Obesity-susceptibility loci and the tails of the pediatric BMI distribution

OBJECTIVE To determine whether previously identified adult obesity susceptibility loci were associated uniformly with childhood BMI across the BMI distribution. DESIGN AND METHODS Children were recruited through the Children's Hospital of Philadelphia (n = 7,225). Associations between the following loci and BMI were assessed using quantile regression: FTO (rs3751812), MC4R (rs12970134), TMEM18 (rs2867125), BDNF (rs6265), TNNI3K (rs1514175), NRXN3 (rs10146997), SEC16B (rs10913469), and GNPDA2 (rs13130484). BMI z-score (age and gender adjusted) was modeled as the dependent variable, and genotype risk score (sum of risk alleles carried at the 8 loci) was modeled as the independent variable. RESULTS Each additional increase in genotype risk score was associated with an increase in BMI z-score at the 5th, 15th, 25th, 50th, 75th, 85th, and 95th BMI z-score percentiles by 0.04 (±0.02, P = 0.08), 0.07 (±0.01, P = 9.58 × 10(-7) ), 0.07 (±0.01, P = 1.10 × 10(-8) ), 0.09 (±0.01, P = 3.13 × 10(-22) ), 0.11 (±0.01, P = 1.35 × 10(-25) ), 0.11 (±0.01, P = 1.98 × 10(-20) ), and 0.06 (±0.01, P = 2.44 × 10(-6) ), respectively. Each additional increase in genotype risk score was associated with an increase in mean BMI z-score by 0.08 (±0.01, P = 4.27 × 10(-20) ). CONCLUSION Obesity risk alleles were more strongly associated with increases in BMI z-score at the upper tail compared to the lower tail of the distribution.