Childhood obesity: genetic and environmental overlap with normal-range BMI

Objective: To understand the overlap between the etiology of obesity and normal variation in BMI in children. Methods and Procedures: Height and weight data were available from a large UK representative sample of twins: 2,342 same‐sex pairs at 7 years and 3,526 same‐sex pairs at 10 years. The twin method and model‐fitting techniques were used to estimate genetic and environmental contributions to BMI. DeFries‐Fulker (DF) extremes analysis was used to investigate genetic and environmental influences on the mean difference between obese and normal‐weight children. Obesity was classified using the International Obesity Task Force (IOTF) criteria. Results: At both ages, BMI and obesity were highly heritable (0.60–0.74) and only modestly influenced by shared environmental factors (0.12–0.22). Extremes analyses indicated that genetic and environmental influences on obesity are quantitatively and qualitatively similar to those operating across the range of BMI. Discussion: Obesity is the extreme of the same genetic and environmental factors responsible for variation throughout the distribution of BMI. This finding implies that genes that influence obesity will also be associated with BMI in the normal range, and similar environmental influences will affect BMI in the clinical and normal range. Knowing that obesity is influenced by the same genetic and environmental factors that affect weight at all levels has implications for investigating the mechanisms for weight gain and developing interventions for weight control.     

Associations between an obesity related genetic variant (FTO rs9939609) and prostate cancer risk

Observational studies suggest that obese men have a lower risk of incident prostate cancer, but an increased risk of advanced and fatal cancers. These observations could be due to confounding, detection bias, or a biological effect of obesity. Genetic studies are less susceptible to confounding than observational epidemiology and can suggest how associations between phenotypes (such as obesity) and diseases arise. To determine whether the associations between obesity and prostate cancer are causal, we conducted a genetic association study of the relationship between a single nucleotide polymorphism known to be associated with obesity (FTO rs9939609) and prostate cancer. Data are from a population-based sample of 1550 screen-detected prostate cancers, 1815 age- and general practice matched controls with unrestricted prostate specific antigen (PSA) values and 1175 low-PSA controls (PSA <0.5 ng/ml). The rs9939609 A allele, which was associated with higher BMI in the sample, was inversely associated with overall (odds ratio (OR) versus all controls = 0.93; 95% confidence interval (CI): 0.85-1.02 p = 0.12 per allele) and low-grade (OR = 0.90; 0.81-0.99 p = 0.03 per allele) prostate cancer risk, but positively associated with high-grade cancer among cases (OR high- versus low-grade cancer = 1.16; 0.99-1.37 p = 0.07 per allele). Although evidence for these effects was weak, they are consistent with observational data based on BMI phenotypes and suggest that the observed association between obesity and prostate cancer is not due to confounding. Further research should confirm these findings, extend them to other BMI-related genetic variants and determine whether they are due to detection bias or obesity-related hormonal changes. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN20141297.     

Associations between parental and child overweight and obesity

Results of the analysis showed that parents and children overweight/obesity were significantly correlated. The sample includes 318 pairs of mothers and children, and 336 pairs of fathers and children at the age 11.3 +/- 0.4 years in Trogir, Croatia. Child overweight and obesity were defined according to body mass index (BMI) 25 and 30 equivalents (kg/m2). The prevalence of total overweight in girls was 25.6% and among boys was 20.5%. Mother's weight (p = 0.003) and BMI (p = 0.006) were greater in obese than in other groups of children. Overweight/obese children were more often found among overweight/obese mothers (p = 0.009) and fathers (p = 0.039). Correlation between overweight/obese children and their father (odds ratio 3.2, 95% CI 1.5-6.8) was stronger than between overweight/obese children and their mothers (odds ratio 2.2, 95% CI 1.2-3.9). Associations with mothers' and daughters' overweight/obesity were stronger (p = 0.017) than mothers' and sons'(p = 0.12). Correlations between children's BMI and fathers' BMI (r = 0.265, p < 0.0001) and between children's BMI and mothers' BMI (r = 0.173, p = 0.002) were significant. Children whose parents are overweight/obese look for greater attention in future preventive programme.     

