A genome-wide association study of body mass index across early life and childhood

Abstract

Background: Several studies have investigated the effect of known adult body mass index (BMI) associated single nucleotide polymorphisms (SNPs) on BMI in childhood. There has been no genome-wide association study (GWAS) of BMI trajectories over childhood.

Methods: We conducted a GWAS meta-analysis of BMI trajectories from 1 to 17 years of age in 9377 children (77,967 measurements) from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Western Australian Pregnancy Cohort (Raine) Study. Genome-wide significant loci were examined in a further 3918 individuals (48,530 measurements) from Northern Finland. Linear mixed effects models with smoothing splines were used in each cohort for longitudinal modelling of BMI.

Results: A novel SNP, downstream from the FAM120AOS gene on chromosome 9, was detected in the meta-analysis of ALSPAC and Raine. This association was driven by a difference in BMI at 8 years (T allele of rs944990 increased BMI; PSNP = 1.52 × 10(-8)), with a modest association with change in BMI over time (PWald(Change) = 0.006). Three known adult BMI-associated loci (FTO, MC4R and ADCY3) and one childhood obesity locus (OLFM4) reached genome-wide significance (PWald < 1.13 × 10(-8)) with BMI at 8 years and/or change over time.

Conclusions: This GWAS of BMI trajectories over childhood identified a novel locus that warrants further investigation. We also observed genome-wide significance with previously established obesity loci, making the novel observation that these loci affected both the level and the rate of change in BMI. We have demonstrated that the use of repeated measures data can increase power to allow detection of genetic loci with smaller sample sizes.

Keywords: ALSPAC; Body mass index; Raine; childhood; genome-wide association study; trajectory.

Figure 1.

Population average trajectories for females (A) and males (B) from the ALSPAC cohort with 0, 1 or 2 copies of the C allele at the FAM120AOS, rs944990, locus.

Figure 2.

Associations from the ALSPAC cohort between the genome-wide significant SNPs and BMI from age one to 16 years. Error bars represent the regression coefficient of BMI on the natural log scale and 95% confidence intervals derived from the longitudinal additive genetic models. The SNPs are aligned to the minor allele.

Figure 3.

Associations from the ALSPAC cohort between the genome-wide significant SNPs and weight from age one to 16 years. Error bars represent the regression coefficient of weight on the natural log scale and 95% confidence intervals derived from the longitudinal additive genetic models. The SNPs are aligned to the minor allele.

Figure 4.

Associations from the ALSPAC cohort between the genome-wide significant SNPs and height from age one to 16 years. Error bars represent the regression coefficient of height and 95% confidence intervals derived from the longitudinal additive genetic models. The SNPs are aligned to the minor allele.

Figure 5.

Association results of SNP effect at age 8 years for known adult BMI-associated loci. The y-axis displays the effect size from published meta-analyses and the x-axis displays the effect size from the meta-analysis presented in this paper of the BMI intercept at age 8. Effect sizes are aligned to the adult BMI-increasing allele. Colour indicates association P-values from the longitudinal model over childhood: dark grey = P < 5 × 10⁻⁸, medium grey = 5 × 10⁻⁸≤ P < 0.001, light grey = 0.001 ≤ P < 0.01, white = P ≥ 0.01. The dotted grey line indicates the mean effect size for the 33 SNPs in the longitudinal model parameters. The effect sizes from the meta-analysis were transformed from the log scale using an intercept of 2.80 and standard deviation of 0.057, for comparison with the adult effect sizes.