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

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 = 1.85610 x
10(-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 = 4.84 x 10(-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 similar to 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.