The intergenerational transmission of BMI in China

Based on the China Health and Nutrition Survey longitudinal data from 1989 to 2009 and using BMI z-score as the measure of adiposity, we estimate the intergenerational transmission of BMI in China. The OLS estimates suggest that a one standard deviation increase in father's or mother's BMI is associated with an increase of around 20% in child's Body Mass Index (BMI) z-score. These estimates decrease to around 14% when we control for family fixed effects. We examine the heterogeneity of this BMI intergenerational transmission process across family income, parental occupation and poverty status and also find this intergenerational correlation tends to be higher among children of higher BMI levels, though this tendency becomes weaker as children approach adulthood.     

Parent-Child Resemblance in Weight Status and Its Correlates in the United States

Background

Few studies have examined parent-child resemblance in body weight status using nationally representative data for the US.

Design

We analyzed Body Mass Index (BMI), weight status, and related correlates for 4,846 boys, 4,725 girls, and their parents based on US nationally representative data from the 2006 and 2007 Medical Expenditure Panel Survey (MEPS). Pearson partial correlation coefficients, percent agreement, weighted kappa coefficients, and binary and multinomial logistic regression were used to examine parent-child resemblance, adjusted for complex sampling design.

Results

Pearson partial correlation coefficients between parent and child’s BMI measures were 0.15 for father-son pairs, 0.17 for father-daughter pairs, 0.20 for mother-son pairs, and 0.23 for mother-daughter pairs. The weighted kappa coefficients between BMI quintiles of parent and child ranged from −0.02 to 0.25. Odds ratio analyses found children were 2.1 (95% confidence interval (CI): 1.6, 2.8) times more likely to be obese if only their father was obese, 1.9 (95% CI: 1.5, 2.4) times more likely if only their mother was obese, and 3.2 (95% CI: 2.5, 4.2) times more likely if both parents were obese.

Conclusions

Parent-child resemblance in BMI appears weak and may vary across parent-child dyad types in the US population. However, parental obesity status is associated with children’s obesity status. Use of different measures of parent-child resemblance in body weight status can lead to different conclusions.     

Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes.

A total of 254 affected parent-child pairs with Huntington disease (HD) and 440 parent-child pairs with CAG size in the normal range were assessed to determine the nature and frequency of intergenerational CAG changes in the HD gene. Intergenerational CAG changes are extremely rare (3/440 [0.68%]) on normal chromosomes. In contrast, on HD chromosomes, changes in CAG size occur in approximately 70% of meioses on HD chromosomes, with expansions accounting for 73% of these changes. These intergenerational CAG changes make a significant but minor contribution to changes in age at onset (r2 = .19). The size of the CAG repeat influenced larger intergenerational expansions (> 7 CAG repeats), but the likelihood of smaller expansions or contractions was not influenced by CAG size. Large expansions (> 7 CAG repeats) occur almost exclusively through paternal transmission (0.96%; P < 10(-7)), while offspring of affected mothers are more likely to show no change (P = .01) or contractions in CAG size (P = .002). This study demonstrates that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene. Similar paternal sex effects are seen in the evolution of new mutations for HD from intermediate alleles and for large expansions on affected chromosomes. Affected mothers almost never transmit a significantly expanded CAG repeat, despite the fact that many have similar large-sized alleles, compared with affected fathers. The sex-dependent effects of major expansion and contractions of the CAG repeat in the HD gene implicate different effects of gametogenesis, in males versus females, on intergenerational CAG repeat stability.     

Increasing heritability of BMI and stronger associations with the FTO gene over childhood

The growing evidence of health risks associated with the rise in childhood obesity adds to the urgency of understanding the determinants of BMI. Twin analyses on repeated assessments of BMI in a longitudinal sample of >7,000 children indicated that the genetic influence on BMI becomes progressively stronger, with heritability increasing from 0.48 at age 4 to 0.78 at age 11. In the same large twin sample, the association between a common variant in the FTO gene and BMI increased in parallel with the rise in heritability, going from R(2) < 0.001 at age 4 to R(2) = 0.01 at age 11. These findings suggest that expression of FTO may become stronger throughout childhood. Increases in heritability may also be due to children increasingly selecting environments correlated with their genetic propensities.     

