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

den Hoed M, Ekelund U, Brage S, Grontved A, Zhao JH, Sharp SJ, Ong KK, Wareham NJ, Loos RJ - Diabetes (2010)

Bottom Line: The near-TMEM18 variant had the strongest effect (0.098 SD/allele P = 8.5 × 10(-11)).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).Whereas the association of some variants may differ with age, the cumulative effect size is similar.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK.

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.

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Related in: MedlinePlus

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.
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Figure 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.

Mentions: Based on effect allele frequencies (supplementary Table 1) and effect sizes for BMI reported earlier in children/adolescents (Fig. 2), the power to detect single SNP associations with anthropometric traits in EYHS alone ranged from <10% for variants in/near ETV5, BDNF (SNP 2), MTCH2, and SH2B1 to 80% for the SNP in FTO (supplementary Fig. 1). This may explain why few associations reached statistical significance. The meta-analysis in up to 13,071 children and adolescents, however, showed significant associations with BMI for 9 of 13 variants (Fig. 2). There was little heterogeneity in effect size across the three studies except for the near-NEGR1, SEC16B, FTO, and near-MC4R variants (Pheterogeneity = 0.13, 0.045, 0.006, and 0.069, respectively). The most pronounced effect on BMI was observed for the near-TMEM18 variant (0.098 SD/allele [95% CI 0.07–0.13]), followed by variants in or near FTO (0.076 [0.05–0.10]), SEC16B (0.068 [0.03–0.10]), and MC4R (0.067 [0.04–0.09]) (Fig. 2). Variants in/near ETV5, BDNF (SNP 2), MTCH2, and SH2B1 were not significantly associated with BMI in the meta-analysis.


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

den Hoed M, Ekelund U, Brage S, Grontved A, Zhao JH, Sharp SJ, Ong KK, Wareham NJ, Loos RJ - Diabetes (2010)

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.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2963559&req=5

Figure 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.
Mentions: Based on effect allele frequencies (supplementary Table 1) and effect sizes for BMI reported earlier in children/adolescents (Fig. 2), the power to detect single SNP associations with anthropometric traits in EYHS alone ranged from <10% for variants in/near ETV5, BDNF (SNP 2), MTCH2, and SH2B1 to 80% for the SNP in FTO (supplementary Fig. 1). This may explain why few associations reached statistical significance. The meta-analysis in up to 13,071 children and adolescents, however, showed significant associations with BMI for 9 of 13 variants (Fig. 2). There was little heterogeneity in effect size across the three studies except for the near-NEGR1, SEC16B, FTO, and near-MC4R variants (Pheterogeneity = 0.13, 0.045, 0.006, and 0.069, respectively). The most pronounced effect on BMI was observed for the near-TMEM18 variant (0.098 SD/allele [95% CI 0.07–0.13]), followed by variants in or near FTO (0.076 [0.05–0.10]), SEC16B (0.068 [0.03–0.10]), and MC4R (0.067 [0.04–0.09]) (Fig. 2). Variants in/near ETV5, BDNF (SNP 2), MTCH2, and SH2B1 were not significantly associated with BMI in the meta-analysis.

Bottom Line: The near-TMEM18 variant had the strongest effect (0.098 SD/allele P = 8.5 × 10(-11)).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).Whereas the association of some variants may differ with age, the cumulative effect size is similar.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK.

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.

Show MeSH
Related in: MedlinePlus