Genetic susceptibility to obesity and related traits in childhood and adolescence: influence of loci identified by genome-wide association studies

Abstract

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 (N(total) = 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 × 10(-11)). 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 × 10(-5)), 0.039 SD, in sum of skinfolds (P = 1.7 × 10(-7)), and 0.022 SD in waist circumference (P = 1.7 × 10(-4)), which is comparable with reported results in adults (0.039 SD/allele for BMI and 0.033 SD/allele for waist circumference).

Conclusions: Most 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.

FIG. 1.

Distribution of the GPS-17 and cumulative effects of the effect alleles from the 17 obesity susceptibility variants on inverse normally transformed BMI, sum of skinfolds, and waist circumference.

FIG. 2.

Meta-analysis for summary statistics of the association between variants in the obesity susceptibility loci with BMI in the EYHS, CHP (28), and ALSPAC (20). I² and P values for heterogeneity between cohorts are provided. For associations within cohorts, effect sizes (B) and 95% CIs are shown; for the meta-analysis, P values for effect sizes are additionally provided.

FIG. 3.

Association of variants in the obesity susceptibility loci with BMI after meta-analysis in a maximal sample of 13,071 (NEGR1, TMEM18, GNPDA2, MTCH2, SH2B1, FTO, MC4R, and KCTD15) or 8,120 (SEC16B, ETV5, BDNF, and BCIN3D) children and adolescents compared with 20,431 adults from the EPIC-Norfolk cohort. Effect sizes (B) and 95% CIs are shown; I² and P values for heterogeneity between age-groups are additionally provided.