GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Fig. 1. Regional association and forest plot of the novel genome-wide significant locus associated with BMI-AP. Purple diamond indicates the most significantly associated SNP in stage 1 meta-analysis, and circles represent the other SNPs in the region, with coloring from blue to red corresponding to r2 values from 0 to 1 with the index SNP. The SNP position refers to the National Center for Biotechnology Information (NCBI) build 36. Estimated recombination rates are from HapMap build 36. Forest plots from the meta-analysis for each of the identified loci are plotted abreast. Effect size [95% confidence interval (CI)] in each individual study, discovery, follow-up, and combined meta-analysis stages is presented from fixed-effects models (heterogeneity of the SNP rs9436303 in LEPR/LEPROT; see fig. S6). At this locus, there was heterogeneity between the studies in discovery (I2 = 72.1%, P = 0.01) and combined stage (I2 = 59.3%, P = 0.002) fixed-effects meta-analyses that was mainly due to LISA-D, EDEN, and the larger well-defined NFBC1966 study (fig. S6, A and D). Removing the studies that showed inflated results from meta-analyses did not change the point estimates (fig. S6, C, F, and G).…

Fig. 2. Tissue-specific posterior probabilities (PPs) of colocalization for LEPR and LEPROT. PP of eQTL and GWAS SNP sharing a causal variant regulating the gene expression levels of (A) LEPR and (B) LEPROT. Colocalization reported for GTEX eQTLs data in 34 tissues that express at least one of the genes. Bar plot color-coded according to the –log10 P value eQTL direct lookup in the corresponding GTEx tissue of the GWAS SNP. LEPR and LEPROT eQTLs colocalized with BMI-AP variant rs9436303.

Fig. 3. Genetic correlations between five early growth traits and a subset of 37 phenotypes. Only a selected list of 37 phenotypes is represented on the correlation matrix. Genetic correlation results for all 72 phenotypes are given in table S16. Blue, positive genetic correlation; red, negative genetic correlation. The correlation matrix underneath represents the genetic correlation among the five early growth traits themselves. The size of the colored squares is proportional to the P value, where larger squares represent a smaller P value. Genetic correlations that are different from 0 at P < 0.05 are marked with an asterisk. The genetic correlations that are different from 0 at an FDR of 1% are marked with a circle. Genetic correlations estimated with stage 1 meta-analysis GWAS summary statistics from the current and literature studies using LD score regression.

Fig. 4. Adult BMI GRS analysis of early growth traits. Scatter plots show the effect size estimates (SD units) of the 97 adult BMI-associated SNP in GIANT consortium in the x axis and the corresponding effect size estimates (SD units) of the looked-up SNP of stage 1 meta-analysis GWAS on (A) BMI-AR and (B) Age-AR in the y axis. The effect size of the adult BMI increasing allele is plotted. The solid red line is the estimated effect of the GRS on the early growth phenotype, taking into account the uncertainty of the point estimates. The dashed line is the 95% CI of the predicted effect. Stage 1 meta-analysis GWAS SNPs with P < 0.05 are plotted with a solid circle and labeled with the nearest gene name. The scatter plots of the other early growth phenotypes are given in fig. S10.

Fig. 5. Proposed model of child BMI suggesting the superimposition of two biological phenomena under the genetic control of different loci. The schematic diagram shows the four genome-wide significant loci associated with early childhood growth traits and highlights the fact that only SNPs associated with phenotypes ascertained at AR are associated with adult BMI. The red curve represents the mean BMI trajectory from birth to puberty in the NFBC1966 cohort.