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 X 10(-7)), 0.07 (+/- 0.01, P = 1.10 x 10(-8)), 0.09 (+/- 0.01, P = 3.13 x 10(-22)), 0.11 (+/- 0.01, P = 1.35 x 10(-25)), 0.11 (+/- 0.01, P = 1.98 x 10(-20)), and 0.06 (+/- 0.01, P = 2.44 x 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 x 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.