BMD-associated variation at the Osterix locus is correlated with childhood obesity in females

Recent genome wide association studies (GWAS) have revealed a number of genetic variants robustly associated with bone mineral density (BMD) and/or osteoporosis. Evidence from epidemiological and clinical studies has shown an association between BMD and BMI, presumably as a consequence of bone loading. We investigated the 23 previously published BMD GWAS-derived loci in the context of childhood obesity by leveraging our existing genome-wide genotyped European American cohort of 1106 obese children (BMI ≥ 95th percentile) and 5997 controls (BMI < 95th percentile). Evidence of association was only observed at one locus, namely Osterix (SP7), with the G allele of rs2016266 being significantly over-represented among childhood obesity cases (P = 2.85 × 10(-3)). When restricting these analyses to each gender, we observed strong association between rs2016266 and childhood obesity in females (477 cases and 2867 controls; P = 3.56 × 10(-4)), which survived adjustment for all tests applied. However, no evidence of association was observed among males. Interestingly, Osterix is the only GWAS locus uncovered to date that has also been previously implicated in the determination of BMD in childhood. In conclusion, these findings indicate that a well established variant at the Osterix locus associated with increased BMD is also associated with childhood obesity primarily in females.     

What money can buy: Family income and childhood obesity

This paper investigates the relationship between family income and childhood obesity. Using the Early Childhood Longitudinal Study, Kindergarten Class of 1998-99 (ECLS-K), I report three new findings. First, family income and childhood obesity are generally negatively correlated, but for children in very low-income families, they are positively correlated. Second, the negative association between family income and Body Mass Index (BMI) is especially strong and significant among high-BMI children. Third, the difference in obesity rates between children from low- and high-income families increases as children age. This study further investigates potential factors that might contribute to a rapid increase in the obesity rate among low-income children. I find that their faster weight gain, rather than slower height growth, is a greater contributor to the rapid increase in their BMI over time. On the other hand, I also find that the faster weight gain by low-income children cannot be attributed to any single factor, such as participation in school meal programs, parental characteristics, or individual characteristics. These findings add to the current obesity debate by demonstrating that the key to curbing childhood obesity may lie in factors generating different obesity rates across income levels.     

Education modifies genetic and environmental influences on BMI

Obesity is more common among the less educated, suggesting education-related environmental triggers. Such triggers may act differently dependent on genetic and environmental predisposition to obesity. In a Danish Twin Registry survey, 21,522 twins of same-sex pairs provided zygosity, height, weight, and education data. Body mass index (BMI = kg weight/ m height(2)) was used to measure degree of obesity. We used quantitative genetic modeling to examine how genetic and shared and nonshared environmental variance in BMI differed by level of education and to estimate how genetic and shared and nonshared environmental correlations between education and BMI differed by level of education, analyzing women and men separately. Correlations between education and BMI were -.13 in women, -.15 in men. High BMI's were less frequent among well-educated participants, generating less variance. In women, this was due to restriction of all forms of variance, overall by a factor of about 2. In men, genetic variance did not vary with education, but results for shared and nonshared environmental variance were similar to those for women. The contributions of the shared environment to the correlations between education and BMI were substantial among the well-educated, suggesting importance of familial environmental influences common to high education and lower BMI. Family influence was particularly important in linking high education and lower levels of obesity.     

Genetic Variations in the Serotoninergic System Contribute to Body-Mass Index in Chinese Adolescents

Objective

Obesity has become a worldwide health problem in the past decades. Human and animal studies have implicated serotonin in appetite regulation, and behavior genetic studies have shown that body mass index (BMI) has a strong genetic component. However, the roles of genes related to the serotoninergic (5-hydroxytryptamine,5-HT) system in obesity/BMI are not well understood, especially in Chinese subjects.

