Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

Abstract

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.

Figure 1.

Manhattan plot of results of the discovery meta-analysis of 20 studies. Chromosomes are shown on the x-axis, the –log₁₀ of the P-value on the y-axis. The gray dotted line represents the genome-wide significance cutoff of 5 × 10⁻⁸. Genes shown in black are the known loci that were significantly associated with childhood BMI in the joint discovery and replication analysis. Genes shown in gray were significant in the discovery, but not in the joint discovery and replication analysis. *indicates novel loci that were significantly associated with childhood BMI in the joint discovery and replication analysis. See also Table 1.

Figure 2.

Regional plots of the three novel loci for childhood BMI. On the x-axis, the position of SNPs on the chromosome is shown. On the left y-axis is the –log₁₀ of the P-values from the discovery analysis, on the right y-axis is the estimated recombination rate (from HapMap), shown by the light blue line in the figure. The named SNP is the most significant SNP in the locus from the discovery meta-analysis. The linkage disequilibrium of all SNPs with the most significant SNP is shown by the symbols, with dark gray diamonds indicating an R² of ≥0.8, inversed dark gray triangles indicating an R² of 0.6–0.8, dark gray triangles indicating an R² of 0.4–0.6, dark gray circles indicating an R² of 0.2–0.4 and light gray circles indicating an R² of 0–0.2. Genes (from HapMap release 22) are plotted below the x-axis.

Figure 3.

Association of the weighted risk score with BMI. Along the x-axis, categories of the weighted risk score are presented, the mean standard deviation score (SDS)-BMI per group is shown on the right y-axis, with the line representing the regression of the mean SDS–BMI values on the categories of the weighted risk score. The left y-axis represents the number of children in each risk score category, shown in the histogram. The P-value is derived from the analysis of the continuous risk score. Analysis was performed in the PIAMA Study (n = 1955).