Two new Loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and german study groups

Abstract

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85x10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84x10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at approximately 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.

Figure 1. Study design to discover consistently associated genetic loci for (early-onset) obesity.

In the DISCOVERY step we jointly analysed two GWAS focussing on extremely obese children and adolescents. Markers with the smallest p-values of the GWAS were validated in independent case-control and nuclear family samples again with a focus on overweight/obese children and adolescents. Afterwards, in the GENERALIZATION step, we extended the focus in two dimensions—(i) from the extremes to the population level and (ii) from children and adolescents to adults. Note that we used controls selected from the population-based samples for the cases-control comparison with obese individuals for the GENERALIZATION (BMI quartile < median for children & BMI <25 kg/m² for adults).

Figure 2. Results of the meta-analysis of two genome-wide association studies for early-onset extreme obesity.

SNPs are plotted on the x-axis according to their position on each chromosome (HapMap, release 22) against the association signal on the y-axis (shown as -log₁₀ of the two-sided (deflated/adjusted) p-value). SNPs genotyped in the independent samples of the DISCOVERY step are shown as blue circles (some of them are proxy SNPs of the best signals). SNPs followed-up in the GENERALIZATION step as well are shown as orange squares. For details on the marker selection see Text S1.