Subjects and Design

With a sample of 478 healthy Chinese volunteers, this study investigated the relation between BMI and genetic variations of the serotoninergic system as characterized by 136 representative polymorphisms. We used a system-level approach to identify SNPs associated with BMI, then estimated their overall contribution to BMI by multiple regression and verified it by permutation.

Results

We identified 12 SNPs that made statistically significant contributions to BMI. After controlling for gender and age, four of these SNPs accounted for 7.7% additional variance of BMI. Permutation analysis showed that the probability of obtaining these findings by chance was low (p = 0.015, permuted for 1000 times).

Conclusion

These results showed that genetic variations in the serotoninergic system made a moderate contribution to individual differences in BMI among a healthy Chinese sample, suggesting that a similar approach can be used to study obesity.     

Racial Differences in the Tracking of Childhood BMI to Adulthood

Objective: The possibility that there are racial differences in the patterns of BMI (kilograms per meter squared) change throughout life has not been examined. For example, the high prevalence of obesity among black women could result from a higher prevalence of obesity among black girls or because normal‐weight black girls experience larger BMI increases in adolescence or adulthood than do their white counterparts. Therefore, we examined the tracking of childhood BMI into adulthood in a biracial (36% black) sample. Research Methods and Procedures: Five‐ to 14‐year‐old children (2392) were followed for (mean) 17 years. Childhood overweight was defined as BMI ≥ 95th percentile, and adult obesity was defined as BMI ≥ 30 kg/m². Results: The tracking of childhood BMI differed between whites and blacks. Among overweight children, 65% of white girls vs. 84% of black girls became obese adults, and predictive values among boys were 71% (whites) vs. 82% (blacks). These racial differences reflected contrasting patterns in the rate of BMI change. Although the initial BMI of black children was not higher than that of white children, BMI increases with age were larger among black girls and overweight black boys than among their white counterparts. In contrast, relatively thin (BMI < 50th percentile) white boys were more likely to become overweight adults than were their black counterparts. Discussion: These findings emphasize the black/white differences in BMI changes with age. Because of the adult health consequences of childhood‐onset obesity, early prevention should be given additional emphasis.     

A genome-wide study reveals copy number variants exclusive to childhood obesity cases

The prevalence of obesity in children and adults in the United States has increased dramatically over the past decade. Genomic copy number variations (CNVs) have been strongly implicated in subjects with extreme obesity and coexisting developmental delay. To complement these previous studies, we addressed CNVs in common childhood obesity by examining children with a BMI in the upper 5(th) percentile but excluding any subject greater than three standard deviations from the mean in order to reduce severe cases in the cohort. We performed a whole-genome CNV survey of our cohort of 1080 defined European American (EA) childhood obesity cases and 2500 lean controls (< 50(th) percentile BMI) who were genotyped with 550,000 SNP markers. Positive findings were evaluated in an independent African American (AA) cohort of 1479 childhood obesity cases and 1575 lean controls. We identified 17 CNV loci that were unique to at least three EA cases and were both previously unreported in the public domain and validated via quantitative PCR. Eight of these loci (47.1%) also replicated exclusively in AA cases (six deletions and two duplications). Replicated deletion loci consisted of EDIL3, S1PR5, FOXP2, TBCA, ABCB5, and ZPLD1, whereas replicated duplication loci consisted of KIF2B and ARL15. We also observed evidence for a deletion at the EPHA6-UNQ6114 locus when the AA cohort was investigated as a discovery set. Although these variants may be individually rare, our results indicate that CNVs contribute to the genetic susceptibility of common childhood obesity in subjects of both European and African ancestry.     

