Abstract
Genome-wide studies have identified several common genetic variants that are robustly associated with adult obesity risk. Exploration of these genotype associations in children may provide insights into the timing of weight changes leading to adult obesity. Children from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were genotyped for ten genetic variants previously associated with adult BMI. Eight variants that showed individual associations with childhood BMI (in/near: FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, and ETV5) were used to derive an "obesity-risk-allele score" comprising the total number of risk alleles (range: 2-15 alleles) in each child with complete genotype data (n = 7,146). Repeated measurements of weight, length/height, and body mass index from birth to age 11 years were expressed as standard deviation scores (SDS). Early infancy was defined as birth to age 6 weeks, and early infancy failure to thrive was defined as weight gain between below the 5th centile, adjusted for birth weight. The obesity-risk-allele score showed little association with birth weight (regression coefficient: 0.01 SDS per allele; 95% CI 0.00-0.02), but had an apparently much larger positive effect on early infancy weight gain (0.119 SDS/allele/year; 0.023-0.216) than on subsequent childhood weight gain (0.004 SDS/allele/year; 0.004-0.005). The obesity-risk-allele score was also positively associated with early infancy length gain (0.158 SDS/allele/year; 0.032-0.284) and with reduced risk of early infancy failure to thrive (odds ratio = 0.92 per allele; 0.86-0.98; p = 0.009). The use of robust genetic markers identified greater early infancy gains in weight and length as being on the pathway to adult obesity risk in a contemporary birth cohort.
Highlights
The increasing prevalence of overweight and obesity even in young preschool children [1] highlights the need to understand the very early determinants and potential targets for prevention of obesity
Recent technological advances and the massive increases in scale and statistical rigour of genome-wide association (GWA) studies has allowed the identification of common genetic variants associated with adult body mass index (BMI) and obesity risk that are consistently replicable in other populations
Data from the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort and other childhood obesity studies have shown the relevance of individual variants in FTO [4], MC4R [5], TMEM18, GNPDA2, KCTD15, and NEGR1 [6] for childhood BMI and body fat mass. By further analysing these adult obesity susceptibility loci in the ALSPAC birth cohort, with the addition of variants in BDNF and ETV5 [7], we aimed to identify the specific timing of childhood weight gain and growth associated with adult obesity risk
Summary
The increasing prevalence of overweight and obesity even in young preschool children [1] highlights the need to understand the very early determinants and potential targets for prevention of obesity. Recent technological advances and the massive increases in scale and statistical rigour of genome-wide association (GWA) studies has allowed the identification of common genetic variants associated with adult BMI and obesity risk that are consistently replicable in other populations. The first such common genetic variation shown to be associated with adult body mass index (BMI) was in the FTO gene region, published in 2007 by Frayling et al [4]. Genome-wide studies have identified several common genetic variants that are robustly associated with adult obesity risk Exploration of these genotype associations in children may provide insights into the timing of weight changes leading to adult obesity. BMI can be used to screen children for being overweight and or obese but a diagnosis requires further information
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