We examined whether selecting only a single variant from each locus for follow-up led us to underestimate the fraction of phenotypic variation explained by the associated loci. To search for additional independent loci at each of the 32 associated BMI loci, we repeated our GWA meta-analysis, conditioning on the 32 confirmed SNPs. Using a significance threshold of 5 × 10−6 for SNPs at known loci, we identified one apparently independent signal at the MC4R locus; rs7227255 was associated with BMI (P = 6.56 × 10−7) even after conditioning for the most strongly associated variant near MC4R (rs571312) (Fig. 5). Interestingly, rs7227255 is in perfect LD (r2 = 1) with a relatively rare MC4R missense variant (rs2229616, V103I, minor allele frequency = 1.7%) that has been associated with BMI in two independent meta-analyses39,40. Furthermore, mutations at the MC4R locus are known to influence early-onset obesity24,41, supporting the notion that allelic heterogeneity may be a frequent phenomenon in the genetic architecture of obesity.