Asthma and Maternal Body Mass Index Are Related to Pediatric Body Mass Index and Obesity: Results from the Third National Health and Nutrition Examination Survey

Objective: Clinical research has shown an increased prevalence of obesity in children with asthma. This study was designed to assess the relationship between asthma and pediatric body mass index (BMI) in a national database and to examine factors that may modify this relationship. Design: The cross‐sectional relationship between asthma and pediatric BMI and obesity (BMI ≥ 85th percentile) was studied. Variables that may influence the relationship between asthma and pediatric BMI, such as race/ethnicity and television watching were included in the model for the total sample. A smaller sample of 3009 white and African American youth were studied in regression models including maternal BMI. Study Population: A nationally representative crosssectional sample of 5154 children and adolescents of 6 to 16 years of age from the Third National Health And Nutrition Examination Survey. Results: In the full sample, asthma and television watching were related to BMI, accounting for 3% of the variance in BMI. When maternal BMI was included in the nonHispanic sample, television watching, maternal BMI, and the interaction of maternal BMI and asthma were related to youth BMI, accounting for 15% of the variance. The standardized BMI z‐score for those youth without asthma and no maternal obesity was 0.06, which increased to 0.33 if the youth had asthma, to 0.70 if the youth did not have asthma but the mother was obese, and to 1.71 if the youth had asthma and the mother was obese. Asthma, television watching, and maternal BMI were independent predictors of youth obesity. Conclusions: BMI and prevalence of obesity is higher in youth with asthma. Pediatric BMI, but not obesity, is also related to the interaction of asthma and maternal BMI in white and African American youth. Comorbidity of asthma and obesity may complicate treatment of either condition, and prevention of obesity should be encouraged for asthmatic children.     

Association of African Genetic Admixture with Resting Metabolic Rate and Obesity Among Women

Objective: To investigate the role of genetic admixture in explaining phenotypic variation in obesity‐related traits in a sample of African‐American women (n = 145) and to determine significant associations between obesity traits and admixture genetic markers. Research Methods and Procedures: Associations between genetic admixture and BMI, resting metabolic rate, fat mass, fat‐free mass, and bone mineral density were tested using linear regression considering the estimation of admixture by 1) a maximum‐likelihood approach (MLA) and 2) a Bayesian analysis. Results: Both the conservative MLA and the Bayesian approach support an association between African genetic admixture and BMI. Evidence for the associations of African genetic admixture with fat mass and fat‐free mass was supported by the Bayesian analysis; the MLA supported an association with bone mineral density. When the individual ancestry informative markers that were used to estimate admixture were tested for associations with BMI, significant associations were identified in chromosomes 1, 11, and 12. Discussion: These results provide evidence supporting the application of admixture mapping methods to the identification of genes that result in higher levels of obesity among African‐American women. Further research is needed to replicate and further explore these findings.     

The Role of Obesity‐associated Loci Identified in Genome‐wide Association Studies in the Determination of Pediatric BMI

The prevalence of obesity in children and adults in the United States has increased dramatically over the past decade. Besides environmental factors, genetic factors are known to play an important role in the pathogenesis of obesity. A number of genetic determinants of adult BMI have already been established through genome‐wide association (GWA) studies. In this study, we examined 25 single‐nucleotide polymorphisms (SNPs) corresponding to 13 previously reported genomic loci in 6,078 children with measures of BMI. Fifteen of these SNPs yielded at least nominally significant association to BMI, representing nine different loci including INSIG2, FTO, MC4R, TMEM18, GNPDA2, NEGR1, BDNF, KCTD15, and 1q25. Other loci revealed no evidence for association, namely at MTCH2, SH2B1, 12q13, and 3q27. For the 15 associated variants, the genotype score explained 1.12% of the total variation for BMI z‐score. We conclude that among 13 loci that have been reported to associate with adult BMI, at least nine also contribute to the determination of BMI in childhood as demonstrated by their associations in our pediatric cohort.     

Similarities between parents and their adopted children

As shown in 7,230 parent-child pairs (6,726 biological and 504 adoptive), adoptive parents and their adopted children tend to resemble each other in height, weight and fatfolds to an extent paralleling height, weight and fatfold resemblances of natural (biological) parents and their children. Accordingly, the magnitudes of parent-child resemblances commonly given may not be indicative of the extent of heritability of stature, weight and subcutaneous fat.     

