of health professionals. Weight SD scores were calculated by using UK 1990 reference data. A path analysis was used to examine prospective associations in each direction over sequential 6-mo intervals and over the same 12-mo period, with the significance of differences between the 2 paths established with bootstrapping. RESULTS Path analyses included 2213 infants. For each appetitive trait, the path to subsequent weight (standardized coefficients: 0.17-0.33) was significantly larger than the path from weight to subsequent appetite (coefficients: 0.07-0.13). Results were confirmed when both associations were analyzed by using changes from 3 to 15 mo. CONCLUSION Longitudinal analyses showed that associations between appetitive traits and subsequent weight were stronger than between weight and subsequent appetite, which supports the idea that differences in appetitive traits, in conjunction with environmental opportunities to overeat, influence weight gain in early childhood.

Gemini: a UK twin birth cohort with a focus on early childhood weight trajectories, appetite and the family environment

Gemini is a cohort study of young twins in the United Kingdom designed to assess genetic and environmental influences on early childhood weight trajectories with a focus on infant appetite and the family environment. A total of 2402 families with twins born in England and Wales between March and December 2007 agreed to participate and returned completed baseline questionnaires. The sample includes 1586 same-sex and 816 opposite-sex twins. The study is currently funded for 5 years of follow-up, but is planned to continue into early adolescence and beyond, pending funding. With current funding of the study, families will be followed up when twins are: 8 months old (baseline), and then at 15, 20, 24, 36 and 48 months of age. Gemini is in its early stages, with baseline and first follow-up data collection completed. This is the first twin cohort to focus on childhood weight gain with detailed and repeated measures of childrens appetite, food preferences, activity behavior and parental feeding styles, alongside detailed and repeated collection of anthropometrics. This article reviews the rationale for the Gemini study, its representativeness and the main measures.

Appetite and Growth: A Longitudinal Sibling Analysis

IMPORTANCE Identifying early markers of future obesity risk can help target preventive interventions. Several studies have shown that a heartier appetite in infancy is a risk factor for more rapid weight gain, but to date no investigations have been able to rule out familial confounding. OBJECTIVES To use a sibling design (data from same-sex, dizygotic twin pairs) to test the hypothesis that sibling differences in infant appetite predicted differential weight gain during childhood. DESIGN, SETTING, AND PARTICIPANTS Gemini is a population-based twin cohort among the general United Kingdom population born between March 1, 2007, and December 15, 2007. Growth trajectories were analyzed from birth to age 15 months. Appetite-discordant pairs were selected from 800 nonidentical, same-sex twin pairs. EXPOSURES Appetite during the first 3 months of life was assessed with the food responsiveness (FR) and satiety responsiveness (SR) subscales from the Baby Eating Behaviour Questionnaire. Discordance was defined as a within-pair difference of at least 1 SD. MAIN OUTCOMES AND MEASURES A mean of 11.5 weight measurements per child were available between birth and age 15 months. Multilevel models, adjusted for sex and birth weight, compared growth curves for the higher-appetite vs lower-appetite twins. RESULTS In total, 172 pairs were discordant for SR and 121 pairs for FR. Within-pair analyses showed that those with higher FR and those with lower SR grew faster than their sibling. At age 6 months, those with higher FR were 654 (95% CI, 395-913) g heavier and at age 15 months were 991 (95% CI, 484-1498) g heavier. For sibling pairs discordant for SR, the weight differences between siblings were 637 (95% CI, 438-836) g at age 6 months and 918 (95% CI, 569-1267) g at age 15 months. CONCLUSIONS AND RELEVANCE A heartier appetite (indexed with higher FR or lower SR) in early infancy is prospectively associated with more rapid growth up to age 15 months in a design controlling for potential familial confounding, supporting a causal role for appetite in childhood weight gain. Appetite could be an early marker for risk of weight gain in the current obesogenic environment and might be a potential target for preventive interventions.

Nature and nurture in children's food preferences

BACKGROUND Health professionals identify food provision in the home as a key influence on childrens food preferences. In contrast, parents often perceive childrens food preferences to be inborn. One explanation for this discrepancy could be that environmental and genetic influences vary by food type. OBJECTIVE We assessed genetic and environmental contributions to preferences for a wide variety of foods in a large pediatric twin sample. DESIGN Data were from Gemini, which is a cohort of UK twins born in 2007. Preferences for 114 foods were assessed by parent-completed questionnaire when children were aged 3 y (n = 2686). Foods tried by >75% of respondents were grouped into protein, vegetables, fruit, dairy, starches, and snacks. Quantitative model-fitting analyses were used to assess genetic and environmental influences for each food group. RESULTS The genetic influence was higher for vegetables (54%; 95% CI: 47%, 63%), fruit (53%; 95% CI: 45%, 61%), and protein (48%; 95% CI: 40%, 57%) but lower for starches (32%; 95% CI: 26%, 38%), snacks (29%; 95% CI: 24%, 35%), and dairy (27%; 95% CI: 20%, 35%). In contrast, shared-environment effects were higher for snacks (60%; 95% CI: 54%, 65%), starches (57%; 95% CI: 51%, 62%), and dairy (54%; 95% CI: 47%, 60%) and lower for vegetables (35%; 95% CI: 27%, 42%), fruit (35%; 95% CI: 26%, 43%), and protein (37%; 95% CI: 27%, 45%). Nonshared environment effects were small for all foods (11-19%). CONCLUSIONS Both genetic and environmental effects were significant for all food groups, but genetic effects dominated for more nutrient-dense foods (vegetables, fruit, and protein), whereas shared environmental effects dominated for snacks, dairy, and starches. These findings endorse the view of health professionals that the home environment is the main determinant of childrens liking for energy-dense foods implicated in excessive weight gain but suggest that parents are also correct by identifying innate differences in liking, particularly for nutrient-dense foods that parents and health educators try to encourage.

Genetic and Environmental Influences on Infant Growth: Prospective Analysis of the Gemini Twin Birth Cohort

Objective Infancy is a critical period during which rapid growth potentially programs future disease risk. Identifying the modifiable determinants of growth is therefore important. To capture the complexity of infant growth, we modeled growth trajectories from birth to six months in order to compare the genetic and environmental influences on growth trajectory parameters with single time-point measures at birth, three and six months of age. Methods Data were from Gemini, a population sample of 2402 UK families with twins. An average 10 weight measurements per child made by health professionals were available over the first six months. Weights at birth, three and six months were identified. Longitudinal growth trajectories were modeled using SITAR utilizing all available weight measures for each child. SITAR generates three parameters: size (characterizing mean weight throughout infancy), tempo (indicating age at peak weight velocity (PWV)), and velocity (reflecting the size of PWV). Genetic and environmental influences were estimated using quantitative genetic analysis. Results In line with previous studies, heritability of weight at birth and three months was low (38%), but it was higher at six months (62%). Heritability of the growth trajectory parameters was high for size (69%) and velocity (57%), but low (35%) for tempo. Common environmental influences predominated for tempo (42%). Conclusion Modeled growth parameters using SITAR indicated that size and velocity were primarily under genetic influence but tempo was predominantly environmentally determined. These results emphasize the importance of identifying specific modifiable environmental determinants of the timing of peak infant growth.