To estimate the combined impact of these variants on BMI, we examined our largest population-based stage 2 sample (the EPIC–Norfolk cohort), analyzing the 14,409 individuals who had no missing genotypes for associated SNPs at any of the eight validated loci (TMEM18, KCTD15, SH2B1, MTCH2, NEGR1 and GNPDA2, plus FTO and MC4R). We calculated a genotype score for each individual, weighting the number of BMI-increasing alleles by their relative effect sizes (so that FTO alleles had the largest weight and MTCH2 alleles the smallest). In this cohort, the 1.2% (n = 178) of the sample with 13 or more ‘standardized’ BMI-increasing alleles across these eight loci is on average 1.46 kg/m2 (equivalent to 3.7–4.7 kg for an adult 160–180 cm in height) heavier than the 1.4% (n = 205) of the sample with ≤3 standardized BMI-increasing alleles, and 0.59 kg/m2 (1.5–1.9 kg for an adult 160–180 cm in height) heavier than the average individual in our study (Fig. 3).