Validity of the body mass index and fat mass index as an indicator of obesity in children aged 3-5 year

The validity of the BMI and fat mass index (FMI) as indicators of obesity was evaluated in a group of 3-5 yr old (n=486) children. Bioelectrical impedance analysis (BIA) was measured (using 50 kHz and tetrapolar electrodes) in order to calculate percent fat mass (%FM) and FMI (fat mass/stature squared). For boys, obesity was defined as > or =20%FM. For girls, the cutoff for obesity was > or =25%FM. However, obesity was defined as a BMI at or above the 90th percentile of age- and sex-specific data in this study. The percentile cutoffs for FMI were the same as for BMI using the same sample. There were correlations between BMI or FMI and %FM, but there was no significant correlation between BMI or FMI and stature. Therefore, it appears that both the BMI and FMI in this study are far more useful indices with which to assess obesity, and are reasonable indicators of fatness. However, with the use of %FM by BIA as the criterion for obesity, BMI and FMI had high specificities (95.5-96.4% for BMI and 99.5-100% for FMI) and lower but variable sensitivities (30.4-37.5% for BMI and 42.9-68.8% for FMI). Thus, almost all children who were not obese were classified correctly. In contrast, many obese children were not correctly identified by BMI and FMI. Therefore, we conclude that BMI should be used with caution as an indicator of childhood obesity. The new recommendations based on the FMI approach for defining childhood obesity are associated with a level of sensitivity that is somewhat higher than that of the BMI approach. Caution should, however, be used in generalizing from the findings in this study, and a further investigation of the issue is required.     

Long-term changes in body weight, BMI, and adiposity rebound among children and adolescents in the Czech republic

The Czech Republic has undergone rapid political, social, and economic transformation since the late 1980s. While obesity rates among children and adolescents in the Czech Republic have been previously relatively low, this has changed in recent years. Across the past 50 years, body weight, body mass index (BMI)-for-age, and adiposity rebound (AR) (the time when a child reaches the lowest BMI before their BMI gradually begins to increase until adulthood) occurs earlier. The most dramatic changes have been observed among school-aged children, where BMI values have increased at the 50th, 90th, and 97th percentiles. In contrast, adolescent girls appear to be thinner than in the past. The analyses of weight-for-height percentiles indicated that the 50th percentile of the body weight among boys and girls remained similar in nearly all age categories across the past 50 years. Although the growth pattern of children at the 50th percentile has not changed, the 10th and 90th percentiles have expanded. Our findings suggest that the secular trend of increased height, accelerated growth, and earlier maturation is responsible for Czech children experiencing adiposity rebound at earlier ages compared to the past.     

Early Life Predictors of Increased Body Mass Index among Indigenous Australian Children

Aboriginal and Torres Strait Islander Australians are more likely than non-Indigenous Australians to be obese and experience chronic disease in adulthood—conditions linked to being overweight in childhood. Birthweight and prenatal exposures are associated with increased Body Mass Index (BMI) in other populations, but the relationship is unclear for Indigenous children. The Longitudinal Study of Indigenous Children is an ongoing cohort study of up to 1,759 children across Australia. We used a multilevel model to examine the association between children’s birthweight and BMI z-score in 2011, at age 3-9 years, adjusted for sociodemographic and maternal factors. Complete data were available for 682 of the 1,264 children participating in the 2011 survey; we repeated the analyses in the full sample with BMI recorded (n=1,152) after multilevel multiple imputation. One in ten children were born large for gestational age, and 17% were born small for gestational age. Increasing birthweight predicted increasing BMI; a 1-unit increase in birthweight z-score was associated with a 0.22-unit (95% CI:0.13, 0.31) increase in childhood BMI z-score. Maternal smoking during pregnancy was associated with a significant increase (0.25; 95% CI:0.05, 0.45) in BMI z-score. The multiple imputation analysis indicated that our findings were not distorted by biases in the missing data. High birthweight may be a risk indicator for overweight and obesity among Indigenous children. National targets to reduce the incidence of low birthweight which measure progress by an increase in the population’s average birthweight may be ignoring a significant health risk; both ends of the spectrum must be considered. Interventions to improve maternal health during pregnancy are the first step to decreasing the prevalence of high BMI among the next generation of Indigenous children.