Genetic Susceptibility to Obesity and Related Traits in Childhood and Adolescence: Influence of Loci Identified by Genome-Wide Association Studies

Marcel den Hoed Ulf Ekelund Sren Brage Anders Grontved Jing Hua Zhao Stephen J. Sharp Ken K. Ong Nicholas J. Wareham Ruth J.F. Loos OBJECTIVE-Large-scale genome-wide association (GWA) studies have thus far identified 16 loci incontrovertibly associated with obesity-related traits in adults. We examined associations of variants in these loci with anthropometric traits in children and adolescents. RESEARCH DESIGN AND METHODS-Seventeen variants representing 16 obesity susceptibility loci were genotyped in 1,252 children (mean SD age 9.7 0.4 years) and 790 adolescents (15.5 0.5 years) from the European Youth Heart Study (EYHS). We tested for association of individual variants and a genetic predisposition score (GPS-17), calculated by summing the number of effect alleles, with anthropometric traits. For 13 variants, summary statistics for associations with BMI were meta-analyzed with previously reported data (Ntotal 13,071 children and adolescents). RESULTS-In EYHS, 15 variants showed associations or trends with anthropometric traits that were directionally consistent with earlier reports in adults. The meta-analysis showed directionally consistent associations with BMI for all 13 variants, of which 9 were significant (0.033- 0.098 SD/allele; P 0.05). The near-TMEM18 variant had the strongest effect (0.098 SD/allele P 8.5 1011 ). Effect sizes for BMI tended to be more pronounced in children and adolescents than reported earlier in adults for variants in or near SEC16B, TMEM18, and KCTD15, (0.028 - 0.035 SD/allele higher) and less pronounced for rs925946 in BDNF (0.028 SD/allele lower). Each additional effect allele in the GPS-17 was associated with an increase of 0.034 SD in BMI (P 3.6 105 ), 0.039 SD, in sum of skinfolds (P 1.7 107 ), and 0.022 SD in waist circumference (P 1.7 104 ), which is comparable with reported results in adults (0.039 SD/allele for BMI and 0.033 SD/allele for waist circumference). - CONCLUSIONSMost obesity susceptibility loci identified by GWA studies in adults are already associated with anthropometric traits in children/adolescents. Whereas the association of some variants may differ with age, the cumulative effect size is similar. Diabetes 59:29802988, 2010 Oobesity has reached epidemic proportions not ver the past three decades, the prevalence of only in adults, but in children and adolescents alike (1,2). A high BMI during childhood and adolescence often persists into adulthood (35) and has been independently associated with cardiovascular risk factors, coronary heart disease events, and all-cause mortality (2,6 9). Family and twin studies have estimated that 40 70% of the variance in obesity-related traits is due to genetic factors (10,11). Longitudinal twin studies have shown that the genetic contribution to BMI increases from childhood to adolescence (1214), and cross-sectional twin studies suggest that the heritability of BMI is higher in adolescence than during adulthood (15,16). Six genome-wide association (GWA) studies in adults of white European descent have thus far identified 16 obesity susceptibility loci; 12 loci were consistently associated with BMI (1722), and 4 loci were identified in GWA studies for waist circumference. Only variants in the FTO and near-MC4R loci have as of yet convincingly been associated with obesity-related traits in children and adolescents (12,18,20,2327). Two studies have examined the effect of variants in GWA-derived loci other than FTO and MC4R in children and adolescents (20,28). However, both studies focused only on BMI and neither study examined the association of all 16 obesity susceptibility loci or their cumulative effect. Examining the association of these obesity susceptibility loci with measures of adiposity in childhood and adolescence may provide insight into their impact on obesity risk early in life. Furthermore, it has been suggested that physical activity modifies the association of genetic variation with general adiposity in adults (29 31). Thus far, this has not been demonstrated in children. In this study, we examined whether obesity susceptibility loci identified by GWA studies in adults are associated with anthropometric traits and risk of obesity in children and adolescents from the European Youth Heart Study (EYHS). To increase statistical power and to compare effect sizes in children/adolescents and adults, we additionally meta-analyzed our findings with those reported by others (20,28). Furthermore, we examined the cumulative effect of variants in the 16 loci on anthropometric traits in EYHS and tested whether the association between genetic predisposition and anthropometric traits is modified by physical activity. Data are means SD. Obese, BMI 95th percentile; overweight but nonobese, BMI 85th percentile and 95th percentile; normal weight, BMI 85th percentile. For moderate and vigorous intensity physical activity, data were available for 408 and 462 children (male and female, respectively) and 166 and 247 adolescents. RESEARCH DESIGN AND METHODS Study population and anthropometry. The EYHS is a school-based, mixed longitudinal study of pre- and early pubertal children and adolescents aged 9.7 0.4 and 15.5 0.5 years, respectively (32). Participants were randomly selected via application of a two-stage sampling strategy in four countries (Denmark, Estonia, Norway, and Portugal). The present study includes 1,252 children and 790 adolescents from Denmark and Estonia (944 boys and 1,098 girls) for whom data on anthropometric traits were available at baseline (Table 1). DNA was not available for the other two EYHS centers. Body mass and height were measured using standard procedures, with participants dressed in light clothing and barefoot (33). The BMI was standardized according to BMI reference charts derived by Coles LMS method (34). Thickness of skinfolds was measured at four locations (triceps brachi, biceps brachi, sub-scapula and supra-iliaca in millimeters) (35) and was combined to obtain the sum of skinfolds. Waist circumference was measured using a metal anthropometric tape midway between the lower rib margin and the iliac crest at the end of a gentle expiration. Sexual maturity was assessed using the five-stage Tanner scale for breast development in girls and pubic hair in boys (Table 1) (36). Overall physical activity and the fraction of time spent on moderate and vigorous intensity physical activity (2,000 cpm [ref. 37]) were measured in daily life during 2 weekdays and 2 weekend days with a validated MTI Actigraph accelerometer (Manufacturing Technology, Fort Walton Beach, FL) (38). For the present study, physical activity data were available for 870 children and 413 adolescents (Table 1). The study was approved by the local scientific committees and was performed in accordance with the Declaration of Helsinki. All parents gave written informed consent for their child to participate, and all children and adolescents gave verbal consent. Genotyping. Seventeen (...truncated)