The two GWAS that first reported on FTO as an obesity susceptibility gene each identified a different SNP in the first intron as the most significantly associated with BMI; i.e. rs99396098, rs99305069 (Figure 1b). Subsequent GWAS studies for obesity-related traits in European ancestry populations all confirmed the FTO locus, but reported a number of other FTO SNPs, located in the same chromosomal region.11-22 For example, the most recent GWAS for BMI, which included data from up to 247,796 individuals of European ancestry, found rs1558902 to be most significantly associated SNP (PGWAS < 10−60) as shown in Figure 1a.16 But also the neighboring SNPs (Figure 1a, in red) show highly significant associations with BMI (PGWAS < 10−50). All these GWAS-identified FTO SNPs are part of the same cluster of highly correlated SNPs (linkage disequilibrium (LD) r2>0.80) and, as a consequence, they are all highly significantly associated with BMI (Figure 1a) and other obesity related traits. In European ancestry populations, this SNP cluster stretches across ~46,000 base pairs in FTO’s first intron that likely harbors the causal variant(s).
