New insights from GWAS on BMI-related growth traits in a longitudinal cohort of admixed children with Native American and European ancestry

Abstract

Body-mass index (BMI) is a hallmark of adiposity. In contrast with adulthood, the genetic architecture of BMI during childhood is poorly understood. The few genome-wide association studies (GWAS) on children have been performed almost exclusively in Europeans and at single ages. We performed cross-sectional and longitudinal GWAS for BMI-related traits on 904 admixed children with mostly Mapuche Native American and European ancestries. We found regulatory variants of the immune gene HLA-DQB3 strongly associated with BMI at $1.5-2.5$ years old. A variant in the sex-determining gene DMRT1 was associated with the age at adiposity rebound (Age-AR) in girls (P $=9.8\times {10}^{-9}$ ). BMI was significantly higher in Mapuche than in Europeans between 5.5 and 16.5 years old. Finally, Age-AR was significantly lower (P $=0.004$ ) by 1.94 years and BMI at AR was significantly higher (P $=0.04$ ) by 1.2 kg/ $m^2$ , in Mapuche children compared with Europeans.

Keywords: Genomics; Health sciences; Human genetics.

Graphical abstract

Figure 1

Estimation of Age-AR and BMI-AR Fitted BMI (kg/${\mathrm{m}}^2$) curves over time (years) in the whole cohort as well as in boys and girls considered separately. Vertical and horizontal dotted lines pinpoint the observed mean Age-AR and mean BMI-AR in boys and girls.

Figure 2

Effect of global Mapuche and European ancestry on BMI trajectory, Age-AR and BMI-AR (A) BMI (kg/${\mathrm{m}}^2$) estimated at each age stratum for hypothetical individuals with 100% Mapuche (red dots) and 100% European global ancestry (blue dots). SE bars are included. ∗P$<0.05$; ∗∗P$<0.01$. (B) Linear model of Age-AR with Mapuche ancestry and maternal educational level (MEL) as covariates. MEL Group 1 was chosen arbitrarily to illustrate this effect because all MEL categories behave similarly (Figure S3). (C) Linear model of BMI-AR with Mapuche ancestry and MEL as covariates.

Figure 3

Cross-sectional genome-wide associations for BMI (A) GWAS at age stratum $1.5-2.5$. Manhattan plot showing genome-wide per-SNP association p-values represented as-log10 p-value, along the 22 autosomes. Variants with-log10(p-value) between 0 and 2 are not shown. (B) Association peak of chromosome 6 across age strata. The region shown has physical coordinates $6:32676320-32683820$ and was centered at the variant with the strongest association.