Abstract P223: Larger Effect Sizes of Established BMI Genetic Variants During Adolescence, a Vulnerable Period of Weight Gain

Abstract

In the past five years genome-wide association studies (GWAS) have identified common genetic loci associated with body mass index (BMI) mainly in European middle-aged adult populations. The influence of these loci in adolescence, a period of risk for weight gain, and whether there are different associations across adolescent groups at highest risk (e.g., ethnic minority populations), remains largely unknown. We examined whether obesity susceptibility loci identified from previous GWAS in adults were associated with BMI in an ethnically diverse adolescent cohort. Using 8918 participants from the National Longitudinal Study of Adolescent Health, or Add Health (aged 12-21 years in 1996, 52.6 % female), we assessed the association of 43 SNPs, selected based on statistical significance in previous GWAS, with BMI across four ethnic US subpopulations (5,296 European Americans, EA, 1,815 African Americans, AfA, 1,356 Hispanic Americans, HA, and 451 Asian Americans, AsA). Buccal cells from participants were extracted and genotyped using TaqMan (sample call rate: 97.5%, SNP call rate: 100%). Inverse normal transformed BMI residuals, adjusted for gender and age, were used in ethnicity-stratified models with SNPs in PLINK, assuming an additive model. An inverse-variance-weighted meta-analysis was used to combine results across the 4 ethnic groups. Average BMI across all ethnic groups was 23.6±5.2 kg/m2, ranging from 22.6±5.2 kg/m2 in AsA to 24.3±5.8 kg/m2 in AfA. The effect estimates for all 43 SNPs were directionally consistent across ethnicity with previously published results. Of the 43 SNPs, 20 were associated with BMI at p<0.05 in the meta-analysis (17 in EA, 7 in AfA, 4 in HA, and 5 in AsA). Based on t-test comparisons, 16 of the 20 SNPs had larger and 2 loci had smaller effect sizes (p<0.05) in the Add Health adolescent sample than published effect sizes for BMI in adults. Only FTO (rs9939609) showed significant heterogeneity across ethnicity (p=0.01 for I2=73.5). TMEM18 (rs6548238, meta-analysis p-value p=1.32E-10), had one of the largest differences in effect size compared to middle-aged European adults (Willer et al 2009) with a per allele increase of 0.70±0.11 kg/m2 in this sample versus 0.26±0.07 kg/m2 in adults (beta[SE] difference = 0.44[0.08]; p=1.4E-08). Variants associated with BMI in adults were also associated with BMI in adolescents, with some comparatively larger effects during this vulnerable period. R01HD057194